Conditions: Ulcerative Colitis (UC)
Keywords: TD-1473 Janus kinase inhibitor JAK inhibitor Inflammatory Bowel Disease IBD Ulcerative colitis UC Gut selective
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 239
Healthy volunteers: no

Brief summary:
A Phase 2b/3 set of studies to evaluate the efficacy and safety of induction and maintenance therapy with TD-1473 in subjects with moderately-to-severely active ulcerative colitis with up to 60 weeks of treatment.

Detailed description:
This protocol consists of 3 separate studies: an 8-week Phase 2b dose-finding induction study, an 8-week dose-confirming Phase 3 induction study, and a 44-week Phase 3 maintenance study. Subjects who respond to induction will enter the maintenance study; those who do not will receive TD-1473 during extended induction. The safety and efficacy data of the Phase 2b study will be analyzed to select the induction and maintenance dose regimens for the confirmatory Phase 3 studies. Participants who have disease relapse or complete the maintenance study may be eligible to enter a separate long-term safety study. Efficacy, pharmacokinetic, biomarkers, and safety will be evaluated in all 3 studies.

240 subjects are planned for the Phase 2b and the planned Primary Completion Date for this portion of the study is JULY 2021. 640 subjects are planned for the Phase 3 portion of the study.

Arms:
arm 1: Participants will be randomized to receive an oral daily dose of TD-1473. Responders will be re-randomized into the Phase 3 Maintenance portion of the study. Non-responders may participate in an extended induction. arm 2: Participants will be randomized to receive an oral daily dose of TD-1473. Responders will be re-randomized into the Phase 3 Maintenance portion of the study. Non-responders may participate in an extended induction. arm 3: Participants will be randomized to receive an oral daily dose of TD-1473. Responders will be re-randomized into the Phase 3 Maintenance portion of the study. Non-responders may participate in an extended induction. arm 4: Participants will be randomized to receive an oral daily dose of placebo. Participants who received Placebo (and were non-responders) may move to an extended induction. Subjects who are on placebo will be assigned to active TD-1473 for the extended induction (they will be blinded to dose).

Interventions: intervention 1: TD-1473 Dose A intervention 2: TD-1473 Dose B intervention 3: TD-1473 Dose C intervention 4: Placebo
Intervention descriptions: intervention 1: See Arm description intervention 2: See Arm description intervention 3: See Arm description intervention 4: See Arm description

Protocol document:
Prot_000.pdf: 
Protocol Number: 0157 
Official Title: A Phase 2B/3 Multi-Center, Randomized, Double-Blind, Multi-Dose, Placebo-
Controlled, Parallel-Group Set of Studies to Evaluate the Efficacy and Safety of Induction and 
Maintenance Therapy with TD˗1473 in Subjects with Moderately-to-Severely Active Ulcerative 
Colitis 
NCT Number: NCT03758443 
Document Date:  14 May 2020 






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The key secondary objective(s) of the Study are to assess the rates of the following associated 
with TD-1473 compared to placebo treatment: 
• Endoscopic healing, symptomatic remission, clinical response, mucosal healing 
(endoscopic and histologic), and deep symptomatic remission at Week 8 
Maintenance Study  
Subjects who achieve clinical response to induction therapy with a total of 8 weeks of any 
dose of TD--1473 will be re-randomized into the Maintenance Study and contribute to the 
primary analysis of the study. 
The primary objective(s) of the Study are as follows: 
• Establish the clinical remission rate associated with TD-1473 compared to placebo 
treatment at Maintenance Week 44 
• Establish the safety and tolerability of TD-1473 with up to 44 additional weeks of 
treatment 
The key secondary objectives of the Study are to assess the rates of the following associated 
with TD-1473 compared to placebo treatment: 
• Clinical response, endoscopic healing, symptomatic remission, mucosal 
(endoscopic & histologic) healing, and deep symptomatic remission at 
Maintenance Week 44 
• Corticosteroid-free remission at Maintenance Week 44 
• Maintenance of clinical remission at Maintenance Week 44 in those who were in 
remission at Maintenance Week 0 
Study Design:   
Summary: This protocol includes three studies: a Phase 2b dose-finding Induction Study 
(8-16 weeks), a Phase 3 dose-confirming Induction Study (8-16 weeks), and a Phase 3 
randomized-withdrawal Maintenance Study (up to 44 weeks) [Figure 1] characterizing the 
general treatment paradigm in UC. Each of the studies will utilize multi-center, randomized, 
double blind, placebo-controlled, and parallel-group designs to evaluate 1 or more dose(s) of 
TD-1473 compared to placebo in subjects with moderately-to-severely active UC. 
The duration of treatment in the Phase 2b and Phase 3 Induction Studies will be 8 weeks for 
those who achieve clinical response, as defined by an adapted Mayo score (total Mayo score 
without inclusion of the Physician Global Assessment [PGA] component, using a centrally 
read Mayo endoscopic subscore), at Week 8. For subjects who do not achieve clinical 
response at Week 8, dosing will continue for an extended induction period of 8 weeks 
(16 weeks in total; TD-1473 subjects will receive the same dose for a total of 16 weeks and 
placebo subjects will receive a dose of 80 mg for the extended duration period). Subjects who 
achieve clinical response at either at Week 8 or Week 16 of the Induction Study will enter the 
Maintenance Study. Subjects who do not achieve clinical response by Week 16 will complete 
the study at Week 16 plus the End of Study visit.  


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During the Maintenance Study, subjects will be treated with either placebo or one of several 
TD-1473 doses for 44 weeks. Subjects who A) demonstrate persistent loss of response 
(no improvement at approximately 8 weeks after meeting loss of response criteria) or B) 
experience repeated (two) Clinical Flares during the Maintenance Study after loss of response 
or C) complete the Maintenance Study will exit the Maintenance Study and may be eligible 
for the long-term safety (LTS) Study (separate protocol, Protocol 0164). 
Subjects will be required to maintain an electronic symptom diary to be completed on a daily 
basis. See below for details of the Induction and Maintenance Studies. 
Figure 1: 
Protocol Schema 
 
Phase 2b Dose-Finding Induction and Phase 3 Dose-Confirming Induction Studies 
To determine initial eligibility, subjects will undergo assessments during the Screening 
Stage 1 period. Refer to Schedule of Study Procedures (Table 1) for a schedule of the 
screening requirements. Disease activity will be assessed by partial, adapted, and total Mayo 
scores. Subjects who meet inclusion criteria and no exclusion criteria, as described in 
Section 4, will undergo an endoscopic exam (i.e., sigmoidoscopy or colonoscopy) with 
biopsies to complete screening Stage 2. 
If the subject meets eligibility criteria, including a Mayo endoscopic subscore ≥ 2 points from 
the Screening Stage 2 visit and an adapted Mayo score between 4 and 9 points, inclusive, on 
Day 1, the subject may be randomized. Randomization will be stratified by prior biologics 
failure status (yes or no) and corticosteroid use at enrollment (yes or no) into the Induction 
Study. 
The Induction Studies consist of treatment for 8 weeks for those who demonstrate clinical 
response at Week 8 or 16 weeks for those who did not have a response. Subjects will return 
for safety, PK, biomarker, and disease assessments, as well as an endoscopy with biopsies 
according to the Schedule of Study Procedures provided in Table 1. 
The Phase 2b Induction Study will enroll approximately 240 subjects, randomized 1:1:1:1 to 
placebo or 1 of the 3 TD-1473 doses (20 mg, 80 mg, or 200 mg). After all 240 subjects have 


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either completed Week 8 or been withdrawn from the Study prior to Week 8, an analysis of all 
efficacy and safety data up to Week 8 will be conducted (Refer to Section 8). Results from the 
Phase 2b dose-finding Induction Study analysis will be used to inform the dose selection for 
the Phase 3 dose-confirming Induction Study as well as the remainder of the Maintenance 
Study. 
Following the 240th subject enrolled, recruitment will be placed on hold until the Phase 2b 
Induction study analysis is complete. A component of the analysis and interpretation is dose 
selection for further development. The Phase 3 Induction Study will commence after dose 
selection.  
Extended Induction 
Subjects who do not demonstrate clinical response at Week 8 will receive an additional 
8 weeks of treatment with TD-1473 staying on the same dose as the first 8 weeks, except those 
who had received placebo during the first 8 weeks will now receive TD-1473 at 80 mg 
(Figure 3). All subjects who undergo extended induction treatment will receive active drug, 
and thus, this portion of the Induction Study will not be placebo-controlled but blinding as to 
the specific dose of TD-1473 will be maintained. During this time, at the discretion of the 
investigator, subjects are permitted but are not required to begin corticosteroid taper. Those 
who demonstrate clinical response at the end of Week 16 will enter the Maintenance Study; 
those who do not demonstrate clinical response at the end of Week 16 will have an EOS visit 
and exit the study. 
Maintenance Study 
Subjects who are eligible (i.e., achieving clinical response by adapted Mayo score) for the 
Maintenance Study at Week 8 of the Induction Study will continue directly from the Induction 
Studies to the Maintenance study. Previously TD-1473 dosed subjects will be re-randomized 
to receive placebo or one of the TD-1473 doses. Subjects who achieved clinical response on 
placebo at Week 8 during Induction will continue on placebo in a blinded manner and will not 
be included in the primary efficacy analysis population of the Maintenance Study.  
Subjects who are eligible (i.e., achieving clinical response by adapted Mayo score) for the 
Maintenance Study at Week 16 of one of the Induction Studies will continue from the 
Induction Studies to the Maintenance Study. Subjects who received 16 weeks of TD-1473 
treatment will continue on the same study drug treatment in a blinded manner and will not be 
included in the primary efficacy analysis. Subjects who received 8 weeks of placebo and 
8 weeks of TD-1473 80 mg will be re-randomized to placebo or one of the TD-1473 doses and 
contribute to the primary efficacy analysis population of the Maintenance Study. 
The Maintenance Study consists of treatment for 44 weeks. During the Maintenance Study, 
subjects must start (or continue if they started during extended induction) tapering their 
corticosteroid dose using the regimen outlined in Section 6.5.3 if they entered the study on 
corticosteroids. 
Prior to the Phase 2b Induction Study Week 8 data analysis and subsequent dose selection, 
qualifying subjects from the Phase 2 Induction Study will be randomized 1:1:1:1 to placebo or 
1 of the 3 TD-1473 doses (20 mg, 80 mg or 200 mg) into the Maintenance study. 


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After the Phase 2b Induction primary Week 8 data analysis and subsequent dose selection 
have been completed, subjects enrolling into the remaining of the Maintenance Study will be 
randomized to either placebo or one of up to two selected TD-1473 doses in a 1:1:1 ratio. 
Those who are still completing the Maintenance Study on a de-selected dose will remain on 
that dose unless there is a safety signal detected up to point of dose selection. The 
randomization will be stratified by clinical remission status (yes or no) (using adapted Mayo 
score component definition) at Maintenance Week 0 (mWeek 0) and corticosteroid use at 
enrollment (yes or no) into the Maintenance Study. Separate randomization schedules will be 
prepared for subjects who reach clinical response after receiving 8 weeks of TD-1473 and 
subjects who reach clinical response after receiving placebo during the first 8 weeks and then 
TD-1473 80 mg during extended induction. 
During the Maintenance Study, subjects will return for safety, PK, biomarker, and disease 
assessments, as well as a final endoscopy with biopsies according to the Schedule of Study 
Procedures provided in Table 2. Subjects who experience a clinical flare (Refer to 
DEFINITION OF TERMS) of their symptoms during the Maintenance Study will undergo 
assessment for loss of response as per Table 3. Loss of response may lead to initiation of 
rescue medication (e.g., initiation or increase in corticosteroid dose [Refer to Section 6.5.4]), 
which may lead to meeting the definition of treatment failure during the Maintenance Study. 
Subjects who complete the Maintenance Study or experience persistent loss of response or 
Clinical Flare twice after loss of response may enter the LTS Study (separate protocol) if they 
meet the applicable eligibility criteria. Subjects who do not enter into the LTS study will need 
to complete an End of Study visit 4 weeks after the last dose of study drug. 
Refer to Section 2 Study Design in the main body of the protocol for further information.  
Duration of Study Participation:  Maximum of 68 weeks (4 weeks screening, 52/60 weeks 
treatment [includes 8 weeks of Extended Induction], and 4 weeks follow-up) 
Number of Subjects:  Approximately 880 subjects including 240 subjects enrolled in the 
Phase 2b dose-finding Induction Study. The total sample size could vary depending on the 
outcome of the Phase 2b Induction data analysis. 
Study Population: 
Subjects with moderately-to-severely active UC as defined by a baseline adapted Mayo score 
between 4 and 9 points, inclusive, and a Mayo endoscopic subscore ≥ 2 points (where 
endoscopic subscore of 1 requires absence of friability), who are corticosteroid-dependent or 
demonstrate an inadequate response or a loss of response or a failure to tolerate conventional 
therapy (aminosalicylates, corticosteroids and immunomodulators [i.e., azathioprine or 
6-mercaptopurine]) or biologic therapy [e.g., anti-TNF therapy or anti-integrin]. 
Inclusion Criteria for Induction Studies: 
To be eligible subjects must meet all the following criteria: 
1. Are male or female 18 years of age or older at Screening 


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2. Has ≥ 3 months history of UC prior to screening (with involvement beyond the rectum 
to at least 15 cm from the anal verge) 
a. Diagnosed by sigmoidoscopy or colonoscopy AND 
b. If possible, corroborated by histology report or documentation of histological 
results in a physician note. However, if there was no biopsy done previously or 
if no prior endoscopy or histology report is available for review, the subject 
must have a colonoscopy instead of a sigmoidoscopy at screening. 
3. Must be willing to have a sigmoidoscopy or colonoscopy at screening. Colonoscopy 
will be performed instead of a sigmoidoscopy at screening in the following scenarios, 
(outlined in Section 6.4.1.20): 
a. If UC diagnosis precedes screening by ≥ 8 years for pan-colitis or ≥12 years for 
left-sided colitis and the subject does not have documentation of a surveillance 
colonoscopy within 12 months prior to screening to rule out dysplasia (report 
must be reviewed by the investigator and included in the source documents). 
During colonoscopy, if chromoendoscopy or surveillance biopsies are indicated 
as per locally adopted guidelines, these should be performed. 
b. If UC diagnosis precedes screening by < 12 years and the subject does not have 
documentation of a colonoscopy within 2 years prior to screening (report must 
be reviewed by investigator and included in the source documents). 
c. If there is no documented histology report from prior endoscopy showing 
chronic colitis or other signs of UC. In this case, consideration should be made 
to do biopsies during the screening endoscopy with histology sent locally to 
confirm diagnosis of UC, if there is doubt of diagnosis  
If chromoendoscopy has to be performed or ≥ 10 biopsies are to be collected for 
dysplasia surveillance, either should be done after completion of a full colonoscopy to 
avoid chromoendoscopy dye or biopsy-related bleeding artifact from interfering with 
endoscopic images for central reading. 
4. Has moderately-to-severely active UC, defined as having: 
a. a centrally read Mayo endoscopic subscore of ≥ 2 points based on the results of 
the Screening Stage 2 endoscopy  
AND  
b. an adapted Mayo score between 4 and 9 points, inclusive, on Day 1. 
5. Is corticosteroid-dependent or had intolerance or inadequate response to any of the 
following: aminosalicylates, corticosteroids, immunomodulators (azathioprine or 
6-mercaptopurine), or biologics (anti-TNF, anti-integrin, or anti-IL-12/23) [Refer to 
Appendix 7] 
NOTE: For subjects in Portugal, subject must have had intolerance or inadequate 
response to biologics 
6. If currently receiving an oral corticosteroid, subject is eligible if: 
a. the subject has been on corticosteroids for a minimum of 4 weeks prior to 
Day 1  
AND 


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b. the dose is equivalent to or less than:  
o prednisone 25 mg/day OR  
o beclomethasone diproprionate (i.e., Clipper) at 5 mg/day OR 
o budesonide 9 mg/day  
AND 
c. the dose is stable for at least 2 weeks prior to Screening Stage 2 visit  
7. If subject is currently receiving oral aminosalicylate (e.g., mesalamine products, 
balsalazide, or sulfasalazine): subject is eligible provided the subject has been on it at a 
stable dose for ≥ 4 weeks prior to Day 1. 
8. During the Study and for 7 days after receiving the last dose of the Study drug, females 
of childbearing potential or men 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). 
9. All male subjects must agree to refrain from semen donation during the Study and for 
7 days after the last dose of Study drug. 
10. Must be able and willing to adhere to the Study visit schedule and comply with other 
protocol requirements. 
11. Are capable of providing informed consent, which must be obtained prior to any 
Study-related procedures. 
Inclusion Criteria for Extended Induction (additional 8 weeks): 
12. Did not meet criteria for clinical response by adapted Mayo score using centrally read 
endoscopic subscore at Week 8a 
Inclusion Criteria for Maintenance Study: 
13. Must have met the criteria for a clinical response by adapted Mayo score using 
centrally read endoscopic subscore during Induction at Week 8a or during Extended 
Induction Study at Week 16 
Exclusion Criteria for Induction Study: 
Subjects meeting any of the following criteria may not be enrolled in the Study: 
Gastrointestinal: 
1. Has symptoms or signs suggestive of fulminant colitis, toxic megacolon, intestinal 
perforation 
2. Has primary sclerosing cholangitis (PSC) 
3. Is likely to require surgery for UC or any other type of major surgery (i.e., surgical 
procedure requiring general anesthesia) during the Study 


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4. Has had a clinically significant, as deemed by the investigator, prior intestinal resection 
for UC or for other gastrointestinal diseases (e.g., that may have resulted in chronic 
diarrhea) 
5. Has carried or carries a diagnosis of Crohn’s disease, microscopic colitis, ischemic 
colitis, radiation colitis, diverticular disease associated with colitis, or indeterminate 
colitis, or the subject has a current or past diagnosis of a fistula or abdominal abscess. 
6. Has unresected colonic mucosal dysplasia or history of resected high-grade colonic 
dysplasia within 3 years prior to screening (Subjects with raised adenomas that have 
been completely resected or with pathology results of indefinite dysplasia with reactive 
atypia will not be excluded). 
Concomitant or previous medications received: 
7. Taken or taking any prohibited medications as listed in Appendix 6, including: 
a. Immunomodulators (azathioprine, 6-mercaptopurine [6-MP], methotrexate) within 
the 14 days prior to Day 1 
b. 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 
c. intravenous corticosteroids within the 14 days prior to Day 1 
d. rectal mesalamine or corticosteroid (i.e., enemas or suppositories) taken within the 
14 days prior to Day 1 
e. vedolizumab, ustekinumab, mycophenolic acid, tacrolimus, sirolimus, or 
cyclosporine taken within 60 days or 5 half-lives, whichever is longer, prior to 
Day 1 
f. Any prior exposure to an approved JAK inhibitor (e.g. tofacitinib) or potential 
exposure to an experimental 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)  
g. Any prior exposure to natalizumab, rituximab, efalizumab, fingolimod, daclizumab 
cyclophosphamide, or thalidomide 
h. 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). 
i. Anakinra, abatacept, or any other immune-modifying biologic agent taken within 
90 days prior to Day 1 
j. A JAK inhibitor (e.g. tofacitinib) within 60 days prior to Day 1 
k. Any prior exposure to TD-1473 
Note:  For biologics specified in items b and e above, there is no requirement for a 
washout period if there is a documented finding of undetectable drug level by a 
validated assay (e.g., through commercially available testing). 
8. If subject has recently discontinued aminosalicylates or corticosteroids, these must 
have been stopped at minimum of 2 weeks before screening endoscopic procedure. 


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9. Has had inadequate response (i.e., either primary or secondary non-response) to 
≥ 3 biologics of ≥ 3 different mechanisms of action (i.e., anti-TNF, anti-integrin, and 
anti-IL12/23, refer to Appendix 8).  
Note:  Up to approximately 10% of the study population can have had inadequate 
response to all 3 biologics mechanisms approved for UC, regardless of total 
number of biologics. 
10. 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 CYP450 3A4 or is a substrate of P-gp or BCRP and has a narrow 
therapeutic index (refer to Appendix 6 for Prohibited medications). 
11. Taking non-UC concomitant prescription medications that the investigator deems may 
confound the safety assessment of the study drug and that have started or have had a 
dose adjustment within 28 days prior to Day 1 (with the exception of corticosteroids, 
antibiotics for infections, sedating agents for sigmoidoscopy or colonoscopy, hormonal 
contraceptives, hormone replacement therapy, iron, vitamin D, insulin therapy, and 
replacement thyroid hormone - Refer to Appendix 6 for Prohibited medications). 
Anti-diarrheal medications and probiotics are allowed only if dose has been stable for 
minimum of 14 days prior to Day 1. 
12. Taking over-the-counter medications or dietary supplements that the investigator 
deems may confound the safety assessment of the study drug and that have started or 
have had a dose adjustment within 14 days 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 ≤ 325 mg per day for cardiovascular prophylaxis, and over 
the counter doses of vitamin D, (Refer to Appendix 6 for Prohibited medications). 
Infections or predisposition to infections 
13. 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 successful completion of treatment 
regimen and b) viral load during Screening is undetectable 
d. Hepatitis E immunoglobulin M (IgM) antibody 
Human immunodeficiency virus (HIV) antibody 
14. Subject has had a live viral vaccine (e.g., MMR, varicella zoster, herpes zoster, oral 
polio virus, FluMist®, attenuated typhoid fever vaccine, attenuated rotavirus vaccine, 
yellow fever vaccine, or any investigational live vaccine) within 4 weeks prior to 
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. 


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15. 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 Stage 1 or during the Screening Period (Stage 1/Stage 2), 
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. 
c. Subject who has a history of latent or active tuberculosis (TB) may be included if 
criteria outlined in Section 6.4.1.11 are met. 
Note:   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. 
16. Has any of the following: 
a. An active, clinically significant, bacterial, parasitic, fungal, mycobacterial 
(including atypical infection), or viral infection, except for local skin or nail bed 
infection, within 2 weeks prior to Day 1. 
b. Any infection requiring intravenous antibiotics within 30 days prior to screening. 
c. Any infection requiring oral antimicrobial treatment within 2 weeks prior to Day 1. 
d. A history of more than two episodes of herpes zoster or one or more episodes of 
disseminated/complicated herpes zoster (complicated: multi-dermatomal, 
ophthalmic, or CNS involvement or post-herpetic neuralgia) or disseminated 
herpes simplex. 
e. Has had a chest radiograph or equivalent chest imaging within 90 days prior to 
Screening or at Screening that shows an abnormality suggestive of a malignancy of 
current active infection, including TB, chronic lung disease or a potentially active 
fungal, viral, or bacterial infection. 
f. Has C. difficile or other gastrointestinal infections (e.g., Salmonella, Shigella, 
Yersinia, Campylobacter, E. coli 0157, etc.) on stool testing or cytomegalovirus 
(CMV) colitis suspected on endoscopy within 30 days of Day 1. 
17. Has ever had a bone marrow transplant. 
Coexisting medical conditions or past medical history: 
18. Are pregnant, lactating, breastfeeding or planning to become pregnant during the Study 
or within 7 days after the last dose of Study Drug 
19. Has known moderate or severe hepatic impairment (e.g., Child-Pugh Class B or C) 
20. Has clinically significant abnormalities in the results of laboratory evaluations at 
screening visit as determined by the investigator, including: 
a. AST, ALT, or alkaline phosphatase ≥ 2x the upper limit of normal (ULN) 
b. Total bilirubin > 2x ULN (unless diagnosis of Gilbert’s syndrome) 
c. Creatinine clearance as calculated by the Cockcroft-Gault formula < 30 mL/min 
(Refer to Appendix 2) 
d. Total white blood cell count (WBC) < 3 x 109/L 


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e. Absolute neutrophil count < 1.5 x 109/L 
f. Absolute lymphocyte count < 0.8 x 109/L 
g. Hemoglobin < 8 g/dL, or 
h. Platelet count < 100 x 109/L. 
21. Has a clinically significant abnormal electrocardiogram (ECG) at screening, including 
QTcF > 450 msec for males and > 470 msec for females. 
22. 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 UC), genitourinary, psychiatric, oncologic or neurological disease or other medical 
disorder that would compromise subject safety or confound Study safety assessment 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. 
23. Has known hypersensitivity to excipients or contents of the Study drug. 
24. 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). 
25. Have or has a history of alcohol or drug abuse within 1 year of screening, per the 
judgment of the investigator. 
26. Has a current, or history of, malignancy requiring radiation or pharmacologic treatment 
within 5 years prior to screening, except for completely resected basal cell carcinoma 
or squamous cell carcinoma of the skin without recurrence for ≥1 year, 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. 
27. Is deemed by the investigator to be inappropriate for this Study; or has any condition 
which would confound or interfere with the evaluation of the safety, tolerability, or PK 
of the investigational drug; or is unable or unwilling to comply with the Study 
protocol. 
Exclusion Criteria Maintenance Study 
28. Subjects who required change of UC medications (such as initiated or increased oral 
corticosteroid dose or initiated rectal aminosalicylates or corticosteroids) or any 
prohibited medication to control UC symptoms during Induction Study, including 
during extended induction, if applicable. 
Exclusion Criterion for Induction Study Related to SARS-CoV-2 
29. Within 4 weeks of screening or during screening, has [1] confirmed severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 
2019 [COVID-19]) (test positive), OR [2] suspected SARS-CoV-2 infection (clinical 




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Pharmacokinetic Assessments: 
A sparse plasma PK sampling strategy is being employed in this Study where random samples 
will be taken at select Study visits both immediately prior to treatment with Study drug and 
during treatment with Study drug; time of Study drug ingestion needs to be carefully 
documented the day before and the day of each Study visit where PK samples will be 
collected.  
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: 
Phase 2b Induction Sample Size Considerations 
A sample size of 60 subjects per group is estimated to give approximately 90% power to 
detect a 2-point improvement relative to placebo in total Mayo score at all three doses, under 
the following assumptions: 
• Hochberg step-up procedure adjustment for multiple comparisons (2-sided tests) 
• Family-wise type 1 error rate to be controlled at 5% 
• Residual change standard deviation (SD) of 3 points 
• The estimated power to detect a 2-point improvement relative to placebo for at 
least one of the three doses is greater than 98%. 
Assuming a slightly larger residual change SD of 3.5 points, then the estimated power to 
detect a 2-point active dose group vs. placebo improvement in total Mayo score at all three 
doses was approximately 73% and the estimated power to detect a 2-point improvement at one 
or more of the doses was approximately 94%. 
Estimates were obtained using East software, with 10,000 simulations per case. 
Phase 3 Induction Sample Size Considerations 
Upon completion of the analyses based on the Phase 2b Induction data, the sample size may 
be refined. Currently, it is estimated that 320 subjects per dose group (640 subjects total) will 
provide at least 90% power to demonstrate the selected TD-1473 dose is effective compared to 
placebo for the primary endpoint of clinical remission at Week 8 under the following 
assumptions: 
• Type 1 error rate of 5% (2-sided tests) 
• Clinical remission rate of 9.5% for placebo at Week 8 
• Clinical remission rate of 23.5% for TD-1473 at Week 8 


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If two TD-1473 doses are selected, then 320 subjects per group will have 90% disjunctive 
power to demonstrate at least one of the two TD-1473 doses is effective compared to placebo 
for clinical remission at Week 8 under the following assumptions: 
• Hochberg step up procedure adjustment for multiple comparisons 
• Family-wise type 1 error rate to be controlled at 5% (2-sided) 
• Clinical remission rate of 9.5% for placebo at Week 8 
• Clinical remission rate of 23.5% for the more effective TD-1473 dose and 16.5% 
for the less effective TD-1473 dose. 
For the Phase 2 and Phase 3 Inductions studies, subjects will be stratified by prior biologics 
failure and baseline corticosteroids use at randomization. In addition, randomization caps will 
be placed on both prior biologics failure subgroups (no to biologics failure [60%] and yes to 
biologics failure [60%]) to ensure that neither subgroup is overrepresented.  
Phase 3 Maintenance Sample Size Considerations 
Upon completion of the analyses based on the Phase 2b Induction data, the sample size may 
be refined. Currently, it is estimated that 120 subjects per dose group (360 subjects total) will 
provide at least 90% disjunctive power to demonstrate at least one of the two TD-1473 doses 
is effective compared to placebo for the primary endpoint of clinical remission at Maintenance 
Week 44 under the following assumptions: 
• Hochberg step-up procedure adjustment for multiple comparisons 
• Family-wise type 1 error rate to be controlled at 5% (2-sided) 
• Clinical remission rate of 15% for placebo at Week 44 
• Clinical remission rate of 30% and 40% for the two active TD-1473 doses at 
Maintenance Week 44 
A total of 360 subjects total will provide 80% conjunctive power to demonstrate both doses of 
TD-1473 are effective compared to placebo for clinical remission at Maintenance.  
Study Endpoints: 
Phase 2b Induction Primary and Secondary Efficacy Endpoints: 
Primary: 
• Change in total Mayo score from baseline at Week 8 
Key Secondary (with multiplicity control): 
• Clinical remission by adapted Mayo score at Week 8 
Phase 3 Induction Primary and Key Secondary Efficacy Endpoints (with multiplicity 
control) in order of testing: 
Primary: 
• Clinical remission by adapted Mayo score at Week 8 


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Key Secondary: 
• Endoscopic healing at Week 8 
• Symptomatic remission at Week 8 
• Clinical response by adapted Mayo score definition at Week 8 
• Mucosal healing at Week 8 
• Deep symptomatic remission at Week 8 
Phase 3 Maintenance Primary and Key Secondary Efficacy Endpoints (with multiplicity 
control) in order of testing: 
Primary: 
• Clinical remission by adapted Mayo score at Maintenance (m)Week 44 
Key Secondary: 
• Maintenance of clinical response at mWeek 44 
• Endoscopic healing at mWeek 44 
• Symptomatic remission at mWeek 44 
• Corticosteroid-free remission at mWeek 44 
• Maintenance of clinical remission at mWeek 44 in those who were in remission at 
mWeek 0 
• Mucosal healing at mWeek 44 
• Deep symptomatic remission at mWeek 44 
Refer to DEFINITION OF TERMS for detailed definition of primary and key secondary 
endpoints 
Safety Endpoints: 
Incidence and severity of treatment-emergent adverse events; changes in laboratory test 
results, ECG intervals and abnormalities, and vital sign measurements 
Analysis: 
In general, binary endpoints will be analyzed using Cochran-Mantel-Haenszel tests, stratifying 
by randomization stratum. Subjects with missing binary outcomes will be counted as not 
meeting the endpoint for analysis purpose. Logistic regression models may be fitted for 
selected endpoints to evaluate dose-response curves. 
Continuous endpoints will be analyzed by fitting mixed effect or analysis of covariance 
models which include terms for treatment, stratification factors, and baseline score. 
The primary analysis set for efficacy endpoints will be a modified intent-to-treat (mITT) set 
comprising all subjects who receive at least one dose of study drug, summarized by 
randomized treatment. 


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For each Study, the family-wise type 1 error rate for primary and key secondary endpoints 
included in the statistical testing hierarchy will be controlled at 5% by use of a gatekeeping 
procedure with a pre-specified testing sequence. All comparisons will be 2-sided. 
Safety data will be summarized by actual treatment received using frequency of events or 
descriptive summary statistics, as appropriate. 
Individual data listings will be prepared for all data collected. 
Further details can be found in Section 8 of the main body of the protocol. 
 














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with endoscopy screening. This partial Mayo Score can be assessed at any time between Screening Stage 1 visit and Screening Stage 2 visit as long as there 
are ≥ 3 days of symptom reporting. The pMS is calculated by the electronic tablet at the Screening Stage 2 visit page and it is recommended that this is 
completed before the subject proceeds with the Screening Stage 2 visit endoscopy. 
25  Subjects will be provided with an electronic diary at the Screening (Stage 1) visit and instructed on diary completion, including symptom monitoring and 
Study drug dosing details. Diaries of symptoms will be collected daily from Screening through the EOS visit.  
26  Diary completion will be monitored for completeness at each Study visit. Subjects will be counseled on missed Study drug doses and missed diary entries. 
Subjects who discontinue study drug early due to AE are permitted to optionally complete their daily diary through to the EOS visit. 
27  Subject will be randomized on Day 1 after all pre-dose procedures have been completed and subject is confirmed to be eligible for the Study. The adapted 
Mayo score criteria for randomization on Day 1 may be calculated within 48 hours of Day 1.  
28  Study drug administration will be in-clinic on Day 1, Week 4, Week 8b and Week 16. All study procedures must be done prior to drug administration with 
the exception of the post-dose PK sample and 
 samples. Refer to footnote 13 for the post-dose instructions for PK collections and 
footnote 15 for the 
 collection window. All other days, subjects will take study drug at home for the rest of the Induction period. 
29  Procedures may be done -3 to +7 days after week 8a visit (i.e., at the next visit, either Week 8b or mWeek0). 
30  
  
31  The adapted Mayo Score at these visits will be calculated by the electronic tablet using the symptoms in the applicable days prior to Day 1, Week8a or 
Week 16 and the centrally read endoscopy score. This will be available once the centrally read endoscopy score has been received by the site and entered 
into the electronic tablet.  
32  ECG at Day 1 is only required during the Phase 2b Dose-finding Induction study.  
33  If the Week 8b visit occurs out of window, the dates of subsequent visits will be based on the Week 8b visit start date to ensure a full 8 weeks of treatment in 
Extended Induction. 
Note:  See Appendix 11 for general guidance on study conduct during the coronavirus disease 2019 (COVID-19) pandemic. Variations from planned assessments 
will still constitute protocol deviations. 
 






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a. 
mWeek 0 (n =2 samples): One predose and one postdose sample collected any time between 0.5 and 6 hours 
b. mWeek 12 and mWeek 28 (n = 1 sample): One sample to be collected anytime during the clinic visit 
c. 
mWeek 44 (n = 3 samples): one predose, and two postdose samples collected any time between 0.5 and 6 hours postdose and separated by at least 
1 hour. NOTE: this PK sample should be obtained either prior to subject receiving bowel prep for endoscopy or >24 hours post bowel prep 
Predose samples will be taken within 1 hour prior to Study drug administration. Postdose sampling times are defined relative to the time of Study drug 
administration on the day of collection. All PK sampling times will be accurately recorded by collection date, hour, and minute. Study drug dosing time on 
the day before each PK collection will also be accurately recorded by dosing date, hour, and minute by the subject; Study drug dosing time on the day of 
each PK collection will be accurately recorded by dosing date, hour, and minute by the Study staff if drug is administered in the clinic or by the subject if 
drug is administered outside of the clinic.  
9. 
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. 
10. Urine 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. 
11. Fecal samples may be collected within 3 full days (approximately 72 hours) of the respective visits up to the end of the day following the visit (but before 
bowel preparation) and has to be delivered to the study site within 24 hours. It is preferable that these stool samples be collected during the first bowel 
movement in the morning. 
12. Refer to Section 6.3.12 for further details on Clinical Flare Assessment Visits 
13. Diaries of symptoms will be collected daily. Diary completion will be monitored for completeness at each Study visit. Subjects will be counseled on missed 
Study drug doses and missed diary entries. Subjects who discontinue study drug early due to AE are permitted to optionally complete their daily diary 
through to the EOS visit. 
14. Study drug administration will be in-clinic on mWeek 44 visit after all pre-dose assessments [mWeek 44: All blood tests need to be collected and 
procedures have been completed prior to dose (except for post-dose PK blood collection and 
, which may be done 
post--visit)]. Subject will take the Study drug at home for the rest of the Study (including Clinical Flare Assessment Visits). On days of endoscopy (mWeek 
and Clinical Flare Assessment Visit 2, if applicable), study drug can be administered before or after endoscopy; if done before endoscopy, study drug will 
be taken with whatever the volume of water is allowed by the endoscopy team before endoscopic sedation. 
15. Applicable assessments should be done only if not done within the prior 14 days. 
16. 
. 
17. The centrally read endoscopic subscore will be used for all endpoints and for eligibility criteria to enroll a subject into the Long-Term Safety Study. Local 
reading of the endoscopic subscore will also be collected. 
Note:  See Appendix 11 for general guidance on study conduct during the coronavirus disease 2019 (COVID-19) pandemic. Variations from planned assessments 
will still constitute protocol deviations. 
 




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TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
PROTOCOL SYNOPSIS ................................................................................................................2 
LIST OF ABBREVIATIONS ........................................................................................................36 
DEFINITION OF TERMS ............................................................................................................40 
1. 
INTRODUCTION ......................................................................................................43 
1.1. 
Background and Rationale ..........................................................................................43 
1.2. 
Nonclinical Profile ......................................................................................................44 
1.3. 
Pharmacology .............................................................................................................44 
1.3.1. 
Toxicology ..................................................................................................................44 
1.3.2. 
Pharmacokinetics ........................................................................................................45 
1.4. 
Clinical Experience .....................................................................................................46 
1.5. 
Risks and Benefits ......................................................................................................47 
2. 
OBJECTIVES .............................................................................................................49 
3. 
STUDY DESIGN .......................................................................................................51 
3.1. 
Overview .....................................................................................................................51 
3.2. 
Rationale for Study Design .........................................................................................55 
3.3. 
Selection of Dose Ranges and Duration of Treatment ...............................................56 
3.4. 
Study Endpoints ..........................................................................................................57 
3.4.1. 
Phase 2b Induction Efficacy Endpoints ......................................................................57 
3.4.2. 
Phase 3 Induction Efficacy Endpoints ........................................................................58 
3.4.3. 
Phase 3 Maintenance Efficacy Endpoints ...................................................................59 
3.4.4. 
Safety Endpoints .........................................................................................................60 
3.5. 
Minimization of Bias ..................................................................................................60 
3.5.1. 
Blinding ......................................................................................................................61 
3.5.2. 
Treatment Assignment ................................................................................................62 
3.6. 
End of Trial Definition ...............................................................................................63 
4. 
STUDY POPULATION .............................................................................................64 
4.1. 
Induction Studies and Maintenance Study Inclusion Criteria ....................................64 
4.2. 
Induction Studies and Maintenance Study Exclusion Criteria ...................................66 
4.3. 
Women of Childbearing Potential (WOCBP) and Acceptable Birth Controls ...........70 
5. 
STUDY DRUGS ........................................................................................................72 


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5.1. 
Description of Study Drugs ........................................................................................72 
5.1.1. 
TD-1473 ......................................................................................................................72 
5.1.2. 
Placebo ........................................................................................................................72 
5.2. 
Dosage and Administration ........................................................................................72 
5.2.1. 
TD-1473 ......................................................................................................................72 
5.2.1.1. 
Induction Study ...........................................................................................................72 
5.2.1.2. 
Maintenance Study .....................................................................................................73 
5.2.2. 
Placebo ........................................................................................................................73 
5.2.2.1. 
Induction Studies ........................................................................................................73 
5.2.2.2. 
Maintenance Study .....................................................................................................73 
5.3. 
Treatment Compliance ................................................................................................74 
5.4. 
Missed Dose(s) ...........................................................................................................74 
5.5. 
Drug Accountability and Reconciliation ....................................................................74 
6. 
STUDY PROCEDURES ............................................................................................75 
6.1. 
Schedule of Study Procedures ....................................................................................75 
6.2. 
Total Blood Volume ...................................................................................................75 
6.3. 
Procedures by Visit .....................................................................................................75 
6.3.1. 
Induction Study – Screening Stage 1 ..........................................................................75 
6.3.2. 
Induction Study – Screening Stage 2 ..........................................................................75 
6.3.3. 
Induction Study – Day 1 .............................................................................................76 
6.3.4. 
Induction Study – Week 2 ..........................................................................................76 
6.3.5. 
Induction Study – Week 4 ..........................................................................................76 
6.3.6. 
Induction Study – Week 8a .........................................................................................76 
6.3.7. 
Extended Induction – Week 12 and Week 16 (only for subjects who do not 
demonstrate clinical response to Induction at Week 8) ..............................................76 
6.3.8. 
Maintenance Study – mWeek 0 ..................................................................................76 
6.3.9. 
Maintenance Study – mWeek 4 and mWeek 36 .........................................................77 
6.3.10. 
Maintenance Study – mWeek 12 to mWeek 28 .........................................................77 
6.3.11. 
Maintenance Study – mWeek 44 ................................................................................77 
6.3.12. 
Clinical Flare Assessment...........................................................................................77 
6.3.13. 
Early Study Drug Discontinuation..............................................................................80 
6.3.14. 
End of Study (EOS) ....................................................................................................80 


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6.4. 
Description of Study Assessments ..............................................................................80 
6.4.1. 
Demographic and Baseline Assessments....................................................................80 
6.4.1.1. 
Informed Consent, Demographics, and Inclusion/Exclusion Criteria ........................80 
6.4.1.2. 
Medication History .....................................................................................................81 
6.4.1.3. 
Medical History ..........................................................................................................81 
6.4.1.4. 
Smoking Status ...........................................................................................................81 
6.4.1.5. 
Height Measurements .................................................................................................81 
6.4.1.6. 
Body Weight ...............................................................................................................81 
6.4.1.7. 
Vital Signs ..................................................................................................................82 
6.4.1.8. 
12-Lead Electrocardiograms .......................................................................................82 
6.4.1.9. 
Physical Examination .................................................................................................82 
6.4.1.10. 
Chest X-ray or equivalent imaging .............................................................................83 
6.4.1.11. 
Tuberculosis (TB) Test ...............................................................................................83 
6.4.1.12. 
Concomitant Medications ...........................................................................................84 
6.4.1.13. 
Adverse Events (AEs) .................................................................................................84 
6.4.1.14. 
Pregnancy Test (females of child-bearing potential only) ..........................................84 
6.4.1.15. 
Follicle-Stimulating Hormone (FSH) .........................................................................85 
6.4.1.16. 
Chemistry, Hematology, and Urinalysis .....................................................................85 
6.4.1.17. 
Overnight Fasting Lipid Panel ....................................................................................85 
6.4.1.18. 
Serology Panel ............................................................................................................86 
 
 
6.4.1.20. 
Endoscopy and Biopsies .............................................................................................86 
6.4.1.21. 
Fecal Sampling ...........................................................................................................87 
6.4.1.22. 
Whole Blood and Serum Biomarker Sampling ..........................................................88 
6.4.1.23. 
Optional Genetic Testing ............................................................................................88 
6.4.1.24. 
Pharmacokinetic Sampling .........................................................................................88 
6.4.2. 
Efficacy Assessments .................................................................................................89 
6.4.2.1. 
Mayo score ..................................................................................................................89 
 
 
 
 
 
 
 
 


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6.4.3. 
Pharmacokinetic and Pharmacodynamics Assessments .............................................92 
6.4.4. 
Safety Assessments .....................................................................................................92 
6.4.4.1. 
Adverse Events ...........................................................................................................92 
6.4.4.2. 
Medical History ..........................................................................................................92 
6.4.4.3. 
Physical Examination .................................................................................................92 
6.4.4.4. 
Vital Signs ..................................................................................................................92 
6.4.4.5. 
Laboratory Tests .........................................................................................................92 
6.5. 
Concomitant Medications ...........................................................................................92 
6.5.1. 
Prohibited Medications ...............................................................................................92 
6.5.2. 
Permitted Medications ................................................................................................93 
6.5.3. 
Corticosteroid Tapering ..............................................................................................94 
6.5.4. 
Rescue Medications During Maintenance Study ........................................................95 
6.5.5. 
Restrictions on Alcohol Consumption and Illicit Drug Use .......................................95 
6.6. 
Discontinuation ...........................................................................................................95 
6.6.1. 
Subject Discontinuation ..............................................................................................95 
6.6.2. 
Subject Replacement ..................................................................................................96 
6.6.3. 
Study Discontinuation ................................................................................................96 
6.7. 
Pregnancy ...................................................................................................................97 
7. 
ADVERSE EVENTS..................................................................................................98 
7.1. 
Definitions ..................................................................................................................98 
7.1.1. 
Adverse Events (AE) ..................................................................................................98 
7.1.2. 
Serious Adverse Event (SAE) ....................................................................................99 
7.1.3. 
Additional Considerations for Serious Adverse Events .............................................99 
7.1.4. 
Adverse Events of Special Interest (AESI) ..............................................................100 
7.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ..............................................................100 
7.3. 
Assessment of Adverse Events .................................................................................102 
7.3.1. 
Severity .....................................................................................................................102 
7.3.2. 
Causal Relationship to Study Medication .................................................................102 
7.3.3. 
Clinical Events Committee (CEC) ............................................................................103 
7.4. 
AE Reporting and Recording ....................................................................................103 


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7.4.1. 
AE Reporting ............................................................................................................103 
7.4.2. 
AE, SAE and AESI Recording .................................................................................103 
7.4.3. 
SAE and AESI Reporting Timeline ..........................................................................104 
7.5. 
Adverse Event Follow-up .........................................................................................105 
8. 
STATISTICAL CONSIDERATIONS .....................................................................106 
8.1. 
General Considerations .............................................................................................106 
8.2. 
Sample Size and Power ............................................................................................107 
8.2.1. 
Induction Phase 2b Sample Size Considerations ......................................................107 
8.2.2. 
Induction Phase 3 Sample Size Considerations ........................................................107 
8.2.3. 
Phase 3 Maintenance Sample Size Considerations ..................................................108 
8.3. 
Analysis Sets .............................................................................................................109 
8.3.1. 
Analysis Sets .............................................................................................................109 
8.3.2. 
Examination of Subgroups .......................................................................................109 
8.3.3. 
Major Analysis Protocol Deviations .........................................................................110 
8.4. 
General Analyses ......................................................................................................110 
8.4.1. 
Demographics and Other Baseline Characteristics ...................................................110 
8.5. 
Analysis of Efficacy .................................................................................................110 
8.5.1. 
Phase 2b Induction Efficacy Endpoints ....................................................................110 
8.5.2. 
Phase 3 Induction Efficacy Endpoints ......................................................................111 
8.5.3. 
Phase 3 Maintenance Efficacy Endpoints .................................................................112 
8.5.4. 
Primary Efficacy Evaluation .....................................................................................114 
8.5.5. 
Secondary and Additional Efficacy Evaluations ......................................................114 
8.5.6. 
Multiplicity Adjustment............................................................................................115 
8.6. 
Analysis of Pharmacokinetics ...................................................................................115 
8.7. 
Analysis of Pharmacodynamics ................................................................................115 
8.8. 
Safety Analyses ........................................................................................................116 
8.8.1. 
Extent of Exposure ...................................................................................................116 
8.8.2. 
Adverse Event Data ..................................................................................................116 
8.8.3. 
Concomitant Medications .........................................................................................117 
8.8.4. 
Laboratory Data ........................................................................................................117 
8.8.5. 
Vital Signs Data ........................................................................................................117 
8.8.6. 
ECG Data ..................................................................................................................117 


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8.9. 
Data Handling Rules .................................................................................................118 
8.10. 
Independent Data Monitoring Committee (IDMC) ..................................................119 
8.11. 
End of Induction Phase 2b Dose Selection ...............................................................119 
9. 
STUDY ADMINISTRATION .................................................................................121 
9.1. 
Principal Investigator Responsibilities .....................................................................121 
9.2. 
Institutional Review Board/Independent Ethics Committee ....................................122 
9.3. 
Informed Consent .....................................................................................................122 
9.4. 
Data Recording and Quality Assurance ....................................................................122 
9.5. 
Document Retention .................................................................................................123 
9.6. 
Confidentiality ..........................................................................................................123 
9.7. 
Access to Data and Documents ................................................................................124 
9.8. 
Quality Control: Study Monitoring and Auditing ....................................................124 
9.9. 
Publication ................................................................................................................125 
10. 
REFERENCES .........................................................................................................126 
APPENDIX 1. PROTOCOL SIGNATURE FORM .................................................................127 
APPENDIX 2. COCKCROFT-GAULT CALCULATION ......................................................128 
APPENDIX 3. MAYO SCORING SYSTEM FOR ASSESSMENT OF ULCERATIVE 
COLITIS ACTIVITY ...............................................................................................129 
 
 
APPENDIX 6. PROHIBITED MEDICATIONS ......................................................................132 
APPENDIX 7. DEFINITION OF INTOLERANCE OR INADEQUATE RESPONSE 
AND DEFINITION OF CORTICOSTEROID DEPENDENCE .............................134 
APPENDIX 8. DEFINITION OF PRIOR BIOLOGICS FAILURE: PRIMARY AND 
SECONDARY NON˗RESPONDER OR INTOLERANT TO PREVIOUS 
BIOLOGICS .............................................................................................................136 
APPENDIX 9. PATIENT REPORTED OUTCOME MEASURES .........................................138 
APPENDIX 10. GUIDELINE ALGORITHM FOR MONITORING, ASSESSMENT, 
AND EVALUATION OF ABNORMAL LIVER TESTS IN 
PARTICIPANTS WITH NO UNDERLYING LIVER DISEASE ..........................139 
APPENDIX 11. SPONSOR GUIDANCE ON STUDY CONDUCT DURING THE 
CORONAVIRUS DISEASE 2019 (COVID-19) PANDEMIC ...............................143 
 


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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures – Induction and Extended Induction Studies .............18 
Table 2: 
Schedule of Study Procedures – Maintenance Study .................................................25 
Table 3: 
Schedule for Clinical Flare Assessment Visits ...........................................................28 
Table 4: 
Thresholds for Vital Signs ........................................................................................117 
Table 5: 
Thresholds for ECG ..................................................................................................118 
 
LIST OF FIGURES 
Figure 1: 
Protocol Schema ...........................................................................................................4 
Figure 2: 
Phase 2b Dose-Finding Induction Study ....................................................................52 
Figure 3: 
Extended Induction Treatment Regimen ....................................................................53 
Figure 4: 
Phase 3 Dose-Confirming Induction Study Schema ..................................................53 
Figure 5: 
Phase 3 Maintenance Study Treatment Regimen .......................................................55 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analyzed by fitting analysis of covariance 
AST 
aspartate aminotransferase 
BCG 
Bacille Calmette Guerin 
BCRP 
breast cancer resistance protein 
BMI 
body mass index 
BP 
blood pressure 
CFA 
Clinical Flare Assessment  
CFR 
(United States) Code of Federal Regulations 
CI 
confidence interval 
CMV 
cytomegalovirus  
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
 
 
CYP 
cytochrome P450 
CSR 
Clinical Study Report 
DDI 
drug-drug interaction 
DNA 
deoxyribonucleic acid 
DVT 
deep vein thrombosis 
 
 
IDMC 
independent data monitoring committee 
ECG 
electrocardiogram 
eCOA 
Electronic Clinical Outcome Assessments  
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay  
EOS 
End-of-Study 
 
 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 


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Abbreviation 
Description 
GI 
gastrointestinal 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HDPE 
high-density polyethylene 
HPMC 
hydroxypropyl methylcellulose 
HR 
heart rate 
IDAP 
Induction data analysis plan 
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 
IEC 
Independent Ethics Committee 
INH 
Isoniazid 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRSG 
Independent Reporting Statistical Group 
ITT 
intent to treat 
IUD 
intrauterine device 
JAK 
Janus kinase 
LTS 
Long Term Safety Study 
MAD 
multiple ascending dose 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities (MedDRA®) 
mITT 
Modified intent-to-treat 
MMRM 
mixed model repeated measures 
mRNA 
messenger ribonucleic acid 
mWeek 
Maintenance Week  
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
OTC 
Over-the-Counter 
PA 
posterior anterior 


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Abbreviation 
Description 
PD 
Pharmacodynamics(s) 
PI 
principal investigator 
P-gp 
p-glycoprotein 
PIC 
powder in capsule 
PK 
pharmacokinetic(s) 
pMS 
partial Mayo score  
PP 
Per-Protocol 
PPI 
protein pump inhibitor 
 
  
PT 
Preferred Term 
QD 
Once daily 
QTc 
corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
REB 
Research Ethics Board 
RNA 
ribonucleic acid 
RR 
Re-Randomized 
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 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SF 
Stool Frequency 
SOC 
System Organ Class 
SOP 
standard operating procedure 
STAT 
signal transducer and activator of transcription 
TEAE 
Treatment Emergent Adverse Event  
TESAE 
Treatment Emergent Serious Adverse Event 
TB 
Tuberculosis 
TBPH 
Theravance Biopharma 
tMS 
total Mayo score 
TNF 
tumor necrosis factor 


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Abbreviation 
Description 
UC 
ulcerative colitis 
ULN 
upper limit of normal 
WOCBP 
Women of Childbearing Potential 
 
  
 


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DEFINITION OF TERMS 




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




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Phase 3 Maintenance Study 
The primary objectives of the Study are as follows: 
• Assess the clinical remission rates associated with TD-1473 compared to placebo 
treatment at mWeek 44 
• Assess the safety and tolerability of TD-1473 with up to 44 additional weeks of 
treatment 
The key secondary objectives of the Study are to assess the rates of the following associated with 
TD-1473 compared to placebo treatment: 
• Clinical response, endoscopic healing, symptomatic remission, mucosal healing, and 
deep symptomatic remission at mWeek 44 
• Corticosteroid-free remission at mWeek 44 
• Maintenance of clinical remission at mWeek 44 in those who were in clinical 
remission at mWeek 0 
 


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3. 
STUDY DESIGN 
3.1. 
Overview 
This single protocol includes three studies: a Phase 2b dose-finding Induction Study, a Phase 3 
dose-confirming Induction Study, and a Phase 3 randomized-withdrawal Maintenance Study 
(Figure 1). Each of the three studies will utilize a multi-center, randomized, double-blind, 
placebo-controlled, parallel-group design to evaluate various dose(s) of TD-1473 compared to 
placebo in subjects with moderately-to-severely active UC. The Induction Studies will target 
subjects with moderately-to-severely active UC who demonstrate an inadequate response or 
failure to tolerate conventional or biologic therapy. The Maintenance Study will be a randomized 
withdrawal study targeting subjects with moderately-to severely-active UC who demonstrate a 
clinical response to induction treatment with TD-1473. 
Induction Studies: 
To determine initial eligibility, subjects will undergo assessments during the Screening Stage 1 
period. Refer to Schedule of Study Procedures (Table 1) for a schedule of the Screening 
requirements. Disease activity will be assessed by the total, adapted, and partial Mayo scores and 
PRO2 score. Subjects who meet inclusion and no exclusion criteria, as described in Section 4, 
will undergo an endoscopic exam (i.e., sigmoidoscopy or colonoscopy) with biopsies to 
complete screening Stage 2. 
If the subject meets all eligibility criteria, including a centrally read Mayo endoscopic subscore 
≥ 2 during Screening Stage 2 and an adapted Mayo score between 4 and 9, inclusive, on Day 1, 
the subject may be randomized. The randomization will be stratified by prior biologic failure 
status and corticosteroid use at enrollment into the Induction Study. Biologic failure is defined as 
having demonstrated primary or secondary non-response or intolerance to one or more biologics 
(i.e., anti-TNF and anti-integrin), as described in more detail in Appendix 7. 
The Induction Studies consist of treatment for: a) 8 weeks for those who demonstrate clinical 
response at Week 8 and b) 16 weeks for those who do not, during which, subjects will return for 
safety, PK, biomarker, and disease assessments, as well as a endoscopy with biopsies according 
to the Schedule of Study Procedures provided in Table 1. 
Subjects who do not demonstrate clinical response at Week 8 will receive an additional 8 weeks 
of treatment during an extended induction period. Those that had been randomized to TD-1473 
during the first 8 weeks will remain on the same dose; those who received placebo during the 
first 8 weeks will receive TD-1473 80 mg from Week 8 to 16. This portion of the Induction 
Study will not be placebo-controlled but blinding as to the specific dose of TD-1473 will be 
maintained. Those who demonstrate clinical response at Week 16 will enter the Maintenance 
Study; those who do not exit the study. 
Randomization ratios and dosing regimens are described below: 
a) Phase 2b Dose-Finding Induction Study 
The Phase 2b-Dose Finding Induction Study (Figure 2) will enroll approximately 
240 subjects, randomized 1:1:1:1 to placebo or 1 of the 3 active TD-1473 doses (20 mg, 


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80 mg or 200 mg). After all 240 subjects have either completed the Week 8 visit or 
terminated participation prior to Week 8, an analysis of all efficacy and safety data up to 
Week 8 will be performed (Refer to Section 8). Results from this analysis will be used to 
inform the dose selection for the Phase 3 dose-confirming Induction Study and the 
remainder of the Phase 3 Maintenance Study, which would be ongoing at that time. 
Figure 2: 
Phase 2b Dose-Finding Induction Study 
 
b) EXTENDED INDUCTION 
Subjects who do not demonstrate clinical response at Week 8 will receive an additional 8 weeks 
of treatment with active drug staying on the same dose of TD-1473 as the first 8 weeks, and 
those who had received placebo during the first 8 weeks will now receive TD-1473 at 80 mg 
(Figure 3). All subjects who undergo extended induction treatment will receive active drug, and 
thus, this portion of the Induction Study will not be placebo-controlled but blinding as to the 
specific dose of TD-1473 will be maintained. During this time, at the discretion of the 
investigator, subjects are permitted but are not required to begin corticosteroid taper. Those who 
demonstrate clinical response at Week 16 will enter the Maintenance Study; those who do not 
demonstrate clinical response at Week 16 will have an EOS visit and exit the study. 


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Figure 3: 
Extended Induction Treatment Regimen 
 
Phase 3 Dose-Confirming Induction Study  
The Sponsor plans to identify 1 dose for the Phase 3 dose-confirming Induction Study, guided by 
the results of the Phase 2b Induction Study. The Phase 3 Induction Study will not begin until an 
induction dose has been selected. In that study, a to-be-determined number of subjects (currently 
estimated as 640, but the final number will be determined after the Phase 2b Induction Study 
data analysis is completed) will be randomized in a 1:1 ratio to placebo or TD-1473. The Phase 3 
Induction Study has the same study design as the Phase 2b Induction Study, with the exception 
of the number of treatment arms. 
Figure 4: 
Phase 3 Dose-Confirming Induction Study Schema 
 
 
 
 


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PHASE 3 MAINTENANCE STUDY 
Subjects who are considered to have achieved clinical response by adapted Mayo score (Refer to 
DEFINITION OF TERMS) using centrally read endoscopic subscore at either Week 8 or 
Week 16 during the Induction studies will continue in the Maintenance Study: 
• Subjects who achieved clinical response on TD-1473 during induction at Week 8 will 
be re-randomized into the Maintenance Study to placebo or one of the TD-1473 doses 
and contribute to the primary efficacy analysis population of the Maintenance Study. 
• Subjects who achieved clinical response on placebo during Induction at Week 8 will 
continue to receive placebo in the Maintenance Study in a blinded manner to maintain 
blind. However, these subjects will not be included in the primary efficacy analysis 
population of the Maintenance Study. 
• Subjects who did not achieve clinical response by adapted Mayo score using centrally 
read endoscopic subscores to the first 8 weeks of induction treatment but responded at 
Week 16 will continue into the Maintenance Study: 
− Subjects who received 8 weeks of placebo and 8 weeks of TD-1473 80 mg will be 
re-randomized into the Maintenance Study to placebo or one of the TD-1473 
doses and contribute to the primary efficacy analysis population of the 
Maintenance Study.  
− Subjects who received 16 weeks of TD-1473 during Induction will continue to 
receive same dose of TD-1473 in the Maintenance Study in a blinded manner to 
maintain blind. However, these subjects will not be included in the primary 
efficacy analysis population of the Maintenance Study. 
 
In summary, subjects who demonstrate clinical response to a total of 8 weeks of TD-1473 
induction therapy, either at Week 8 or Week 16, will be re-randomized. Those who demonstrate 
response to placebo at Week 8 or those who demonstrate response to a total of 16 weeks of 
TD-1473 treatment at Week 16 will enter the Maintenance Study on the same study drug 
treatment as during Induction for the purpose of maintaining blinding. The Maintenance Study 
consists of treatment for 44 weeks. During the Maintenance Study, subjects must taper their 
corticosteroid dose using the regimen outlined in Section 6.5.3 if they entered the study on 
corticosteroids. 
Before the Phase 2b Induction Week 8 primary data analysis and subsequent dose selection, 
responders to a total of 8 weeks of TD-1473 from the 240 subjects in Phase 2b Induction Study 
will be re-randomized 1:1:1:1 to placebo or 1 of the 3 active TD-1473 doses (20 mg, 80 mg or 
200 mg) when they roll over into the Maintenance Study. 
After the Phase 2b Induction Week 8 primary data analysis and subsequent dose selection have 
been completed, subjects enrolling into the Phase 3 Maintenance Study will be randomized to 
either placebo or 1 of the 2 selected doses of TD-1473 doses in a 1:1:1 ratio. Those who are still 
completing the Maintenance Study on a de-selected dose will remain on that dose unless there is 
a concerning safety signal detected up to point of dose selection, in which case, they will be 
transitioned to the closest of the doses that have been selected. The Sponsor plans to identify 














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3.5.1. 
Blinding 
When the data for the Phase 2b Induction Study are unblinded for dose selection, data from 
subjects in the Maintenance Study will remain blinded. In order to maintain blind of treatment 
assignments in the Induction Study, treatment assignments in the Maintenance Study will be 
assigned by RTSM for those who are eligible for re-randomization to receive placebo or one of 
the TD-1473 doses, and those who continue to receive the same treatment as assigned in the 
Induction Study without re-randomization. 
Subjects who achieved clinical response on placebo during Induction at Week 8, or subjects who 
achieved clinical response on TD-1473 after 16 weeks of treatment will continue to receive the 
same treatment as assigned in the Induction study in the Maintenance study in a blinded manner. 
The RTSM system will be designed to ensure that the user interface is identical for subjects who 
are re-randomized into the Maintenance Study and subjects who enter the Maintenance Study 
without being re-randomized, and hence cannot reveal whether re-randomization has occurred. 
For instance, sites will be required to report steroid use status at enrollment into the Maintenance 
Study for all subjects, rather than only those subjects whose Maintenance Study randomization 
stratum must be determined. 
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 
subject’s treatment assignment is warranted, and unblinding could be done through the RTSM 
system. Subject safety must always be the first consideration in making such a determination. 
Any investigator unblinding will be documented within the appropriate CRF and will be 
captured in the RTSM system. 
Sponsor Drug Safety personnel may independently unblind cases for expedited reporting of 
suspected unexpected serious adverse reactions (SUSARs). Sponsor personnel involved in the 
conduct of the Study, data cleaning, or data analysis will remain blinded to subject treatment 
assignments until each database has been locked for final analysis. Currently, it is estimated that 
there will be 3 final analyses conducted: 1) after 240 subjects either completed the Week 8 
assessment or prematurely withdrew from the Phase 2b Induction Study, 2) at the conclusion of 
the Phase 3 Induction Study, and 3) at the conclusion of the Phase 3 Maintenance Study. 
To facilitate PK analysis, PK data may be provided in a blinded fashion (i.e., PK data cannot be 
linked to an individual subject) to the Sponsor for analysis or analyzed by an independent 
exposure-response analyst in an unblinded fashion and provided to the Sponsor for 
interpretation. If PK data are to be analyzed by an independent exposure-response analyst, a 
guidance document detailing the procedures to maintain the Sponsor’s blind will be written. For 
clarity, this independent exposure-response analyst may be either an external company or an 
individual or group within the Sponsor who are separate from the clinical Study team. 


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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. Four sets 
of randomization schedules will be prepared to support study conduct before and after dose 
selection: 
• Initial Induction schedules 
• Induction schedules modified to include only the active dose(s) selected for continued 
evaluation for Induction 
• Initial Maintenance schedules 
• Maintenance schedules modified to include only the active dose(s) selected for 
continued evaluation for Maintenance 
Subjects who achieved clinical response on placebo during Induction at Week 8, or subjects who 
achieved clinical response on TD-1473 after 16 weeks of treatment are not eligible to be 
re-randomized into the Maintenance study. They will continue to receive the same treatment as 
assigned in the Induction study in the Maintenance study in a blinded manner. 
The Phase 2b and Phase 3 Induction Study randomizations will be stratified by prior biologics 
failure status and corticosteroid use at enrollment into the Induction Studies (4 strata). Biologic 
failure is defined as having had primary or secondary non-response or intolerance to biologics 
therapy. 
Randomization of the Maintenance Study will be stratified by 3 stratification factors (8 strata): 
1) clinical remission status using adapted Mayo score component definition, 2) corticosteroid use 
at enrollment into the Maintenance Study (4 strata), and 3) subjects who achieved clinical 
response on TD-1473 during Induction at Week 8 versus subjects who reach clinical response 
after receiving placebo during the first 8 weeks and then TD-1473 80 mg during extended 
induction. 
All individual-stratum randomization schedules will be reproducible (through use of a 
prespecified random number seed) sequences of randomly permuted treatment assignment 
blocks, generated or reviewed by a Sponsor statistician not involved in the conduct of the Study. 
Randomization 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 Study (Induction and Maintenance) databases have been 
finalized AND locked. 
For the Phase 2b and Phase 3 Induction studies, the RTSM system will implement enrollment 
caps designed to ensure that at least 40% of subjects will have a history of prior biologics failure 
and at least 40% of subjects will not have a history of prior biologics failure [Section 4.1]. These 
enrollment caps will be “soft caps,” i.e., 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 only after confirmation is received from the Sponsor. 


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Further details regarding the randomization procedure will be provided in the RTSM system 
manual. 
3.6. 
End of Trial Definition 
The end of the study is defined as the date of the global, last subject study visit (including the 
4 week follow up visit) in the Phase 3 Maintenance study. 


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4. 
STUDY POPULATION 
The study population consists of subjects with moderately-to-severely active UC as defined by 
an adapted Mayo score between 4 and 9 with a Mayo endoscopic subscore ≥ 2 who are 
corticosteroid-dependent or had intolerance or demonstrate an inadequate response or loss of 
response to conventional therapy (aminosalicylates, corticosteroids or immunomodulators) 
[i.e., as azathioprine or 6-mercaptopurine] or biologics [i.e., anti-TNF-therapy or anti-integrin]. 
4.1. 
Induction Studies and Maintenance Study Inclusion Criteria 
To be eligible subjects must meet all the following criteria: 
1. Are male or female 18 years of age or older at Screening 
2. Has ≥ 3 months history of UC prior to screening (with involvement beyond the rectum to 
at least 15 cm from the anal verge) 
a. Diagnosed by sigmoidoscopy or colonoscopy AND 
b. If possible, corroborated by histology report or documentation of histological 
results in a physician note. However, if there was no biopsy done previously or if 
no prior endoscopy or histology report is available for review, the subject must 
have a colonoscopy instead of a sigmoidoscopy at screening. 
3. Must be willing to have a sigmoidoscopy or colonoscopy at screening. Colonoscopy will 
be performed instead of a sigmoidoscopy at screening in the following scenarios, 
(outlined in Section 6.4.1.20): 
a. If UC diagnosis precedes screening by ≥ 8 years for pan-colitis or ≥12 years for 
left-sided colitis and the subject does not have documentation of a surveillance 
colonoscopy within 12 months prior to screening to rule out dysplasia (report 
must be reviewed by the investigator and included in the source documents). 
During colonoscopy, if chromoendoscopy or surveillance biopsies are indicated as 
per locally adopted guidelines, these should be performed. 
b. If UC diagnosis precedes screening by < 12 years and the subject does not have 
documentation of a colonoscopy within 2 years prior to screening (report must be 
reviewed by investigator and included in the source documents). 
c. If there is no documented pathology report from prior endoscopy showing chronic 
colitis or other signs of UC. In this case, consideration should be made to do 
biopsies during the screening endoscopy with histology sent locally to confirm 
diagnosis of UC, if there is doubt of diagnosis 
If chromoendoscopy has to be performed or ≥ 10 biopsies are to be collected for 
dysplasia surveillance, either should be done after completion of a full colonoscopy to 
avoid chromoendoscopy dye or biopsy-related bleeding artifact from interfering with 
endoscopic images for central reading. 
4. Has moderately-to-severely active UC, defined as having  
a. a centrally read Mayo endoscopic sub score of ≥ 2 points based on the results of 
the Screening Stage 2 endoscopy  
AND 


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b. an adapted Mayo score between 4 and 9 points, inclusive, on Day 1. 
5. Is corticosteroid-dependent or had intolerance or inadequate response to any of the 
following: aminosalicylates, corticosteroids, immunomodulators (azathioprine or 
6-mercaptopurine), or biologics (anti-TNF, anti-integrin, or anti-IL-12/23) [Refer to 
Appendix 7].  
NOTE: For subjects in Portugal, subject must have had intolerance or inadequate 
response to biologics.  
6. If currently receiving an oral corticosteroid, subject is eligible if: 
a. the subject has been on corticosteroids for a minimum of 4 weeks prior to Day 1 
AND 
b. the dose is equivalent to or less than:  
o prednisone 25 mg/day OR 
o beclomethasone diproprionate (i.e., Clipper) at 5 mg/day OR 
o budesonide 9 mg/day  
AND 
c. the dose is stable for at least 2 weeks prior to Screening Stage 2 visit  
7. If subject is currently receiving oral aminosalicylate (e.g., mesalamine products, 
balsalazide, or sulfasalazine): subject is eligible provided the subject has been on it at a 
stable dose for ≥ 4 weeks prior to Day 1. 
8. During the Study and for 7 days after receiving the last dose of the Study drug, females of 
childbearing potential or men 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). 
9. All male subjects must agree to refrain from semen donation during the Study and for 
7 days after the last dose of Study drug. 
10. Must be able and willing to adhere to the Study visit schedule and comply with other 
protocol requirements. 
11. Are capable of providing informed consent, which must be obtained prior to any 
Study-related procedures. 
Inclusion Criteria for Extended Induction (additional 8 weeks): 
12. Did not meet criteria for clinical response by adapted Mayo score using centrally read 
endoscopic subscore at Week 8a 
Inclusion Criteria for Maintenance Study: 
13. Must have met the criteria for a clinical response by adapted Mayo score using centrally 
read endoscopic subscore during Induction at Week 8a or during Extended Induction at 
Week 16  


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4.2. 
Induction Studies and Maintenance Study Exclusion Criteria 
Subjects meeting any of the following criteria may not be enrolled in the Study: 
Gastrointestinal: 
1. Has symptoms or signs suggestive of fulminant colitis, toxic megacolon, intestinal 
perforation 
2. Has primary sclerosing cholangitis (PSC) 
3. Is likely to require surgery for UC or any other type of major surgery (i.e., surgical 
procedure requiring general anesthesia) during the Study 
4. Has had a clinically significant, as deemed by the investigator, prior intestinal 
resection for UC or for other gastrointestinal diseases (e.g., that may have resulted in 
chronic diarrhea) 
5. Has carried or carries a diagnosis of Crohn’s disease, microscopic colitis, ischemic 
colitis, radiation colitis, diverticular disease associated with colitis, or indeterminate 
colitis, or the subject has a current or past diagnosis of a fistula or abdominal abscess. 
6. Has  unresected colonic mucosal dysplasia or history of resected high-grade colonic 
dysplasia within 3 years prior to screening (Subjects with raised adenomas that have 
been completely resected or with pathology results of indefinite dysplasia with 
reactive atypia will not be excluded). 
Concomitant or previous medications received: 
7. Taken or taking any prohibited medications as listed in Appendix 6, including: 
a. Immunomodulators (azathioprine, 6-mercaptopurine [6-MP], methotrexate) 
within the 14 days prior to Day 1 
b. 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 
c. intravenous corticosteroids within the 14 days prior to Day 1 
d. rectal mesalamine or corticosteroid (i.e., enemas or suppositories) taken within 
the 14 days prior to Day 1 
e. vedolizumab, ustekinumab, mycophenolic acid, tacrolimus, sirolimus, or 
cyclosporine taken within 60 days or 5 half-lives, whichever is longer, prior to 
Day 1 
f. Any prior exposure to an approved JAK inhibitor (e.g. tofacitinib) or potential 
exposure to an experimental 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)  
g. Any prior exposure to natalizumab, rituximab, efalizumab, fingolimod, 
daclizumab cyclophosphamide, or thalidomide 


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h. 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). 
i. Anakinra, abatacept, or any other immune-modifying biologic agent taken within 
90 days prior to Day 1 
j. A JAK inhibitor (e.g., Tofacitinib) within 60 days prior to Day 1 
k. Any prior exposure to TD-1473 
Note:  For biologics specified in items b and e above, there is no requirement for a 
washout period if there is a documented finding of undetectable drug level by a 
validated assay (e.g., through commercially available testing). 
8. If subject has recently discontinued aminosalicylates or corticosteroids, these must 
have been stopped at minimum of 2 weeks before screening endoscopic procedure. 
9. Has had inadequate response (i.e., either primary or secondary non-response) to 
≥ 3 biologics of ≥ 3 different mechanisms of action (i.e., anti-TNF, anti-integrin, and 
anti-IL12/23, refer to Appendix 8). 
Note:  Up to approximately 10% of the study population can have had inadequate 
response to all 3 biologics mechanisms approved for UC, regardless of total 
number of biologics. 
10. 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 CYP450 3A4 or is a substrate of P-gp or BCRP and has a narrow 
therapeutic index (refer to Appendix 6 for Prohibited medications). 
11. Taking non-UC concomitant prescription medications that the investigator deems 
may confound the safety assessment of the study drug and that have started or have 
had a dose adjustment within 28 days prior to Day 1 (with the exception of 
corticosteroids, antibiotics for infections, sedating agents for sigmoidoscopy or 
colonoscopy, hormonal contraceptives, hormone replacement therapy, iron, vitamin 
D, insulin therapy, and replacement thyroid hormone - Refer to Appendix 6 for 
Prohibited medications). Anti-diarrheal medications and probiotics are allowed only 
if dose has been stable for minimum of 14 days prior to Day 1. 
12. Taking over-the-counter medications or dietary supplements that the investigator 
deems may confound the safety assessment of the study drug and that have started or 
have had a dose adjustment within 14 days 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 ≤ 325 mg per day for cardiovascular prophylaxis, and 
over the counter doses of vitamin D, (Refer to Appendix 6 for Prohibited 
medications). 
Infections or predisposition to infections 
13. Subject is positive for: 
a. Hepatitis B virus (HBV) surface antigen 


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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 successful completion of 
treatment regimen (reviewed by Study Medical Monitor) and b) viral load during 
Screening is undetectable 
d. Hepatitis E Immunoglobulin M (IgM) antibody 
e. Human immunodeficiency virus (HIV) antibody 
14. Subject has had a live viral vaccine (e.g., MMR, varicella zoster, herpes zoster, oral 
polio virus, FluMist®, attenuated typhoid fever vaccine, attenuated rotavirus vaccine, 
yellow fever vaccine, or any investigational live vaccine) within 4 weeks prior to 
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. 
15. 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 Stage 1 or during the Screening Period (Stage 1/Stage 2), 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. 
c. Subject who has a history of latent or active tuberculosis (TB) may be included if 
criteria outlined in Section 6.4.1.11 are met. 
Note:  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. 
16. Has any of the following: 
a. An active, clinically significant, bacterial, parasitic, fungal, mycobacterial 
(including atypical infection), or viral infection, except for local skin or nail bed 
infection, within 2 weeks prior to Day 1. 
b. Any infection requiring intravenous antibiotics within 30 days prior to screening. 
c. Any infection requiring oral antimicrobial treatment within 2 weeks prior to 
Day 1. 
d. A history of more than two episodes of herpes zoster or one or more episodes of 
disseminated/complicated herpes zoster (complicated: multi-dermatomal, 
ophthalmic, or CNS involvement or post-herpetic neuralgia) or disseminated 
herpes simplex. 
e. Has had a chest radiograph or equivalent chest imaging within 90 days prior to 
Screening or at Screening that shows an abnormality suggestive of a malignancy 
of current active infection, including TB, chronic lung disease or a potentially 
active fungal, viral, or bacterial infection. 


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f. Has C. difficile or other gastrointestinal infections (e.g., Salmonella, Shigella, 
Yersinia, Campylobacter, E. coli 0157, etc.) on stool testing or cytomegalovirus 
(CMV) colitis suspected on endoscopy within 30 days of Day 1. 
 
17. Has ever had a bone marrow transplant. 
Coexisting medical conditions or past medical history: 
18. Are pregnant, lactating, breastfeeding or planning to become pregnant during the 
Study or within 7 days after the last dose of Study Drug 
19. Has known moderate or severe hepatic impairment (e.g., Child-Pugh Class B or C) 
20. Has clinically significant abnormalities in the results of laboratory evaluations at 
screening visit as determined by the investigator, including: 
a. AST, ALT, or alkaline phosphatase ≥ 2x the upper limit of normal (ULN) 
b. Total bilirubin > 2x ULN (unless diagnosis of Gilbert’s syndrome) 
c. Creatinine clearance as calculated by the Cockcroft-Gault formula < 30 mL/min 
(Refer to Appendix 2) 
d. Total white blood cell count (WBC) < 3 x 109/L 
e. Absolute neutrophil count < 1.5 x 109/L 
f. Absolute lymphocyte count < 0.8 x 109/L 
g. Hemoglobin < 8 g/dL, or 
h. Platelet count < 100 x 109/L. 
21. Has a clinically significant abnormal electrocardiogram (ECG) at screening, including 
QTcF > 450 msec for males and > 470 msec for females. 
22. 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 UC), genitourinary, psychiatric, oncologic or neurological disease or other 
medical disorder that would compromise subject safety or confound Study safety 
assessment 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. 
23. Has known hypersensitivity to excipients or contents of the Study drug 
24. 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). 
25. Have or has a history of alcohol or drug abuse within 1 year of screening, per the 
judgment of the investigator. 
26. Has a current, or history of, malignancy requiring radiation or pharmacologic 
treatment within 5 years prior to screening, except for completely resected basal cell 


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carcinoma or squamous cell carcinoma of the skin without recurrence for ≥1 year, 
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. 
27. Is deemed by the investigator to be inappropriate for this Study; or has any condition 
which would confound or interfere with the evaluation of the safety, tolerability, or 
PK of the investigational drug; or is unable or unwilling to comply with the Study 
protocol. 
Exclusion Criteria for Phase 3 Maintenance Study 
28. Subjects who required change of UC medications (such as initiated or increased oral 
corticosteroid dose or initiated rectal aminosalicylates or corticosteroids) or any 
prohibited medication to control UC symptoms during Induction Study 
Exclusion Criterion for Induction Study Related to SARS-CoV-2 
29. Within 4 weeks of screening or during screening, has [1] confirmed severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 
2019 [COVID-19]) (test positive), OR [2] suspected SARS-CoV-2 infection (clinical 
features without documented test results) unless has a negative test for SARS-CoV-2 
two weeks after resolution of symptoms and remains asymptomatic until Day 1, OR 
[3] close contact with a person with known or suspected SARS-CoV-2 infection 
unless has a negative test for SARS-CoV-2 two weeks after contact and remains 
asymptomatic until Day 1. 
4.3. 
Women of Childbearing Potential (WOCBP) and Acceptable Birth 
Controls 
Women of childbearing potential must have documentation of a negative pregnancy test at 
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 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 post-menopausal females only 
to confirm post-menopausal state. 
Highly effective birth control methods are defined as methods that can achieve a failure rate of 
less than 1% per year when used consistently and correctly. Such methods include: combined 
(estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral/intravaginal/transdermal); progestogen-only hormonal contraception associated 
with inhibition of ovulation (oral/injectable/implantable); intrauterine device; intrauterine 


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hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; sexual 
abstinence (if this is in line with the preferred and usual lifestyle). Vasectomised partner is a 
highly effective birth control method provided that partner is the sole sexual partner of the 
WOCBP trial participant and that the vasectomised partner has received medical assessment of 
the surgical success. Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments. More restrictive methods of birth control may be required as per local country 
requirements, and this will be defined in the IRB/IEC approved subject informed consent form.  




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Extended Induction 
Subjects who do not demonstrate clinical response at Week 8 will receive an additional 8 weeks 
of treatment with active drug staying on the same dose as the first 8 weeks, except those who had 
received placebo during the first 8 weeks will now receive TD-1473 at 80 mg. This portion of the 
Induction Study will not be placebo-controlled but blinding as to the specific dose of TD-1473 
will be maintained. Those who demonstrate clinical response at the end of Week 16 will enter 
the Maintenance Study; those who do not demonstrate clinical response at Week 16 will have an 
EOS visit and exit the study. 
Subjects will be instructed not to take their Study drug in the morning of the Week 8b visit since 
Study drug administration of the extended induction regimen will be in-clinic at Week 8b and 
Week 16. Subjects will continue to complete a daily diary to record UC symptoms and Study 
drug administration. Subjects will be instructed to continue dosing beyond Week 16 until they 
return for the mWeek 0 visit if they are deemed to have achieved clinical response from the 
Week 16 adapted Mayo score or until they are deemed not achieved clinical response, in which 
case, Study drug administration should stop. 
5.2.1.2. 
Maintenance Study 
The subject will be continued on their Induction Study drug assignment in a blinded manner or 
re-randomized to receive placebo or one of the TD-1473 doses at mWeek 0. During the 
Maintenance Study, subjects will take TD-1473 dose once daily for up to 44 weeks. 
Study drug administration will be in-clinic as per Table 2 Schedule of Procedures. On all other 
Study days, subjects will self-administer their Study drug at home. Subjects will continue to 
complete a daily diary to record UC symptoms and Study drug administration. 
5.2.2. 
Placebo 
5.2.2.1. 
Induction Studies 
Subjects will take placebo once daily for up to 8 weeks. Study drug will be self-administered 
orally in the morning. Subjects will be instructed to take two tablets once daily at approximately 
the same time each morning. 
With the exception of clinic visit days noted in the Table 1 Schedule of Procedures, subjects will 
be instructed to take two tablets once daily at approximately the same time each morning  
Subjects will be instructed to continue dosing beyond Week 8 before they return for either a 
Week 8b visit or maintenance Week 0 visit depending on whether clinical response was achieved 
according to the Week 8 adapted Mayo score. Subjects will continue to complete a daily diary to 
record UC symptoms and Study drug administration. 
5.2.2.2. 
Maintenance Study 
Subjects will be randomized or re-randomized to receive placebo or one of the TD-1473 doses at 
mWeek 0. If the subject is deemed to have experienced a clinical response by the same criteria at 
the end of Induction but had received placebo during Induction, the subject will continue on 
placebo during the Maintenance phase. 


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Study drug administration will be in-clinic as per Table 2 Schedule of Procedure for the purpose 
of collecting pre-dose and post-dose PK samples. On all other Study days, subjects will 
self-administer their Study drug at home. Subjects will continue to complete a daily diary to 
record UC symptoms and Study drug administration. 
Instructions will be provided to the subject to take two tablets once daily at approximately the 
same time each morning. 
5.3. 
Treatment Compliance 
Compliance will be assessed in subjects when accountability is performed at visits where study 
drug is dispensed to or returned by subjects. Treatment compliance will be assessed by 
reconciliation of used and unused tablets. 
The subjects’ diary entries will also be reviewed at applicable study visits to assess compliance 
with study drug administration per documentation of the daily dosing times. 
Subjects with poor dosing compliance (i.e., < 80% or ≥ 120%), as assessed by tablet counts, 
should receive counseling or assistance, and re-training as appropriate. 
5.4. 
Missed Dose(s) 
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 normal dosing time. If the subject does not take the Study drug 
within 12 hours after the usual time each day, the dose of Study drug should be skipped for that 
day and the subject should be instructed to take the Study drug on the following day at the usual 
time. 
5.5. 
Drug Accountability and Reconciliation 
The investigator or designee is responsible for maintaining accountability records for all Study 
drug(s) received from the Sponsor, in accordance with applicable government regulations and 
Study procedures. The accountability record for Study medication (TD-1473 and placebo) will 
be maintained in a secure location, accessible only to authorized staff members. The 
accountability record will include entries for receipt, distribution or dispensing, and destruction 
of the material(s). 
Subjects will be instructed to return all used and unused Study medication at each applicable 
study visit as detailed in the Schedule of Study Procedures. 
Unused and expired Study drug will be disposed of in accordance with written instructions from 
the Sponsor. Drug accountability is maintained in the Randomization and Trial supply 
management system (RTSM), managed by RTSM supplier.  


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6. 
STUDY PROCEDURES 
6.1. 
Schedule of Study Procedures 
Study procedures will be performed only after written informed consent is obtained. A subject is 
considered to be enrolled once the informed consent has been signed. 
The Screening Induction visits (i.e., Stage 1 and Stage 2) will be performed within 28 days 
before dosing. One repeat Screening Stage 1 visit is allowed for each subject per the 
investigator’s discretion. If the subject does not begin the Day 1 Induction treatment following 
this 28-day window, all 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 with approval from the Sponsor. 
The schedule of Study procedures is summarized in Table 1, Table 2, and Table 3. 
Additional safety tests (beyond those required per protocol), such as vital signs (BP, heart rate, 
respiratory rate, and body temperature), physical exams, ECGs, and laboratory safety tests, may 
be obtained during the course of the Study as clinically indicated 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, FSH (if applicable), 
, 
QuantiFERON®-TB Gold test, PK, biomarker assessments, and genetic testing (if applicable) is 
approximately: 148 mL in the Induction Study (8 weeks); an additional 114 mL if subject 
participates in the Extended Induction (additional 8 weeks); and 210 mL if subject participates in 
the Maintenance Study (48 weeks with EOS visit). Additional samples may be drawn for safety 
laboratory testing as considered necessary by the investigator. 
6.3. 
Procedures by Visit 
6.3.1. 
Induction Study – Screening Stage 1 
Screening Stage 1 visit assessments will be performed between 28 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 schedule of Study procedures is summarized in Table 1. 
6.3.2. 
Induction Study – 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. The Screening Stage 2 
endoscopy should be performed at least 5 calendar days prior to Day 1 randomization to enable 
results from the central reader to be obtained and reviewed and for at least 3 days of symptoms 
starting 2 days after the Screening Stage 2 endoscopy to be recorded for Day 1 Mayo score 
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Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
Screening Stage 2 visit to ensure a minimum 8-hour fast prior to the fasted blood sample 
collection. 
The schedule of Study procedures is summarized in Table 1. 
6.3.3. 
Induction Study – Day 1 
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. 
The schedule of Study procedures is summarized in Table 1. 
6.3.4. 
Induction Study – Week 2 
Subjects will return to the clinic at Induction Week 2 for completion of assessments.  
The schedule of Study procedures is summarized in Table 1. 
6.3.5. 
Induction Study – Week 4 
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 schedule of Study procedures is summarized in Table 1. 
6.3.6. 
Induction Study – Week 8a 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
Week 8a visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
The schedule of Study procedures is summarized in Table 1 and Table 2. 
If a subject is deemed to have experienced a clinical response (Refer to 
DEFINITION OF TERMS) at Induction Week 8a and was on active drug (TD-1473), the subject 
will be re-randomized to receive placebo or one of the TD-1473 doses during Maintenance. If the 
subject is deemed to have experienced a clinical response at Induction Week 8a but had received 
placebo during Induction, the subject will continue on placebo during the Maintenance phase. If 
the subject does not demonstrate clinical response at Week 8a, the subject will continue in the 
Extended Induction Phase for another 8 weeks, during which time, the subject will be 
administered TD-1473. Study treatment will remain blinded (Refer to Section 3.5.1). 
6.3.7. 
Extended Induction – Week 12 and Week 16 (only for subjects who do not 
demonstrate clinical response to Induction at Week 8) 
The schedule of Study procedures is summarized in Table 1. 
6.3.8. 
Maintenance Study – mWeek 0 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
mWeek 0 visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 


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The schedule of Study procedures is summarized in Table 2. Regardless of Study drug treatment 
assignment during Maintenance, subjects must start tapering corticosteroids using the regimen 
recommended in the protocol at mWeek 0 (Refer to Section 6.5.3). 
6.3.9. 
Maintenance Study – mWeek 4 and mWeek 36 
The schedule of Study procedures is summarized in Table 2. 
6.3.10. 
Maintenance Study – mWeek 12 to mWeek 28 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
The schedule of Study procedures is summarized in Table 2. 
6.3.11. 
Maintenance Study – mWeek 44 
Subjects should be instructed to fast from food and non-clear fluids on the evening prior to the 
visit to ensure a minimum 8-hour fast prior to the fasted blood sample collection. 
The schedule of Study procedures is summarized in Table 2. 
6.3.12. 
Clinical Flare Assessment 
During the Maintenance Study, ongoing assessments for Clinical Flare using the partial Mayo 
score will be conducted at each scheduled visit. Subjects will also be encouraged to contact the 
study site in between scheduled visits if the subject notes an increase in stool frequency or rectal 
bleeding. 
Subjects who meet the following criteria during the Maintenance Study will be considered to 
have a Clinical Flare: 
• an increase from Maintenance baseline in the partial Mayo score of ≥ 3 points 
with an absolute partial Mayo score ≥ 4; OR 
• an absolute partial Mayo score ≥ 7 points. 
If increased symptoms are reported outside of a scheduled visit (Table 2), a Clinical Flare 
Assessment (CFA) Visit 1 will be conducted within 14 days of the subject’s reporting of 
increased stool frequency and/or rectal bleeding (Table 3). If increased symptoms are reported or 
found during a scheduled visit, Clinical Flare assessment will be conducted as part of the 
scheduled visit and any assessment that must be done at CFA Visit 1 (Table 3) and not 
performed yet for the scheduled Maintenance Study visit, should be performed (Table 3). 
The schedule for Clinical Flare Assessment visits is summarized in Table 3. 
Note: since each full CFA cycle takes 8 weeks to complete, subjects with increased symptoms 
after mWeek36 (i.e., those who have <8 weeks of the Maintenance Study left) do not undergo 
evaluation through the CFA algorithm. In these cases, it will be up to the investigator to 
determine whether the increased symptoms are due to a UC exacerbation and to decide whether 
to use rescue medication. If such a subject completes the Maintenance Study, then the subject 
may be eligible to enter the LTS Study. 


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Clinical Flare Assessment Visit 1: 
This could be at a scheduled visit or conducted within 14 days after the subject contacts the site 
reporting increasing symptoms. The schedule for Clinical Flare Assessment visits is summarized 
in Table 3. Partial Mayo scores should be calculated with the PGA from this visit. At this visit, 
the Investigator should also assess whether there may be other etiologies for increased symptoms 
(infection, change in diet, etc.). The subject will continue on study drug during this time unless 
they meet criteria defined in Section 6.6.1. 
These are the subjects who should undergo an endoscopy (CFA Visit 2) after CFA Visit 1 to 
assess the Mayo endoscopy subscore: 
a) meet the criteria for Clinical Flare at CFA Visit 1 
b) have no other obvious etiology for increased symptoms 
c) are in Clinical Flare for the first time or have flared previously but had an adapted Mayo 
Score at CFA visit 2 that did not meet the criteria for loss of response 
[Refer to DEFINITION OF TERMS].  
Note, those who decline endoscopy (CFA Visit 2) during the first flare are not eligible for the 
LTS Study (unless they complete the mWeek 44 visit of the Maintenance Study [i.e., have 
endoscopic assessment of disease activity at the end of the study]) and should not undergo 
endoscopy on any subsequent episode of clinical flares. These subjects would be considered to 
have had presumed (and not documented) loss of response, and are able to start rescue 
medication if the investigator deems this to be appropriate. 
Rescue medications should not be withheld if, in the opinion of the investigator, failure to 
prescribe them would compromise subject safety while waiting for their endoscopy subscore.  
Permitted rescue medication (Refer to Section 6.5.2 Permitted Medication) includes 
corticosteroids and aminosalicylates; although initiation in a subject who did not enter the 
Induction Study on corticosteroids or increase above baseline dose may trigger treatment failure 
definition (Refer to Section 8.9). Other immune-modulating agents are prohibited medications.  
• If the subject initiates a permitted rescue medication, the subject will continue to attend 
clinic as specified in the Schedule of Study procedures summarized in Table 2.  
• If the subject initiates a prohibited medication (Appendix 6), the subject will discontinue 
treatment with study medication.  
Clinical Flare Assessment Visit 2 (Endoscopy Visit): 
CFA Visit 2 will be conducted on or within 14 days after CFA Visit 1. A subject who declines to 
undergo an endoscopy or who is not required to undergo an endoscopy will skip the CFA Visit 2 
but still proceed to have CFA Visit 3 to be assessed for improvement by partial Mayo score 
8 weeks after the initial flare (CFA Visit 1). Subjects who are supposed to undergo endoscopy 
during the first clinical flare visit but decline the procedure will be presumed, but not 
documented, to be in loss of response and will not be eligible for the LTS study (unless they 
complete the mWeek 44 visit of the Maintenance Study [i.e., have endoscopic assessment of 


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disease activity at the end of the study]). Subjects who have met Clinical Flare criteria previously 
but declined an endoscopy (and therefore had presumed but not documented loss of response) 
should not undergo endoscopy with subsequent flares. Note: if documented loss of response is 
not confirmed following the endoscopy at CFA Visit 2, the endoscopy will need to be completed 
at subsequent CFA Visit 2, until loss of response is confirmed. 
After endoscopy, the adapted Mayo score at CFA Visit 2 should be calculated as the sum of the 
rectal bleeding and stool frequency subscores obtained at the assessment for Clinical Flare 
(CFA Visit 1 or a scheduled visit) and the Mayo endoscopy subscore at CFA Visit 2. This 
adapted Mayo Score will then be compared with the Induction Study baseline adapted Mayo 
Score (at Day 1) to determine whether the subject is still in clinical response, and if not, then the 
subject has met criteria for loss of response. 
Subjects should continue on study drug after meeting Clinical Flare criteria and while waiting for 
their endoscopy subscore. However, rescue medications (Refer to Section 6.5.2 Permitted 
Medication) should not be withheld if, in the opinion of the investigator, failure to prescribe 
them would compromise subject safety while waiting for their endoscopy subscore. Otherwise, 
subjects with a Clinical Flare are eligible for rescue medication only if they meet the criteria for 
loss of response. Unless the subject initiates a prohibited medication, the subject stays on study 
drug and return for CFA Visit 3. 
The addition of a corticosteroid or oral aminosalicylate or an increase in corticosteroid or oral 
aminosalicylate dose at or above the dose received at Maintenance Study baseline for subjects 
who lose clinical response will be considered a permitted rescue medication (refer to 
Section 6.5). Use of a prohibited medication (e.g., initiation of an immunomodulator, another 
JAK inhibitor or biologics, refer to Appendix 6) requires the subject to discontinue study drug 
and be withdrawn from the Phase 3 Maintenance Study after an EOS visit. 
Clinical Flare Assessment Visit 3: 
At CFA Visit 3, which is to occur approximately 8 weeks after the CFA Visit 1 if the subject has 
presumed or documented loss of response, subject will be assessed for improvement to stay in 
the study. During this 8-week interval between CFA Visits 1 and 3, Clinical Flare criteria will 
not be assessed again, including during regularly scheduled visits. Subjects who have not 
demonstrated improvement (i.e., subjects who have not achieved a decrease from partial Mayo 
score at CFA Visit 1 by ≥2) at CFA Visit 3 will be discontinued from study drug administration. 
If they do not enroll into the LTS study, they should return for an End of Study Visit 4 weeks 
after their last study drug dose. Subjects who are assessed as having shown improvement (i.e., 
have decreased the partial Mayo score by ≥ 2 since CFA Visit 1) will continue in the study on 
study drug. 
After the CFA Visit 3, subjects who remain in the study will continue with the regularly 
scheduled visits and continue to be assessed for recurrence of Clinical Flare during the rest of the 
Maintenance Study using the criteria based on the partial Mayo score. 
Repeated Clinical Flares: 
Once subjects meet criteria for loss of response, they will not undergo another endoscopy 
(i.e., CFA Visit 2) if they subsequently meet the criteria for Clinical Flare. Thus, subjects should 


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undergo endoscopy only once during all series of CFA visits if that endoscopic subscore leads to 
an adapted Mayo Score meeting criteria for loss of response. However, if the endoscopic 
subscore results in an adapted Mayo Score not meeting criteria for loss of response, the subject 
should undergo another endoscopy at a subsequent flare to assess for loss of response. If subjects 
decline an endoscopy at the initial clinical flare, then the subject has presumed loss of response 
and should not undergo endoscopy at any subsequent clinical flares and will not be eligible for 
the LTS study (unless they complete the mWeek 44 visit of the Maintenance Study [i.e., have 
endoscopic assessment of disease activity at the end of the study]). 
Subjects who meet criteria for documented loss of response or have presumed loss of response 
(due to lack of endoscopy) previously will be eligible to receive permitted rescue medication as 
noted above at the time of any subsequent Clinical Flares and be assessed for partial Mayo score 
improvement approximately 8 weeks after the visit at which Clinical Flare was assessed and 
managed. A subject who meets the criteria of Clinical Flare on a second occasion after meeting 
loss of response during the Maintenance Study will be discontinued from study drug 
administration and may be eligible for the LTS study. If they do not enroll into the separate LTS 
study, they will be required to complete an EOS Visit. 
The schedule for Clinical Flare Assessment visits is summarized in Table 3. 
6.3.13. 
Early Study Drug Discontinuation 
Subjects who prematurely discontinue the Study drug due to AEs, lack of response or any other 
reason besides withdrawal of consent during the Phase Induction Studies or Maintenance Study 
will be asked to return for an Early Study Drug Discontinuation visit. This visit will be 
conducted within 5 days after the last dose of Study drug. Subjects will also return for the End of 
Study visit for collection of safety data and assessment of disease activity. 
The Schedule of Study Procedures is summarized in Table 1 and Table 2. 
6.3.14. 
End of Study (EOS) 
An EOS visit will be required for all subjects 4 weeks following their last dose of Study drug 
unless the subject is rolling over into the LTS Study. Subjects who complete an Early Study 
Drug Discontinuation visit during the Phase 2b/ Phase 3 Induction Studies or Phase 3 
Maintenance Study 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 schedule of Study procedures is summarized in Table 1 and Table 2. 
6.4. 
Description of Study Assessments 
6.4.1. 
Demographic and Baseline Assessments 
6.4.1.1. 
Informed Consent, Demographics, and Inclusion/Exclusion Criteria 
Written informed consent must be obtained, signed, and dated after the nature of the Study has 
been explained to the subject and before any Study procedure is performed. 


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Demographic information to be collected will include: year of birth, gender, race, and ethnicity, 
as allowed per local regulations. 
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 of the 
inclusion and none of the exclusion criteria. 
6.4.1.2. 
Medication History 
All non-UC and UC medications (i.e., prescription and over-the-counter medications, herbals, 
vitamins, and supplements) used within 60 days of the screening visit will be recorded. Subjects 
should be asked at screening as to whether, since diagnosis, they ever had been or are currently 
on aminosalicylates, immunomodulators, corticosteroids, anti-TNF therapy (how many TNF 
inhibitors and reason for stopping), vedolizumab, ustekinumab, or alternative therapies, the 
names, duration of use of such therapies, and the reasons for discontinuation (lack of efficacy, 
loss of efficacy, intolerance, or other, where applicable) and should be recorded. Subject’s 
medication history including the name of medication, date started (at minimum, the year) and 
stopped (at minimum, the year), route of administration, indication, dose and reason for stopping 
(if applicable) should be recorded. Please refer to inclusion/exclusion criteria Section 4 and 
Appendix 6 for Prohibited medications. 
6.4.1.3. 
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 UC, the years since diagnosis and extent of disease 
(categorized as proctosigmoiditis, left sided, extensive or pancolitis) should be documented. 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 UC) should be recorded. This will be used to 
calculate the stool frequency subscore. 
6.4.1.4. 
Smoking Status 
Subject’s current use of tobacco, number of years used, and annual pack years used will be 
obtained according to the Schedule of Study Procedures (Table 1). 
6.4.1.5. 
Height Measurements 
Height measurement (in cm and without shoes) will be obtained at screening. 
6.4.1.6. 
Body Weight 
Weight measurement (in kg and without shoes) will be obtained according to the Schedule of 
Study Procedures (Table 1 and Table 2). 


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6.4.1.7. 
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, Table 2, 
and Table 3). 
Blood pressure and heart rate will be measured after the subject has been resting for at least 
5 minutes in the seated or supine position. Subject position, measurement device, and arm 
(left vs. right) should be kept consistent throughout the Study. Blood pressure will be measured 
using a manual or automatic blood pressure device. Heart rate will be recorded by palpation of 
the radial pulse over at least a 30-second period or by the automated blood pressure device. 
Body temperature will be measured and reported in degrees Celsius. The method used to collect 
temperature needs to be consistent throughout the subject’s participation. 
Any vital sign outside the normal range may be repeated at the discretion of the investigator. The 
vital sign measurements (BP and HR) should be performed after the subject has rested 
sufficiently as determined by the appropriate site staff. Collection of additional vital sign 
measurements for routine safety monitoring at additional time points or Study days may be 
performed at the discretion of the investigator, or upon request by the Sponsor. 
6.4.1.8. 
12-Lead Electrocardiograms 
Interpretable ECG recordings (e.g., without artifacts) will be obtained according to the Schedule 
of Study Procedures (Table 1 and Table 2). Twelve-lead safety ECGs will be collected in singlet 
at each scheduled time point. 
ECGs must be performed after the subject has been resting in a supine position for at least 
10 minutes. 
For monitoring purposes, the investigator must review, provide interpretation for ECG 
recordings other than sinus rhythm on the ECG tracing, sign, and date all safety ECG tracings. 
Paper copies of ECG tracings will be kept as part of the subject's Study file at the site. 
If at a particular post dose time point, the QTcF is > 500 msec and/or 60 msec longer than the 
value at screening or Day 1 or the mean QRS interval is > 130 msec, the investigator should 
consider study drug discontinuation if the investigator deems this finding to be clinically 
significant and poses a safety risk for the subject. The investigator should also consider 
evaluating the subject for potential concurrent risk factors (e.g., electrolyte abnormalities, 
concomitant medications known to prolong the QT interval, severe bradycardia). 
Results from a plasma TD-1473 exposure-QTc analysis of data obtained from the SAD and 
MAD Study in healthy subjects and preclinical data were used in considering the frequency and 
replicate ECGs required for this Study  
6.4.1.9. 
Physical Examination 
The physical examination will be performed by a physician, nurse practitioner, physician’s 
assistant, or equivalent, according to local practice standards, at each scheduled time point as 
specified in the Schedule of Study Procedures (Table 1, Table 2, and Table 3). 


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Completion of additional physical examinations for routine safety monitoring at additional time 
points or Study days may be performed at the discretion of the investigator, or upon request by 
the Sponsor. A physical exam of the organ system associated with any reported AE, even if 
resolved, should be performed at subsequent Study visits. 
6.4.1.10. Chest X-ray or equivalent imaging 
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 the investigator. Posterior anterior (PA) 
and lateral views (lateral view may not be necessary if PA view is deemed adequate by the 
investigator) will be obtained. Subjects who have had a chest X-ray or equivalent chest imaging 
within 90 days prior to screening will not require a repeat X-ray unless subject is deemed to be at 
high risk of recent pulmonary infection. 
6.4.1.11. Tuberculosis (TB) Test 
History of latent or signs of latent TB: 
Subjects with a history of latent TB or signs of latent TB on chest X-ray or equivalent chest 
imaging 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 for countries where TB is 
endemic) 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. 
Subjects 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. 
History of active TB: 
Subjects with a history of active TB may be eligible for the Study if: 
a. He or she has completed an adequate course of treatment within 5 years (3 years for 
countries where TB is endemic) prior to Screening (the documentation for which 
must be included in the source document and reviewed by the PI) 
b. The QuantiFERON®-TB Gold within 90 days of screening is negative, and  
c. The subject has not lived in a region with high prevalence of multidrug-resistant TB 
d. Has a benign chest X-ray within 90 days of screening 


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All subjects no matter status of TB: 
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 of 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, then the subject should be excluded and considered a 
Screen Failure. 
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. 
6.4.1.12. Concomitant Medications 
All concomitant non-UC and UC 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. Doses of non-UC 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. 
Refer to Section 6.5 for further details. 
6.4.1.13. Adverse Events (AEs) 
Adverse events, including serious adverse events (SAEs) and adverse events of special interest 
(AESI) will be reviewed and recorded following the time the subject signed the Informed 
Consent Form through the follow-up visit. AEs may be observed by the site Study personnel or 
spontaneously reported by the subject or reported in response to standard questions from site 
Study personnel. Subjects will be reminded to call the site to report AEs that occur between 
visits. Refer to Section 7.1.4 for definition, assessment, and reporting of AEs. 
6.4.1.14. Pregnancy Test (females of child-bearing potential only) 
Urine b-hCG testing will be performed during specified visits, as listed in the Schedule of Study 
Procedures (Table 1 and Table 2), before study drug dosing, on females of childbearing potential 
to confirm the absence of pregnancy. Serum b-hCG testing must be done at Screening. If the 


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urine b-hCG test is positive, a serum b-hCG test must be performed. The pregnancy test must be 
confirmed negative for a subject to be eligible for this Study unless the PI deems the test is 
falsely positive. 
Detailed instructions and collection kits for sample collection, handling, and shipping will be 
provided by the central laboratory. 
6.4.1.15. Follicle-Stimulating Hormone (FSH) 
Follicle-stimulating hormone (FSH) will be tested at screening in post-menopausal females only 
to confirm post-menopausal state. FSH will be performed as specified in Schedule of Study 
Procedures (Table 1) 
6.4.1.16. Chemistry, Hematology, and Urinalysis 
Laboratory assessments will be performed as specified in Schedule of Study Procedures 
(Table 1, Table 2, and Table 3). 
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. One 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. 
6.4.1.17. 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 and Table 2). 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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6.4.3. 
Pharmacokinetic and Pharmacodynamics Assessments 
A sparse PK sampling strategy is being employed in this Study where random samples will be 
taken at select Study visits both immediately prior to treatment with Study drug and during 
treatment with Study drug; time of Study drug ingestion needs to be carefully documented the 
day before and the day of each Study visit where PK samples will be collected. 
Disease-related surrogate markers (e.g., 
) will be 
assessed. Other disease-related biomarkers may be assessed. 
Whole blood, serum, and plasma samples will be collected and stored for potential future 
additional biomarker profiling. 
6.4.4. 
Safety Assessments 
Subject safety will be assessed throughout the Study using standard measures, including vital 
signs, 12-lead ECGs, blood and urine safety laboratory tests, physical examinations, concomitant 
medication usage, and adverse event (AE) monitoring. These will be collected from all subjects 
at visits as indicated in Table 1, Table 2, and Table 3. 
6.4.4.1. 
Adverse Events 
Refer to Section 6.4.1.13 
6.4.4.2. 
Medical History 
Refer to Section 6.4.1.3 
6.4.4.3. 
Physical Examination 
Refer to Section 6.4.1.9 
6.4.4.4. 
Vital Signs 
Refer to Section 6.4.1.7 
6.4.4.5. 
Laboratory Tests 
Refer to Section 6.4.1 
6.5. 
Concomitant Medications 
Refer to Section 6.4.1.12 
6.5.1. 
Prohibited Medications 
Immunomodifying agents (Refer to Appendix 6) are prohibited until the End of Study visit. The 
use of any prohibited UC Medication would result in subject discontinuation as defined in 
Section 6.6.1, except for the use of rectal aminosalicylates or rectal corticosteroids for clinical 
management during clinical flare assessment (during the Maintenance Study) if there is a 
contraindication for oral corticosteroids (see Section 6.5.2). 


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The use of the following medications, which may confound the safety evaluation of the Study, 
are prohibited:  
• Any prescription drugs started or which had a dose adjustment within the 28 days prior to 
Day 1 until the day of the last dose (with the exception of hormonal contraceptives, 
hormone replacement therapy, vitamin D, insulin therapy, iron, corticosteroid [see 
below], and replacement thyroid hormone) unless deemed by the investigator to be 
medically necessary and unlikely to confound the efficacy assessment of Study drug. 
New medications that may confound the efficacy assessment may be considered with 
Sponsor approval on an individual basis. 
• Any initiation or dose adjustment of over-the-counter medications including herbals, 
vitamins, or supplements within 14 days prior to Day 1 until the day of the last Study 
dose, unless deemed unlikely to confound safety assessment of Study drug by the 
investigator. New medications that may confound the efficacy assessment may be 
considered with Sponsor approval on an individual basis. 
• Strong P-gp, BCRP and/or CYP3A4 inhibitors and inducers. This exclusion applies to 
concomitant medications, herbal supplements and ordinary dietary intake. The package 
insert, FDA website, and clinical judgment may be used to assess the potential of 
concomitant medications to interact with Study Drug. Refer to Appendix 6 Prohibited 
Medications. For clarity: 
• Any amount of grapefruit in the diet is prohibited; 
• Curcumin is prohibited as a concentrated supplement, but dietary intake is 
allowed; 
• Corticosteroids at doses not excluded elsewhere in the protocol are not considered 
strong CYP3A4/P-gp/BCRP inducers. 
• Subject must avoid live viral vaccines (e.g., MMR, varicella zoster, herpes zoster, oral 
polio virus, FluMist®, attenuated typhoid fever vaccine, attenuated rotavirus vaccine, 
yellow fever vaccine, or any investigational live vaccine) during the Study and for 
8 weeks following completion of the Study. Subject must be willing to avoid close 
contact with any household member who has been vaccinated with a live attenuated 
vaccine within 2 weeks after vaccination. 
6.5.2. 
Permitted Medications 
Permitted medications include, but are not limited to: 
• Oral corticosteroids for UC are allowed during either the Phase 2b or the Phase 3 
Induction Study but need to stay at a stable dose until Week 8. Note that steroid 
tapering during Induction is discouraged unless medically necessary. During extended 
induction, the subjects may, but are not required to, taper corticosteroids according to 
the regimen suggested below in Section 6.5.3. Reductions or increases in doses 
during the Maintenance Study are permitted as defined in Section 6.5.3. 
Corticosteroids are permitted rescue medications. 


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• Oral corticosteroids for non-UC indications are allowed, if medically necessary, after 
discussion with the Sponsor. The dose should, but does not need to, be tapered as 
outlined in Section 6.5.3. 
• Doses of oral aminosalicylate, probiotics, or antibiotics prescribed for UC should be 
stable during the Phase 2b Induction/Phase 3 Induction Studies and Phase 3 
Maintenance Study. However, they can be discontinued or undergo dose adjustment 
if the investigator deems their use has resulted in adverse effects. Oral 
aminosalicylates are also permitted rescue medications. 
• Rectal aminosalicylates or rectal corticosteroids for clinical management during 
clinical flare assessment (during the Maintenance Study) if there is a contraindication 
for oral corticosteroids.  If these are to be used, the best effort should be made to taper 
or stop these as soon as possible and before mWeek 40, if possible. 
• Anti-diarrheal agents, which can be tapered or stopped if symptoms are improved 
during the Study; however, it is encouraged to continue at the same dose of 
anti-diarrheal medications throughout all studies. The addition of anti-diarrheal 
agents, although allowed, should be discouraged during the study if subject was not 
on an anti-diarrheal agent upon enrollment into the Induction Study. 
• Sedating medications for endoscopy are permitted 
• Antibiotics for infections 
• Addition of, cessation of, or dose adjustments for the following are allowed during 
Screening or any other time during the study: 
a. Hormonal therapy for post-menopausal females 
b. Oral contraception for women of child-bearing potential 
c. NSAIDs taken on a regular (≤ 3 times per week, on average) basis 
d. Aspirin for cardioprotection is permitted at a maximum dose of 
325 mg/day 
e. Vitamin D 
f. Insulin therapy 
g. Replacement thyroid hormone, 
h. Iron, if investigator deems this is medically indicated 
6.5.3. 
Corticosteroid Tapering 
• Oral corticosteroids are permitted at a stable dose ≤ 25 mg/day of prednisone or 
beclomethasone diproprionate (ie, Clipper) at ≤ 5 mg/day or equivalent or ≤ 9 mg/day 
budesonide during Induction Studies (Weeks 1-8). 
• During Extended Induction, the Investigator may taper corticosteroids if he or she 
feels it is indicated, using the tapering regimen for the Maintenance Study described 
below. 
• Upon entering the Phase 3 Maintenance Study (mWeek 0), subjects must start 
tapering their corticosteroid dose OR where corticosteroids have been used as rescue 


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medications, tapering must begin 2 weeks after an increase in corticosteroid therapy, 
using the regimen outlined below: 
o Prednisone (or equivalent) dose should be tapered by 5 mg/day every week 
until 10 mg/day (or prednisone equivalent) and then by 2.5 mg/day every 
week (or prednisone equivalent) until completely off. 
o If subject is on budesonide or beclomethasone, then the dose should be 
tapered according to local clinical practice. 
o If subject is on corticosteroids as a rescue medication during the Maintenance 
Study, the dose may be tapered as outlined above or more quickly than 
recommended above. It is recommended, but not required, to start tapering the 
corticosteroid dose within 2 weeks after initiation or dose increase. 
6.5.4. 
Rescue Medications During Maintenance Study 
Subjects meeting loss of response definition during the Maintenance Study may initiate 
permitted rescue medications, which consist of corticosteroids and aminosalicylates. 
o An increase up to the Induction Study Day 1 corticosteroid or aminosalicylate 
dose is allowed as often as clinically indicated and subject can still stay on 
study drug. 
o Certain increases above the Maintenance Study Week 0 (which should be the 
same as Induction Study Day 1, in most cases) corticosteroid dose or initiation 
of corticosteroid without subject having been on corticosteroid upon Induction 
Study enrollment is allowed, and the subject should remain on study drug, but 
may lead to the subject meeting criteria for treatment failure (further defined 
in the statistical analysis plan). 
o Increases above baseline (the Maintenance Study Week 0, which should be 
the same as Induction Study Day 1) or new initiation of aminosalicylates are 
permitted but may lead to the subject meeting criteria for treatment failure 
(further defined in the statistical analysis plan). 
 
6.5.5. 
Restrictions on Alcohol Consumption and Illicit Drug Use 
Alcohol abuse or illicit drug abuse, per the judgment of the investigator, within 1 year of 
Screening until the EOS visit is not allowed. 
6.6. 
Discontinuation 
6.6.1. 
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. Subjects must also be 
discontinued on study drug for any AESI (except non-melanoma skin cancer, mono-dermatomal 


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herpes zoster, and certain laboratory abnormalities that are deemed by the investigator to not 
place subjects at immediate safety risk) or if the subject becomes pregnant. When possible, the 
tests and evaluations listed for the termination visit should be carried out. If a subject withdraws 
before completing the Study, the reason for withdrawal is to be documented on the CRF. 
The Sponsor will be notified of all subject withdrawals. 
Reasons for which the investigator or the Sponsor may withdraw a subject from the Phase 
2b/Phase 3 Induction Studies or Phase 3 Maintenance Study or a subject may choose to terminate 
participation before completion include the following: 
• Adverse event 
• Subject choice/Withdrawal of consent 
• Major violation of the protocol 
• Termination of the Study by the Sponsor 
• Initiation of a prohibited medication (Appendix 6) for UC (except for rectal 
aminosalicylates and rectal corticosteroids during the clinical flare assessment) 
• Lost to follow-up 
• Pregnancy 
• Colectomy 
Subjects with laboratory abnormalities as outlined in Section 7.2 (i.e., two sequential occurrences 
of renal, leukocyte, leukocyte subset, or hepatic panel abnormalities or hepatic panel 
abnormalities with clinical sign or symptom of acute liver failure) should discontinue the study 
drug. Any non-laboratory-related AE considered an AESI defined in Section 7.1.4, except for 
non-melanoma skin cancer and mono-dermatomal herpes zoster, should also lead to study drug 
discontinuation. 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. 
Subject study completion is defined as completing the last study visit whether or not the subject 
discontinued study drug prematurely. 
6.6.2. 
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. 
6.6.3. 
Study Discontinuation 
The Sponsor reserves the right to discontinue these studies at any time for any reason. 


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Periodic reviews of accumulating data by the IDMC may lead to the committee’s 
recommendation of pausing dosing or terminating the Studies. In the event of premature Study 
termination, best efforts to guarantee appropriate safety follow-up of subjects who have already 
been enrolled will be made and IRB/IEC/REBs and the Regulatory Authorities will be informed. 
6.7. 
Pregnancy 
If a female subject or the partner of a male subject becomes pregnant during the Study or within 
7 days of the subject’s last dose of Study drug, the Sponsor clinical Study director (or designee) 
must be notified immediately. If the female subject is still on Study drug treatment, the Study 
drug must be discontinued immediately. Follow-up information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant will be required. 
All pregnancies whether by the subject participating in the Study or the female partner of the 
male subject in the Study should be reported within 24 hours of awareness using the Pregnancy 
Notification Form. 


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7. 
ADVERSE EVENTS 
7.1. 
Definitions 
The definitions below are based on International Conference on Harmonization (ICH) guideline 
E2A, “Clinical Safety Data Management: Definitions and Standards for Expedited Reporting”. 
7.1.1. 
Adverse Events (AE) 
An AE 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 conduct of 
the Study, the sponsor, will be notified according to the procedures for SAE reporting as outlined 


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in Section 6.4.3. Follow-up information regarding the outcome of the pregnancy and any fetal or 
neonatal sequelae will be obtained and documented. 
7.1.2. 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is defined as any untoward medical occurrence occurring at any 
dose that results in any of the following outcomes: 
• Death 
• Life-threatening situation. “Life-threatening” refers to a situation in which the patient was 
at risk of death at the time of the event; it does not refer to an event which might have 
caused death if it were more severe. 
• Inpatient hospitalization or prolongation of existing hospitalization 
o Note: “Inpatient hospitalization” means the subject has been formally admitted to 
a hospital for medical reasons, for any length of time. This may or may not be 
overnight. It does not include presentation and care within an emergency 
department. A scheduled hospitalization for a pre-existing condition that has not 
worsened during participation in the study does not meet this criterion. 
Pre-planned hospitalizations for an elective medical/surgical procedure, scheduled 
treatments, or routine check-ups do not meet this criterion. Complications that 
occur during hospitalizations are AEs. If a complication prolongs hospitalization, 
it is an SAE. 
• Disability. A persistent or significant incapacity or substantial disruption to 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: 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in hospitalization 
o 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. 


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• “Occurring at any dose” does not imply that the subject is receiving Study drug at the 
time of the event; dosing may have been given as treatment cycles or interrupted 
temporarily before the onset of the SAE but may have contributed to the event. 
7.1.4. 
Adverse Events of Special Interest (AESI) 
At each Study visit, the Investigator (or designee) will specifically query for any adverse events 
of special interest (AESI). The following events are considered AESIs for this Study: 
• Suspected or confirmed intestinal perforation 
• Complicated herpes zoster (multi-dermatomal, disseminated, or with ophthalmic or CNS 
involvement) 
• Malignancy excluding non-melanoma skin cancer 
• Non-melanoma skin cancer 
• Serious infection (e.g., that requires hospitalization or intravenous antibiotics)  
• Opportunistic infections  
• Thromboembolic disease (e.g., DVT, pulmonary embolism) 
• Clinical laboratory abnormalities of concern (Refer to Section 7.2) 
• Major cardiovascular event (e.g., myocardial infarction or cerebrovascular accident) 
All AESIs, except for non-melanoma skin cancers and mono-dermatomal herpes zoster, must be 
reported to TBPH Clinical Safety and Pharmacovigilance within 24 hours of the time the 
Investigator or his/her designee becomes aware of an AESI (Refer to Section 7.4.3). 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 AESI’s should lead to discontinuation of the study drug. For 
each of these AESI, an additional targeted questionnaire needs to be completed to assess for risk 
factors. For thromboembolic events in particular, the subject should undergo evaluation for 
hypercoagulable state (e.g., with clinically relevant investigations, such as referral to a specialist 
and/or blood testing for a predisposition to a hypercoagulable state) and repeat imaging to assess 
resolution of the finding.  
Besides these AESI, for other AEs, study drug may be interrupted and resumed as deemed 
medically appropriate by the investigator (e.g. during an infection that requires oral antimicrobial 
treatment). 
7.2. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events 
Abnormal laboratory findings (such as clinical chemistry, hematology, or urinalysis) or other 
abnormal assessments (such as electrocardiograms [ECGs], X-rays, or vital signs) that are 
associated with signs and/or symptoms or are considered clinically significant in the judgment of 
the investigator must be recorded as AEs or SAEs if they meet the definition of an adverse event 


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(or serious adverse event), as described in Section 7.1.1 (Adverse Event) and Section 7.1.2 
(Serious Adverse Event). 
Clinical laboratory abnormalities of concern may include, but are not limited to, the following 
where the investigator must recheck within 2-7 days, except for AST or ALT > 3x ULN where 
these need to be rechecked within 48-72 hours, as deemed appropriate by the investigator: 
• clinically significant reduction in neutrophils or leukocytes or lymphocytes that may 
place subjects at higher risk for infection such as: 
o moderate or severe neutropenia (e.g., absolute neutrophil count of < 1.0 x 109/L) 
o moderate or severe leukopenia (e.g., white blood cell count of < 2.0 x 109/L) 
o moderate or severe lymphocytopenia (e.g., absolute lymphocyte count of 
< 0.5 x 109/L) 
• abnormal hepatic panel (AST or ALT > 3x ULN) 
• an excessive decrease in creatinine clearance (e.g., a reduction by ≥ 50% from baseline 
(baseline for this purpose is defined as creatinine clearance calculated for Day 1, predose 
activities) 
Depending on the subject’s baseline and individual scenario, the investigator should report as an 
AESI and stop study drug treatment if any of the below is seen: 
• moderate or severe neutropenia (e.g., absolute neutrophil count of < 1.0 x 109/L) on 
two sequential laboratory reports 
• moderate or severe leukopenia (e.g., white blood cell count of < 2.0 x 109/L) on two 
sequential laboratory reports 
• moderate or severe lymphocytopenia (e.g., absolute lymphocyte count of 
< 0.5 x 109/L) on two sequential laboratory reports 
• a reduction by ≥ 50% from baseline in creatinine clearance on two sequential 
laboratory reports 
• Abnormal AST or ALT > 3x ULN on two sequential laboratory reports with bilirubin 
> 2x ULN on at least one of the two laboratory reports or international normalized 
ratio (INR) > 1.5 on at least one of the two reports (INR will be checked locally)  
• AST or ALT > 5x ULN on two sequential laboratory reports at least 2 weeks apart 
• AST or ALT > 3x ULN 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%]) 
• AST or ALT > 8x ULN on one laboratory report 
Note:  See Appendix 10 for an algorithm of evaluating and managing subjects with ALT 
or AST > 3x ULN. 
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. 


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If there are any AE questions, the investigator is encouraged to contact the Sponsor 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. 
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 


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therapies and appears with some degree of certainty to be related based on the known 
therapeutic and pharmacologic actions of the drug. In case of cessation or reduction of 
the dose, the event abates or resolves and reappears upon rechallenge. It should be 
emphasized that ineffective treatment should not be considered as causally related in the 
context of adverse event reporting. 
7.3.3. 
Clinical Events Committee (CEC) 
A clinical events committee (CEC) has been established with external experts and will adjudicate 
thromboembolic and major cardiovascular events. If deemed necessary, the same or a different 
CEC may also be requested to adjudicate other AEs of interest (e.g., for opportunistic infections, 
herpes zoster, malignancy). To allow for unbiased assessment, the CEC will remain blinded to 
treatment assignment. A CEC charter will be drafted with descriptions of membership, the scope 
of the CEC members’ responsibilities, adjudication processes, and definitions used to review and 
assess specific AEs. 
7.4. 
AE Reporting and Recording 
7.4.1. 
AE Reporting 
Timely, accurate, and complete reporting and analysis of safety information from clinical trials is 
crucial for the protection of subjects and is mandated by regulatory agencies. Sponsor has 
established standard operating procedures in compliance with regulatory requirements 
worldwide to ensure appropriate reporting of safety information. All clinical trials sponsored by 
TBPH will be conducted in accordance with these procedures.  
7.4.2. 
AE, SAE and AESI Recording 
All AEs, regardless of seriousness, severity, or causal relationship to Study 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 




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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 or 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 or 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 
This section outlines the data summaries and analyses that will be specified in the applicable 
analysis plan and included in a CSR. A CSR statistical analysis plan (SAP) and separate PK SAP 
will be prepared and finalized by the Sponsor prior to each database lock. In addition, Biomarker 
SAPs will be prepared as required. Also, specifications will be prepared by the Independent 
Reporting Statistical Group and independent exposure-response analyst for the dose selection 
analyses and data reviews described in Section 8.10, Independent Data Monitoring Committee. 
The following formal analyses are planned: 
• Analyses of Phase 2b Induction data after all subjects have either completed the Week 8 
assessments or prematurely withdrawn from the study 
• Analyses of Phase 3 Induction data 
• Analyses of Phase 3 Maintenance data, with primary efficacy summaries restricted to 
placebo and the maintenance doses selected for continued evaluation based on the 
Induction Phase 2b dose selection analyses 
Prior to each analysis, the database for the relevant study will be cleaned and locked. 
Study Day 1 is defined as the day of the first study drug dose. The preceding day is 
Study Day -1. For the Phase 3 Maintenance Study, Study Day 1 is defined as the day of the first 
Maintenance study drug dose. 
All data for each subject will be listed as collected. All statistical summaries and analyses will be 
performed using 
. 
Quantitative data and scores (e.g., adapted Mayo score) will be summarized using an 8-point 
summary (n, mean, standard deviation [SD], median, interquartile range [25th percentile Q1, 
75th percentile Q3], minimum, and maximum) unless otherwise specified in the SAP or table 
shell. Categorical data will be summarized using counts and percentages. 
In general, baseline is the last value (scheduled or unscheduled) obtained before the start of study 
drug dosing. For efficacy endpoints, baseline for those having more than one component 
(e.g., adapted Mayo score) is calculated from the individual component baselines, whether or not 
they were assessed during the same visit, and baseline at Maintenance study entry is the value at 
the last Induction study visit (Week 8 or Week 16). 
Values that are derived from symptom diary data will be derived from the last 3 consecutive days 
for which evaluable data are available during the 7 days preceding the visit; this applies to both 
baseline and postbaseline values. If not found, values will be derived from the 3 most recent days 
for which evaluable data are available. 
Any changes to the data summaries and analyses outlined in this section will be described in the 
applicable SAP. Any major changes to primary and key secondary endpoints will be described in 
a protocol amendment. 


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8.2. 
Sample Size and Power 
It is currently estimated that approximately 880 subjects (240 for Phase 2b Induction and 640 for 
Phase 3 Induction) will be enrolled.  
The number of enrolled subjects is expected to provide at least 90% power for the primary 
endpoints of the Induction Studies and also allow a sufficient number of subjects eligible for 
re-randomization into the Phase 3 Maintenance Study because: 
1. A subset of subjects from the initial Phase 3 Maintenance study before final dose 
selection is determined will be excluded from the analysis of primary and secondary 
efficacy endpoints: i.e., the subjects assigned to doses that were not selected. 
2. Only subjects who received TD-1473 and are considered responders after 8 weeks of 
Induction therapy, including subjects who are randomized to placebo during the first 
8 weeks of Induction Therapy who demonstrate clinical response at Week 16 after 
receiving TD-1473 80 mg from Weeks 9 to 16, are eligible to be re-randomized in the 
Phase 3 Maintenance study.  
3. The average responder rate for the active treatment groups is estimated to be 60%. 
4. It is also estimated that approximately 10% of subjects who are eligible to be 
re-randomized into the Phase 3 Maintenance study will elect not to participate. 
8.2.1. 
Induction Phase 2b Sample Size Considerations 
A sample size of 60 subjects per group was estimated to give approximately 90% (89%) power 
to detect a 2-point active dose group vs. placebo improvement in total Mayo score at all three 
doses, given the following: 
• Hochberg step-up procedure adjustment for multiple comparisons, with family-wise 
type 1 error rate to be controlled at 5% (2-sided tests) 
• Residual change SD of 3 points 
The estimated power to detect a 2-point improvement relative to placebo for at least one of the 
three doses was greater than 98%. 
Assuming a slightly higher residual change SD of 3.5 points, the estimated power to detect a 
2-point active dose group vs. placebo improvement in total Mayo score at all three doses was 
approximately 73% and the estimated power to detect a 2-point improvement at one or more of 
the doses was approximately 94%. Estimates were obtained using East software, with 10,000 
simulations per case. 
Subjects will be stratified by prior biologics failure and baseline corticosteroids use at 
randomization. In addition, randomization caps will be placed on both prior biologics failure 
subgroups [no to biologics failure (60%) and yes to biologics failure (60%)] to ensure that 
neither subgroup is overrepresented.  
8.2.2. 
Induction Phase 3 Sample Size Considerations 
Upon completion of the analyses based on the Phase 2b Induction data, the sample size may be 
refined. Currently, it is estimated that 320 subjects per dose group (640 subjects total) will 


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provide at least 90% power to demonstrate TD-1473 is effective compared to placebo for the 
primary endpoint of clinical remission at Week 8 under the following assumptions: 
• Type 1 error rate of 5% (2-sided) 
• Clinical remission rate of 9.5% for placebo at Week 8 
• Clinical remission rate of 23.5% for TD-1473 at Week 8: 
It is also estimated that 320 subjects per group will provide at least 90% power to demonstrate 
TD-1473 is effective compared to placebo for the key secondary endpoints of symptomatic 
remission and endoscopic healing. 
In the case where two TD-1473 doses are selected, then 320 subjects per group will have at least 
90% disjunctive power to demonstrate at least one of the two TD-1473 doses is effective 
compared to placebo for clinical remission at Week 8 under the following assumptions: 
• Hochberg step up procedure adjustment for multiple comparisons 
• Family-wise type 1 error rate to be controlled at 5% (2-sided) 
• Clinical remission rate of 9.5% for placebo at Week 8 
• Clinical remission rate of 23.5% for more effective TD-1473 dose and 16.5% for the 
less effective TD-1473 dose 
Subjects will be stratified by prior biologics failure and baseline corticosteroids use at 
randomization. In addition, randomization caps will be placed on both prior biologics failure 
subgroups (no to biologics failure (60%) and yes to biologics failure (60%)) to ensure that 
neither subgroup is overrepresented.  
8.2.3. 
Phase 3 Maintenance Sample Size Considerations 
Upon completion of the analyses based on the Phase 2b Induction data, the sample size may be 
refined. Currently, it is estimated that 120 subjects per dose group (360 subjects total) will 
provide at least 90% disjunctive power to demonstrate at least one of the two TD-1473 doses is 
effective compared to placebo for the primary endpoint of clinical remission at Maintenance 
Week 44 under the following assumptions: 
• Hochberg step-up procedure adjustment for multiple comparisons 
• Family-wise type 1 error rate to be controlled at 5% (2-sided) 
• Clinical remission rate of 15% for placebo at Week 44 
• Clinical remission rates of 30% and 40% for the two active TD-1473 doses at 
Maintenance Week 44 
A total of 360 subjects total will provide 80% conjunctive power to demonstrate both doses of 
TD-1473 are effective compared to placebo for clinical remission at Maintenance. In addition, 
360 subjects total will also provide adequate power (at least 80%) to demonstrate that at least one 
of the two TD-1473 doses is effective compared to placebo for the key secondary endpoints of 
symptomatic remission and endoscopic healing at Maintenance Week 44. 


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It is estimated that with 880 subjects enrolled in the Induction studies, approximately 400 
subjects will be eligible for re-randomization into the Maintenance study. However, about 30 of 
these 400 subjects will be assigned to the dose that is de-selected based on the analyses of the 
Phase 2b Induction Study data and therefore not included in the primary efficacy analysis 
population of the Phase 3 Maintenance Study. In addition, approximately 170 subjects will also 
enter Maintenance and continue to receive the same treatment as assigned in the Induction study 
in order to maintain blind. These subjects will also not be included in the primary efficacy 
analysis population of the Phase 3 Maintenance Study.  
8.3. 
Analysis Sets 
8.3.1. 
Analysis Sets 
For the Phase 2b Induction study and Phase 3 Induction study, the modified Intent-to-Treat 
(mITT) analysis set will include all randomized subjects who receive at least one dose of study 
drug. For the Phase 3 Maintenance study, the mITT analysis set comprises all randomized 
subjects who receive at least one dose of study drug and are assigned to receive either placebo or 
a TD-1473 dose selected based on the Phase 2b dose selection analyses, and the Full Analysis 
Set (FAS) comprises all randomized subjects who receive at least one dose of study drug. For 
each study, the mITT set is considered the primary analysis set for efficacy analyses. 
The Per-Protocol (PP) analysis set comprises all subjects in the mITT analysis set with no major 
analysis protocol deviations (Section 8.3.3). Both the mITT and the PP analysis set will be used 
for selected efficacy summaries and analyses to be specified in the applicable SAP. In addition, 
for selected Induction Phase 2b dose-response analyses, a PP completers analysis set will be 
used. The PP completers analysis set comprises all subjects enrolled in the Induction Phase 2b 
Study with no major analysis protocol deviations and non-missing total Mayo score at Week 8. 
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 general (baseline, exposure, and compliance) and 
safety analyses. 
The PK analysis set will include all subjects in the Safety analysis set with at least one evaluable 
postbaseline TD-1473 PK measurement who are adherent to the protocol. Subjects may be 
excluded from the PK analysis set if they deviate significantly from the protocol or if the data are 
unavailable or incomplete, which may influence the PK analysis. The PK analysis set will be 
further defined in the PK SAP. 
Except for the PK analysis set, which is restricted to subjects who received TD-1473, 
membership in each analysis set will be determined prior to database lock. Analyses using the 
mITT analysis set will be by randomized treatment. Analyses using the PP analysis set or the 
safety analysis set will be by actual treatment. 
8.3.2. 
Examination of Subgroups 
Predefined subgroups for the Phase 2b and Phase 3 Induction studies will include those defined 
by the randomization stratification variables: 
• History of biologics failure at screening for the Induction study (Yes, No) 










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8.5.4. 
Primary Efficacy Evaluation 
For efficacy evaluations, the null hypothesis for treatment comparisons will be that there is no 
difference between a given dose level of TD-1473 and placebo; the alternative hypothesis will be 
that there is a difference. 
For primary endpoints of each study, missing data and sensitivity analyses will be performed. 
Further details will be given in each applicable SAP. 
Phase 2b Induction: 
The primary endpoint is reduction in total Mayo score at Week 8. An analysis of covariance 
(ANCOVA) model will be used with terms for the stratification factors, baseline score, and 
treatments, and each TD-1473 dose will be compared to placebo. Missing Week 8 scores will not 
be imputed. 
Phase 3 Induction: 
The primary endpoint is clinical remission at Week 8. Each active dose selected will be 
compared to placebo using a stratified Cochran-Mantel-Haenszel (CMH) test, stratifying by 
randomization stratum. Subjects with missing data or who meet a treatment failure criterion will 
be counted as not meeting the endpoint of clinical remission (Refer to Section 8.9). 
Phase 3 Maintenance: 
The primary endpoint is clinical remission at Maintenance Week 44. Each active dose selected 
for continued evaluation in the Maintenance Study will be compared to placebo using a stratified 
CMH test, stratifying by randomization stratum. Subjects with missing data or who meet a 
treatment failure criterion will be counted as not meeting the endpoint of clinical remission 
(Refer to Section 8.9). 
8.5.5. 
Secondary and Additional Efficacy Evaluations 
Unless otherwise specified, binary endpoints will be analyzed using stratified CMH tests, 
stratifying by randomization stratum, similar to the primary efficacy endpoint. As appropriate, 
subjects with missing data or who meet a treatment failure criterion will be counted as not 
meeting the endpoint. Criterion of treatment failure for each endpoint will be described in the 
SAP. Selected binary endpoints will also be analyzed by fitting logistic regression models and 
choosing a dose-response model by a method specified in the applicable SAP. Confidence 
intervals (95%) for treatment differences will be provided. 
Quantitative and score efficacy endpoints collected at a single scheduled time point postbaseline 
will be analyzed by fitting ANCOVA models including terms for treatment effects and 
stratification factors. The baseline value of each endpoint (or transformed endpoint if a 




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8.8. 
Safety Analyses 
Safety summaries for the Phase 2b Induction, Phase 3 Induction, and Phase 3 Maintenance 
studies will include all subjects who received at least one dose of study drug. This will include 
subjects who are randomized to TD-1473 doses not selected for continued evaluation in the 
Phase 3 studies. 
Summaries will be provided by scheduled visit and time point or for the entire treatment period, 
as appropriate. 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. 
Safety variables to be summarized include vital signs, adverse events, clinical laboratory results 
(hematology, chemistry, and urinalysis), and corrected QT interval (QTcF). 
For the Phase 2b and Phase 3 Induction studies, the primary assessment period for all safety 
endpoints will be the first 8 weeks. 
8.8.1. 
Extent of Exposure 
Extent of exposure will be calculated from data collected in the study drug administration page 
of the CRF and summarized. Reasons for study drug discontinuation will be summarized. For 
each subject, treatment compliance over the interval from first to last dose will be calculated 
from data collected in the study drug administration and drug accountability pages of the eCRF. 
Treatment compliance will be summarized by actual treatment received. 
8.8.2. 
Adverse Event Data 
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 reporting each AE. 
A Treatment Emergent Adverse Event (TEAE) will be defined as any AE that begins on or after 
the date of the first dose of study drug. 
The number and percentage of subjects who reported TEAEs will be summarized as follows: 
• All TEAEs, by SOC and PT and also by PT (by descending overall frequency) 
• All TEAEs of Special Interest (Section 7.1.4) by SOC and PT. 
• All TEAEs, by SOC, PT, and severity 
• All study drug-related TEAEs, by SOC and PT 
• All study drug-related TEAEs, by SOC, PT, and severity 
• All TEAEs leading to premature discontinuation of study drug, by SOC and PT 
• All TEAEs leading to temporary interruption of study drug, by SOC and PT 
• All TESAEs, by SOC and PT 
• All study drug-related TESAEs, by SOC and PT 


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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. AESIs (Section 7.1.4) will also be 
listed. 
8.8.3. 
Concomitant Medications 
Medication names will be mapped according to the World Health Organization Drug Dictionary. 
The following summaries will be provided, by drug class and preferred name: 
• Prior UC medications 
• Prior medications with indications other than UC 
• Concomitant medications, including those with indication for UC 
The prior medications summaries will be restricted to medications stopped before the date of the 
first study drug dose. The summary of concomitant medications will comprise all medications 
taken during the treatment period, including medications ongoing at entry. 
8.8.4. 
Laboratory Data 
Laboratory values, changes from baseline, values relative to normal ranges, and values and 
changes meeting specified criteria of special interest (including those given in Section 6.2) will 
be summarized. 
Reference ranges provided by the laboratory for each test will be used to evaluate the clinical 
significance of laboratory test results. Values falling outside the relevant reference range will be 
flagged, as appropriate, in the data listings. A separate listing or listings will be provided for 
abnormalities in clinical laboratory test results. 
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 4 by visit and 
time point. 
Table 4: 
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 
SAP-specified value and change from baseline categories of special interest. 


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Table 5: 
Thresholds for ECG 
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 
  
  
Optional: 
  
  
≥ 430 
> 60 
  
  
≥ 240 
  
  
≥ 450 
  
  
  
≥ 260 
  
  
≥ 470 
  
  
  
≥ 280 
  
  
≥ 480 
  
  
  
≥ 300 
  
  
≥ 500 
  
  
  
  
  
  
Females: 
  
  
  
  
  
  
< 450 
  
  
  
  
  
  
≥ 450 
  
  
  
  
  
  
≥ 470 
  
  
  
  
  
  
≥ 480 
  
  
  
  
  
  
≥ 500 
  
 
A listing of subjects with extreme values or changes, as specified in the SAP (e.g., values of 
QTcF > 500 msec, QTcF increases from baseline > 60 msec) will be provided. 
8.9. 
Data Handling Rules 
For primary analyses of all applicable efficacy endpoints, including secondary and additional 
endpoints, the following rules will be applied. For sensitivity analyses of primary and key 
secondary endpoints, different rules may be specified in the applicable SAP. 
• Binary endpoints: Subjects who had non-missing data for a binary efficacy endpoint 
meeting the criterion for success but met definition of treatment failure prior to visit 
will be considered as not meeting endpoint. Full rules for the derivation of treatment 
failure will be outlined in the SAP. 
• Missing = endpoint not met 
Quantitative or score endpoints: 
• The treatment failure criteria above are applied to exclude any assessments obtained 
following treatment failure 
• MMRM analysis with data assumed to be “Missing at Random” for quantitative or 
score endpoints assessed more than once postbaseline 
• The analysis of the Phase 2b primary endpoint will be a completers analysis. For 
other quantitative or score endpoints assessed only once post-baseline, imputation for 
missing data will be described in the SAP. 




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The Sponsor will make the final selection of dose(s) to be further investigated in Phase 3 using a 
Dose Selection Committee. This committee will consist of subject matter experts from the 
Sponsor’s Research and Development organization, who are otherwise not involved in the 
routine oversight and conduct of the study. The Dose Selection Committee will have access to 
the unblinded efficacy and safety summary tables and figures, but it will not have access to 
individual subject treatment assignment with the exception of data listings that are considered 
pertinent to safety evaluation such as unblinded listing of SAEs, AEs leading to discontinuation 
of study agent, and markedly abnormal laboratory values for the purpose of safety evaluation. 
To assist with the dose selection process, general guidelines will be provided in the Phase 2b 
SAP and the committee will follow these guidelines to direct the choice of dose(s) for further 
evaluation in the Phase 3 dose-confirmatory Induction and Maintenance studies. The dose 
selection guidelines and the required data presentations and analyses will be prospectively 
described in detail in the Phase 2b SAP and a general framework is provided as follows: 
1. Ruling out doses unlikely to have sufficient efficacy to warrant further evaluation 
(i.e., futility analysis) 
2. Selecting an induction dose (or possibly doses) for which a clinically meaningful 
placebo-adjusted treatment effect is indicated for the primary endpoint of change from 
baseline in total Mayo score and the key secondary endpoint of clinical remission at 
Week 8 
3. Evaluating the safety and tolerability of dose(s) identified in Step 2 
4. If necessary, using Exposure-Response analyses to differentiate doses identified in 
Steps 2 and 3. In this setting, responses will focus on safety endpoints. 
To optimize the therapeutic index for long-term therapy in this chronic disease, the Sponsor 
plans to study 2 doses in the Phase 3 Maintenance study, including the dose being proposed for 
Phase 3 Induction and likely a lower dose to assess long-term efficacy and safety. 
No interim analysis is planned for the Phase 3 Induction and Phase 3 Maintenance studies. 


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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 sub-investigators 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 in 21 CFR, ICH guidelines, and 
all other applicable local regulations. 
• He or she will ensure that the IRB/IEC complies with the requirements of 
21 CFR Part 56, ICH guidelines and other applicable regulations, and conducts initial and 
ongoing reviews and approvals of the Study. He or she will also ensure that any change 
in research activity and all problems involving risks to human subjects or others are 
reported to the IRB/IEC. Additionally, he or she will not make any changes in the 
research without IRB/IEC approval, except where necessary to eliminate apparent 
immediate hazards to human subjects. 


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


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


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


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


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10. 
REFERENCES 
1. Crohn’s and Colitis Foundation of America, About the Epidemiology of IBD. 
http://www.ccfa.org/resources/epidemiology.html, Accessed on 19 October 2015 
2. Johnston, R.D. and R.F. Logan, What is the peak age for onset of IBD? Inflamm Bowel 
Dis, 2008. 14 Suppl 2: p. S4-5. 
3. Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, Panaccione R, 
Ghosh S, Wu JCY, Chan FKL, Sung JJY, Kaplan GG. Worldwide incidence and 
prevalence of inflammatory bowel disease in the 21st century: a systematic review of 
population-based studies. Lancet. 2018 Dec 23;390(10114):2769-2778. doi: 
10.1016/S0140-6736(17)32448-0. Epub16 Oct. 2017 
4. Dyson, J.K. and M.D. Rutter, Colorectal cancer in inflammatory bowel disease: what is 
the real magnitude of the risk? World J Gastroenterol, 2012. 18(29): p. 3839-48. 
5. Gunnarsson, C., et al., The employee absenteeism costs of inflammatory bowel disease: 
evidence from US National Survey Data. J Occup Environ Med, 2013. 55(4): p. 393-401. 
6. Kappelman, 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. 
7. Navarro, F. and S.B. Hanauer, Treatment of inflammatory bowel disease: safety and 
tolerability issues. Am J Gastroenterol, 2003. 98(12 Suppl): p. S18-23. 
8. Sandborn, W.J., et al., Tofacitinib as Induction and Maintenance Therapy for Ulcerative 
Colitis. N Engl J Med, 2017. 376(18): p. 1723-1736. 
9. 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. 
10. Mosli MH, Feagan BG, Zou G, Sandborn WJ, D'Haens G, Khanna R, Shackelton LM, 
Walker CW, Nelson S, Vandervoort MK, Frisbie V, Samaan MA, Jairath V, Driman DK, 
Geboes K, Valasek MA, Pai RK, Lauwers GY, Riddell R, Stitt LW, Levesque BG. 
Development and validation of a histological index for UC. Gut. 2017 Jan;66(1):50-58. 
doi: 10.1136/gutjnl-2015-310393. Epub 16 Oct 2015 
11. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, 
Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, 
Colombel JF. Infliximab for induction and maintenance therapy for ulcerative colitis. N 
Engl J Med. 2005 Dec 8;353(23):2462-76. 
 
References are available upon request. 
 


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APPENDIX 1. PROTOCOL SIGNATURE FORM 
 
Protocol Signature Form 
 
Protocol #:  
0157 
Protocol Title:   
A Phase 2b/3 Multi-Center, Randomized, Double-Blind, Multi˗Dose, 
Placebo-Controlled, Parallel-Group Set of Studies to Evaluate the 
Efficacy and Safety of Induction and Maintenance Therapy with 
TD−1473 in Subjects with Moderately-to-Severely Active Ulcerative 
Colitis 
Study Short Title: 
Rhea: Efficacy and Safety of TD-1473 in Ulcerative Colitis 
Version: 
Amendment 3 
Version Date: 
14 May 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 
 
Date 
 


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






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APPENDIX 7. DEFINITION OF INTOLERANCE OR INADEQUATE 
RESPONSE AND DEFINITION OF CORTICOSTEROID 
DEPENDENCE 
A) Definition of intolerance or inadequate response: 
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 
Corticosteroids: 
• Signs and symptoms suggestive of persistence of active disease despite a) a 4-week 
regimen that included ≥ 2 weeks of ≥ 0.75mg/kg/day of prednisolone or 40mg/day of 
prednisone or equivalent or b) budesonide ≥ 9mg/day or beclomethasone 
diproprionate (i.e., Clipper) at ≥ 5 mg/day given orally for ≥ 4 weeks OR 
• Intolerance: subject developed clinically significant adverse event(s) (including, but 
not limited to hyperglycemia, infection, Cushing’s syndrome, anxiety, weight gain, 
blurry vision, corticosteroid-induced hypertension, intolerable insomnia, 
osteopenia/osteoporosis) unresponsive to dose reduction that preclude the use of 
corticosteroids to treat UC, in the PI’s judgment, or subject has a medical condition 
that precludes use of corticosteroids to treat UC 
Immunomodulators (azathioprine or 6-mercaptopurine): 
• Signs and symptoms suggestive of persistence of active disease despite a) a regimen 
≥ 12 weeks of oral azathioprine (≥ 2.0 mg/kg) or 6-mercaptopurine (≥ 1.0 mg/kg) or a 
lower dose of 6-MP or azathioprine if the local guidelines specify a different 
treatment regimen (included in the source document), b) a dose of 6-MP or 
azathioprine that is confirmed to be therapeutic by thioguanine nucleotide levels 
> 200 pmole/8 x 108 RBCs, or c) the highest dose with anything higher limited by 
leukopenia, elevated AST or ALT, or nausea OR 
• Intolerance to at least one immunomodulator (including, but not limited to 
nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia, 
TPMT genetic mutation, infection) that is unresponsive to dose reduction that 
precludes the use of 6-MP or azathioprine to treat UC or the subject has a medical 
condition that precludes the use of 6-MP or azathioprine 
Biologics (anti-TNF or anti-integrin; Refer to Appendix 8 for further detail): 
• Signs and symptoms suggestive of persistence of active disease despite completing an 
Induction regimen OR 
• Symptom recurrence during maintenance dosing following previously demonstrating 
clinical benefit OR 


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• Intolerance (including, but not limited to infusion-related reaction, rash, injection site 
reaction, demyelination, congestive heart failure, infection) 
B) Definition of corticosteroid dependence: requiring prednisolone ≥10mg/d or 
≥budesonide 3mg/d or equivalent for ≥3 months to control UC, or relapse within 3 
months of stopping steroid therapy or unable to discontinue corticosteroids without flare 
within 3 months after initiating them. 
 


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APPENDIX 8. DEFINITION OF PRIOR BIOLOGICS FAILURE: 
PRIMARY AND SECONDARY NON˗RESPONDER OR 
INTOLERANT TO PREVIOUS BIOLOGICS 
Primary non-responder: 
Subjects were to have received Induction doses of at least one of the following: 
• Infliximab (3 doses of 5-10 mg/kg 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) 
• Vedolizumab 300 mg administered by intravenous infusion at Weeks 0, 2, and 6 or 
earlier 
• Golimumab 100 mg administered by injection at Week 0 (2 100-mg injections), and 
Week 2 (1 100-mg injection) 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 UC occurring within 2 weeks after receiving the last 
dose: 
• Lack of improvement or worsening in stool frequency and/or consistency. 
• Lack of improvement or worsening in bloody stools and/or rectal bleeding. 
• Lack of improvement or worsening in daily abdominal pain. 
• Occurrence, lack of improvement or worsening fever thought to be related to UC. 
• Initiation or increase in antidiarrheal medication. 
Secondary non-responder: 
Initially responded to Induction therapy and received at least 2 of the following Maintenance 
doses: 
• Infliximab (at a dose of ≥ 5 mg/kg) 
• Adalimumab (at a dose of 40 mg every week or every other week) 
• Vedolizumab 300 mg administered every 8 weeks or every 4 weeks 
• Golimumab 100 mg injection at week 6 and every 4 weeks  
• Ustekinumab subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, 
then every 8-12 weeks thereafter or more frequently. 
And had at least 1 of the following signs or symptoms related to recurrence of active UC 
occurring within 2 weeks after receiving the last dose: 
• Lack of improvement or worsening in stool frequency and/or consistency. 
• Lack of improvement or worsening in bloody stools and/or rectal bleeding. 


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• Lack of improvement or worsening in daily abdominal pain. 
• Occurrence, lack of improvement or worsening fever thought to be related to UC. 
• Initiation or increase in antidiarrheal medication. 
 




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APPENDIX 10. 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. 


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


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


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APPENDIX 11. 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, Quality-of-Life 
questionnaires, 
, 
, PGA) 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 PGA. 
• 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: 0157 
Official Title: A Phase 2B/3 Multi-Center, Randomized, Double-Blind, Multi-Dose, Placebo-
Controlled, Parallel-Group Set of Studies to Evaluate the Efficacy and Safety of Induction and 
Maintenance Therapy with TD˗1473 in Subjects with Moderately-to-Severely Active Ulcerative 
Colitis 
NCT Number: NCT03758443 
Document Date:  
Induction Phase - 01 July 2021 
Maintenance Phase  - 20 Oct 2021 


 
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Statistical Analysis Plan – Protocol 0157 Phase 2b 
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STATISTICAL ANALYSIS PLAN 
Protocol Title:  
A Phase 2b/3 Multi-Center, Randomized, Double-Blind, Multi-
Dose, Placebo-Controlled, Parallel-Group Set of Studies to 
Evaluate the Efficacy and Safety of Induction and Maintenance 
Therapy with TD˗1473 in Subjects with Moderately-to-Severely 
Active Ulcerative Colitis 
Protocol Number:  
0157 
Compound Number: 
TD-1473 
Short Title:  
Rhea: Efficacy and Safety of TD-1473 in Ulcerative Colitis  
 
 
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 
128299 
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 
Author: 
 
 
 
Theravance Biopharma Ireland Limited. 
 
Date 
 
 
 
Reviewer: 
 
 
 
Theravance Biopharma US, Inc. 
 
Date 
 
 
 
Reviewer: 
 
 
 
Theravance Biopharma US, Inc. 
 
Date 
 
15 July 2021 | 15:07 PDT
15 July 2021 | 09:59 PDT
15 July 2021 | 09:58 PDT


 
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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 .......................................................................................................12 
1.1.2. 
Key Secondary Objective ...........................................................................................12 
 
 
1.2. 
Study Design ...............................................................................................................12 
1.2.1. 
Summary of Study Design ..........................................................................................12 
1.2.2. 
Definition of Study Drugs ..........................................................................................15 
1.3. 
Treatment Assignment and Blinding ..........................................................................15 
1.4. 
Schedule of Assessments ............................................................................................17 
1.5. 
Sample Size Determination ........................................................................................26 
2. 
ANALYSIS SETS ......................................................................................................27 
3. 
STATISTICAL ANALYSES .....................................................................................28 
3.1. 
General Considerations ...............................................................................................28 
3.1.1. 
Baseline Definition .....................................................................................................28 
3.1.2. 
Study Day ...................................................................................................................28 
3.1.3. 
Visit Windows ............................................................................................................28 
3.1.4. 
Multiple Assessments .................................................................................................29 
3.1.5. 
Study Period Definitions.............................................................................................30 
3.1.5.1. 
Induction Treatment Period ........................................................................................30 
3.1.5.2. 
Extended Induction Treatment Period ........................................................................30 
3.1.6. 
Actual Treatment ........................................................................................................30 
3.2. 
Study Subjects ............................................................................................................30 
3.2.1. 
Subject Disposition and Completion Status ...............................................................31 
3.2.2. 
Demographic and Baseline Characteristics ................................................................31 
3.2.3. 
Protocol Deviations ....................................................................................................33 
3.2.4. 
Medical History ..........................................................................................................34 


3.2.5. 
Prior/Concomitant Medications ..................................................................................34 
3.3. 
Primary Endpoint(s) Analysis .....................................................................................35 
3.3.1. 
Definition of Primary Endpoint(s) ..............................................................................35 
3.3.2. 
Total Mayo Score (tMS) .............................................................................................35 
3.3.3. 
Statistical Hypotheses .................................................................................................36 
3.3.4. 
Primary Efficacy Analyses .........................................................................................36 
3.3.4.1. 
Primary Estimand .......................................................................................................36 
3.3.4.2. 
Analysis Methods .......................................................................................................37 
3.3.4.3. 
Missing Data Handling ...............................................................................................38 
3.3.5. 
Sensitivity Analyses ....................................................................................................38 
3.3.6. 
Supplementary Analyses ............................................................................................38 
3.3.6.1. 
Supplementary Estimand 1 .........................................................................................38 
3.3.6.2. 
Supplementary Estimand 2 .........................................................................................39 
3.3.6.3. 
Subgroup Analysis ......................................................................................................39 
3.3.6.4. 
Total Mayo Score Component Analysis .....................................................................40 
3.3.6.5. 
Total Mayo Score Completeness and Intercurrent Event Summaries ........................40 
3.4. 
Secondary Endpoint(s) Analyses ................................................................................41 
3.4.1. 
Key Secondary Endpoint ............................................................................................41 
3.4.2. 
Statistical Hypotheses .................................................................................................41 
3.4.3. 
Definition of Key Secondary Endpoint ......................................................................41 
3.4.4. 
Key Secondary Efficacy Analyses ..............................................................................42 
3.4.4.1. 
Estimands ....................................................................................................................42 
3.4.4.2. 
Analysis Methods .......................................................................................................42 
3.4.4.3. 
Missing Data Handling ...............................................................................................43 
3.4.5. 
Sensitivity Analyses ....................................................................................................43 
3.4.6. 
Supplementary Analyses ............................................................................................43 
3.4.6.1. 
Change in aMS ...........................................................................................................43 
3.4.6.2. 
Subgroup Analyses .....................................................................................................43 
3.4.6.3. 
Adapted Mayo Score Completeness ...........................................................................43 
3.5. 
Multiplicity Adjustment..............................................................................................44 
 
 
 
 
 
 


 
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3.6.4. 
Supplementary Analyses ............................................................................................49 
3.6.4.1. 
Subgroup analysis .......................................................................................................49 
3.7. 
Safety Analyses ..........................................................................................................49 
3.7.1. 
Extent of Exposure .....................................................................................................49 
3.7.1.1. 
Treatment Compliance ................................................................................................50 
3.7.2. 
Adverse Events ...........................................................................................................50 
3.7.2.1. 
Adverse Events of Special Interest .............................................................................51 
3.7.3. 
Additional Safety Assessments...................................................................................52 
3.7.3.1. 
Clinical Laboratory Parameters ..................................................................................52 
3.7.3.2. 
Vital Signs ..................................................................................................................52 
3.7.3.3. 
Electrocardiograms .....................................................................................................53 
3.8. 
Other Analyses ............................................................................................................54 
3.8.1. 
Patient Reported Outcomes ........................................................................................54 
 
 
 
 
 
 
 
 
3.8.2. 
Biomarkers ..................................................................................................................56 
 
 
 
3.9. 
Interim Analyses .........................................................................................................57 
3.9.1. 
Maintenance of blind following interim analysis .......................................................57 
3.9.2. 
Data Monitoring Committee .......................................................................................57 
4. 
REFERENCES ...........................................................................................................58 
5. 
SUPPORTING DOCUMENTATION ........................................................................59 
5.1. 
Appendix 1: Changes to Protocol-Planned Analyses .................................................59 
5.2. 
Appendix 2: Data Conventions and Transformations ................................................59 
5.2.1. 
Derived and Transformed Data ..................................................................................59 
5.2.1.1. 
Study Day ...................................................................................................................59 
5.2.1.2. 
Change from baseline .................................................................................................59 
5.2.1.3. 
BMI .............................................................................................................................59 


5.2.1.4. 
Ideal Body Weight ......................................................................................................59 
5.2.1.5. 
QTcF ...........................................................................................................................60 
5.2.1.6. 
Time Since Ulcerative Colitis Diagnosis ....................................................................60 
5.2.1.7. 
Prior Biologic Failure .................................................................................................60 
5.2.1.8. 
Prior Biologic Mechanism of Actions ........................................................................60 
5.2.1.9. 
Creatinine Clearance ...................................................................................................60 
5.2.2. 
Missing Date Imputation ............................................................................................61 
5.2.2.1. 
Missing/Incomplete AE/Start Date .............................................................................61 
5.2.2.2. 
Missing/Incomplete AE/Medication End Date/Time .................................................61 
5.2.2.3. 
Missing/Incomplete Start for Medication ...................................................................62 
5.2.3. 
Laboratory Data ..........................................................................................................62 
5.2.4. 
AE Severity .................................................................................................................62 
5.3. 
Adverse Event Start and End Date/Time Imputation Rules .......................................63 
5.4. 
Diary Data derivations ................................................................................................64 
5.4.1. 
Selection of diary days to use in calculation ..............................................................64 
5.4.2. 
Rectal Bleeding ...........................................................................................................65 
5.4.3. 
Stool Frequency ..........................................................................................................65 
5.4.4. 
Diary Weeks ...............................................................................................................65 
 
 
 
 
 
 
 
 
 
 
 
 
5.8. 
CTCAE Grading .........................................................................................................76 
5.9. 
Multiple Imputation ....................................................................................................77 
 
 
 
 
 
LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................8 
Table 2: 
Schedule of Study Procedures – Induction and Extended Induction Studies .............18 


 
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Table 3: 
Analysis Sets ...............................................................................................................27 
Table 4: 
Visit Analysis Windows .............................................................................................29 
Table 5: 
Components of Total Mayo Score ..............................................................................35 
Table 6: 
Clinical Remission by aMS Definition .......................................................................42 
Table 7: 
Clinical Response Definitions ....................................................................................45 
Table 8: 
Clinical Remission by Total Mayo Score ...................................................................46 
Table 9: 
Criteria for Marked Abnormalities in Vital Signs ......................................................53 
Table 10: ECG Interval Categories .............................................................................................53 
Table 11: Diary Weeks ...............................................................................................................65 
 


LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
aMS 
Adapted Mayo Score 
ANCOVA 
Analysis Of Covariance 
ANOVA 
Analysis Of Variance 
C 
Continuous Reporting Format 
CMH 
Cochran Mantel-Haenszel  
CRF 
Case Report Form 
 
 
CSR 
Clinical Study Report 
DOB 
Date Of Birth 
dy 
Days 
 
 
F 
Frequency Reporting Format 
G 
Geometric Mean Reporting Format 
GCP 
Good Clinical Practices 
 
 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat Population 
KM 
Kaplan-Meier 
LLN 
Lower Limit Of Normal 
LOCF 
Last Observation Carried Forward 
LS 
Least Square 
LSM 
Least Square Mean 
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 
OTC 
Over The Counter Medication 
PGA 
Physician Global Assessment 
PLSM 
Poisson Least Square Mean 
pMS 
Partial Mayo Score 
PP 
Per-Protocol Population 
PRO2 
PRO 2 Score 
 
 
SD 
Standard Deviation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System  
tMS 
Total Mayo Score 
UC 
Ulcerative Colitis 
ULN 
Upper Limit Of Normal 


 
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VAS 
Visual Analogue Scale 
WBC 
White Blood Cell Count 
WHO 
World Health Organization  
 
 
yr 
Years 




 
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1. 
INTRODUCTION 
This document outlines the plan for the summarization and analysis of clinical data 
collected in the Phase 2b Induction Study of Protocol 0157 for TD-1473.  
Protocol 0157 comprises 3 separate studies within a single protocol. The purpose of 
multiple studies within a single protocol is to increase operational efficiency and 
reduce operational costs.  
The analyses and summarization of clinical data is divided into 3 separate SAPs 
corresponding to the separate studies within the protocol: 
 Phase 2b Dose-Finding Induction SAP (this document) 
 Phase 3 Dose-Confirming Induction SAP 
 Phase 3 Maintenance SAP 
Each study set of analyses will control Type I error < 0.05. As such, study analyses 
(Phase 2b Induction Study, Phase 3 Induction Study, Phase 3 Maintenance Study) are 
considered independent and no control of multiplicity will occur across the 3 sets of 
analyses.   
The analysis of pharmacokinetics data (derivation and summarization of individual 
PK parameters) is outside the scope of this document and is not addressed here. 
This document describes the a priori plan for analysis.  Any substantive modification 
to  this analysis plan will be identified in the clinical study report (CSR). 
Information in the appendices to the SAP are not considered a formal section of the 
signed SAP.   


1.1. 
Objectives and Endpoints 
1.1.1. 
Primary Objective 
The primary objective of the Phase 2b Dose-Finding Induction is: 
 Assess the effect of TD-1473 taken once daily for 8 weeks at doses of 20 mg, 80 mg, 
and 200 mg on the change from baseline in the total Mayo score 
1.1.2. 
Key Secondary Objective 
 Assess the effect of TD-1473 on rates of clinical remission at Week 8 
1.1.3. 
Additional/Exploratory Objectives 
 
 
 
 
 
 
  
 
 
 
 
1.2. 
Study Design 
1.2.1. 
Summary of Study Design 
This single protocol includes three studies: a Phase 2b dose-finding Induction Study, a Phase 3 
dose-confirming Induction Study, and a Phase 3 randomized-withdrawal Maintenance Study 
(Figure 1).  
Figure 1: 
Protocol Schema 


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Each of the three studies will utilize a multi-center, randomized, double-blind, 
placebo-controlled, parallel-group design to evaluate various doses of TD-1473 compared to 
placebo in subjects with moderately-to-severely active ulcerative colitis (UC).  
The Induction Studies will target subjects with moderately-to-severely active UC who 
demonstrate an inadequate response or failure to tolerate conventional or biologic therapy.  
The Maintenance Study will be a randomized withdrawal study targeting subjects with 
moderately-to severely-active UC who demonstrate a clinical response to induction treatment 
with TD-1473. 
Phase 2b Dosing-Finding Induction Study: 
To determine initial eligibility, subjects will undergo assessments during the Screening Stage 1 
period.  Disease activity will be assessed by the total, adapted, and partial Mayo scores and 
PRO2 score.  Subjects who meet inclusion and no exclusion criteria will undergo an endoscopic 
exam (i.e., sigmoidoscopy or colonoscopy) with biopsies to complete screening Stage 2. If the 
subject meets all eligibility criteria, including a Mayo endoscopic subscore ≥ 2 from central 
review of the Screening Stage 2 endoscopy and an adapted Mayo score between 4 and 9, 
inclusive, on Day 1, the subject may be randomized.  
The randomization will be stratified by prior biologic failure status and corticosteroid use at 
enrollment into the Induction Study. Biologic failure is defined as having demonstrated primary 
or secondary non-response or intolerance to one or more biologics (i.e., anti-TNF-therapy, anti-
integrin, or anti-IL-12/23  ). 
The Induction Study will consist of treatment for  
a. 8 weeks for those who demonstrate clinical response by adapted Mayo Score at 
Week 8, and,  


b. 16 weeks for those who do not demonstrate a clinical response by adapted Mayo 
score at Week 8, 
Subjects who do not demonstrate clinical response at Week 8 will receive an additional 8 weeks 
of treatment during an extended induction period as follows,   
a. Subjects randomized to TD-1473 during the first 8 weeks will remain on the same 
dose of TD-1473;  
b. Subjects who received placebo during the first 8 weeks will receive TD-1473 80 
mg.   
This portion of the Induction Study will not be placebo-controlled, but blinding as to the specific 
dose of TD-1473 will be maintained.  Those who demonstrate clinical response at Week 16 will 
enter the Maintenance Study; those who do not exit the study. 
The Phase 2b-Dose Finding Induction Study (Figure 2) will enroll approximately 240 subjects, 
randomized 1:1:1:1 to placebo or 1 of the 3 active TD-1473 doses (20 mg, 80 mg or 200 mg).   
After all enrolled subjects have either completed the Week 8 visit or terminated participation 
prior to Week 8, an analysis of all efficacy and safety data up to Week 8 will be performed.  
Results from this analysis will be used to inform the dose selection for the Phase 3 dose-
confirming Induction Study and the remainder of the Phase 3 Maintenance Study, which would 
be ongoing at that time. 
Figure 2: 
Phase 2b Dose-Finding Induction Study 
 
Subjects who do not demonstrate clinical response by adapted Mayo score at Week 8 with active 
drug will receive an additional 8 weeks of treatment staying on the same dose of TD-1473 as the 
first 8 weeks, and those who had received placebo during the first 8 weeks will now receive TD-
1473 at 80 mg (Figure 3).   
All subjects who undergo extended induction treatment will receive active drug, and thus, this 
portion of the Induction Study will not be placebo-controlled, but blinding as to the specific dose 
of TD-1473 will be maintained.  During this time, at the discretion of the investigator, subjects 
are permitted but are not required to begin corticosteroid taper.  Those who demonstrate clinical 
response at Week 16 will enter the Maintenance Study; those who do not demonstrate clinical 
response at Week 16 will have an EOS visit and exit the study. 
Figure 3: 
Extended Induction Treatment Regimen 


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1.2.2. 
Definition of Study Drugs 
Study drug comprises the following (placebo and 3 doses of TD-1473): 
 TD-1473 20 mg (2 x 10 mg tablets) once daily: Taken orally for up to 16 (including 
Extended Induction when applicable) weeks in the morning. With the exception of 
clinic visit days, subjects will be instructed to take two tablets once daily at 
approximately the same time each morning. 
 TD-1473 80 mg (2 x 40 mg tablets) once daily: Taken orally for up to 16 (including 
Extended Induction when applicable) weeks in the morning. With the exception of 
clinic visit days, subjects will be instructed to take two tablets once daily at 
approximately the same time each morning. 
 TD-1473 200 mg (2 x 100 mg tablets) once daily: Taken orally for up to 16 
(including Extended Induction when applicable) weeks in the morning. With the 
exception of clinic visit days, subjects will be instructed to take two tablets once daily 
at approximately the same time each morning. 
 Placebo once daily: Taken orally for up to 8 (Induction period only) weeks in the 
morning. With the exception of clinic visit days, subjects will be instructed to take 
two tablets once daily at approximately the same time each morning. Note: Subjects 
who do not respond on placebo during Induction Period will be switched to TD-1473 
80 mg (2 x 40 mg tablets) once daily for the Extended Induction period. 
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.  
Subjects will be randomized at Day 1 to 1 of 4 treatment groups (placebo QD,  TD-1473 20 mg 
QD, TD-1473 80 mg QD or TD-1473 200 mg QD) using permuted block randomization with 


biologic failure status (yes/no) and corticosteroid use at baseline (yes/no) as stratification 
variables. Separate randomization lists will also be created for subjects enrolled in Asia and the 
rest of the world. 
Randomization caps will be placed on both prior biologics failure subgroups (no to biologic 
failure (60%) and yes to biologic failure (60%)) to ensure that neither subgroup is 
overrepresented.  
At Week 8, subjects who are in clinical response will exit the Induction Study and will be re-
randomized into the Phase 3 Maintenance Study with the exception of placebo responders who 
will continue placebo in a blinded fashion during the Maintenance Study. Subjects who do not 
achieve clinical response at Week 8 will enter Extended Induction: those who received TD-1473  
treatment during induction will continue their current randomized treatment for an additional 8 
weeks.  Placebo subjects who do not exhibit clinical response at Week 8 will receive TD-1473  
80 mg for 8 weeks during Extended Induction). 
Maintenance of the Blind 
In order to maintain the blind in subjects whose treatment is known once database lock has 
occurred for the Phase 2b Induction Study, a firewall will be maintained ensuring that Sponsor 
employees who are aware of treatment assignments will not have contact with site personnel. 
In order to maintain the study blind, the study medications will have a label containing the study 
name, Kit ID number, and reference number. The KIT ID number will be automatically entered in 
the case report form (CRF) when the drug is dispensed. The study medications will be identical in 
appearance and packaging. 
The investigator will not be provided with randomization codes. The codes will be maintained 
within the Randomization and Trial supply Management System (RTSM), which has the 
functionality to allow the investigator to break the blind for an individual subject. The date and 
reason for the unblinding will be documented in the appropriate section of the CRF and in the 
source document. The documentation received from the RTSM indicating the code break will be 
retained with the subject's source documents in a secure manner. Subjects who had their treatment 
assignment unblinded by the investigator will be discontinued from study medications. 
Data that may potentially unblind the treatment assignment (i.e., study medication, plasma 
concentrations and treatment allocation) will be handled by the use of subject aliases at the 
Bioanalytical Lab that conducts initial data analyses to ensure that the integrity of the blind is 
maintained and the potential for bias is minimized when transferring said information to the 
Sponsor.  
 
  
Treatment assignment blinding will be maintained for investigative sites, site monitors, and 
subjects participating in this protocol until the Week 44 analyses for the Maintenance Study have 
been completed.  


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An independent DMC will regularly review unblinded safety data.  The committee and its 
statistical support group will have access to unblinded treatment information. They will not 
divulge any information to the Sponsor that may potentially unblind an individual subject’s 
treatment group.  
1.4. 
Schedule of Assessments 
 


Table 2: 
Schedule of Study Procedures – Induction and Extended Induction Studies 
 
 
INDUCTION VISITS 
EXTENDED INDUCTION VISITS(33) 
 
 
Procedures 
Screening 
Period  
Day 
1 
Week 
2 
Week 4 
Week 8a 
(1) 
Week 
8b(2),(3) 
Week 12 
(2) 
Week 16 
(2)(4) 
Early 
Study 
Drug 
D/C(5) 
End of Study 
(4 weeks post 
last study 
dose)  
Study Day/Week 
Day -28 to – 
1 
 
 
Stage 
1 
Stage 
2 
Window 
 
 
 
± 3 
days 
± 3 
days 
-3 to + 5 
days 
+ 1 to 7 
days from 
week 8a 
visit(6) 
-3 to + 5 
days 
-3 to + 7 
days 
+ 5 
days 
-3 to + 5 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
Criteria 
X 
X 
X 
 
 
 
X 
 
 
 
 
Medication and Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
Smoking Status 
 
 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
 
X 
 
 
X(29) 
 
X 
X 
X 
X 
Vital Signs (7) 
X 
 
X(8) 
X 
X 
X(29) 
 
X 
X 
X 
X 
12-Lead ECG (9) 
X 
 
X (32) 
 
 
X(29) 
 
 
X 
X 
X 
Physical Examination(10) 
X 
 
X 
X 
X 
X(29) 
 
 
X 
X 
X 
Chest X-Ray or equivalent 
chest imaging 
X (11) 
 
 
 
 
 
 
 
 
 
 
Tuberculosis Test 
(QuantiFERON) (12) 
X 
 
 
 
 
 
 
 
 
 
 


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Table 2: 
Schedule of Study Procedures – Induction and Extended Induction Studies 
 
 
INDUCTION VISITS 
EXTENDED INDUCTION VISITS(33) 
 
 
Procedures 
Screening 
Period  
Day 
1 
Week 
2 
Week 4 
Week 8a 
(1) 
Week 
8b(2),(3) 
Week 12 
(2) 
Week 16 
(2)(4) 
Early 
Study 
Drug 
D/C(5) 
End of Study 
(4 weeks post 
last study 
dose)  
Study Day/Week 
Day -28 to – 
1 
 
 
Stage 
1 
Stage 
2 
Window 
 
 
 
± 3 
days 
± 3 
days 
-3 to + 5 
days 
+ 1 to 7 
days from 
week 8a 
visit(6) 
-3 to + 5 
days 
-3 to + 7 
days 
+ 5 
days 
-3 to + 5 days 
Plasma PK Samples (13) 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Overnight Fasting Lipid 
Panel 
X(19) 
 
X 
 
X 
X(29) 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Fecal Sample for stool 
infectious analysis(14) 
X 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
  
 
 
16)(19)  
X  
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (females of 
child-bearing potential 
only)(17)  
X(19) 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
FSH(18) (19) 
X 
 
 
 
 
 
 
 
 
 
 
Chemistry, Hematology 
X(19) 
 
X 
X 
X 
X(29) 
 
X 
X 
X 
X 
Urinalysis 
X(19) 
 
X 
 
 
X(29) 
 
 
X 
X 
X 


Table 2: 
Schedule of Study Procedures – Induction and Extended Induction Studies 
 
 
INDUCTION VISITS 
EXTENDED INDUCTION VISITS(33) 
 
 
Procedures 
Screening 
Period  
Day 
1 
Week 
2 
Week 4 
Week 8a 
(1) 
Week 
8b(2),(3) 
Week 12 
(2) 
Week 16 
(2)(4) 
Early 
Study 
Drug 
D/C(5) 
End of Study 
(4 weeks post 
last study 
dose)  
Study Day/Week 
Day -28 to – 
1 
 
 
Stage 
1 
Stage 
2 
Window 
 
 
 
± 3 
days 
± 3 
days 
-3 to + 5 
days 
+ 1 to 7 
days from 
week 8a 
visit(6) 
-3 to + 5 
days 
-3 to + 7 
days 
+ 5 
days 
-3 to + 5 days 
Whole Blood and Serum 
Biomarker Samples 
X 
 
X 
 
X 
X(29) 
 
X 
X 
X 
X 
Genetic Blood Sample 
(optional – only collected for 
subjects who provide genetic 
testing consent) 
 
 
X 
 
 
 
 
 
 
 
 
Endoscopy and Biopsies 
 
X 
(20) 
 
 
 
X(21) 
 
 
X(21) 
 
 
Concomitant Medication 
review (22) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Assessment 
(23) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician Global 
Assessment (PGA)  
X(24) 
  
 X 
X 
X 
X 
 
X 
X 
X 
X 
Partial Mayo score  
 
X  
  
 
 
 
 
 
 
 
 
Adapted Mayo score  
 
 
X(31) 
 
 
X(31) 
 
 
X(31) 
 
 


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Table 2: 
Schedule of Study Procedures – Induction and Extended Induction Studies 
 
 
INDUCTION VISITS 
EXTENDED INDUCTION VISITS(33) 
 
 
Procedures 
Screening 
Period  
Day 
1 
Week 
2 
Week 4 
Week 8a 
(1) 
Week 
8b(2),(3) 
Week 12 
(2) 
Week 16 
(2)(4) 
Early 
Study 
Drug 
D/C(5) 
End of Study 
(4 weeks post 
last study 
dose)  
Study Day/Week 
Day -28 to – 
1 
 
 
Stage 
1 
Stage 
2 
Window 
 
 
 
± 3 
days 
± 3 
days 
-3 to + 5 
days 
+ 1 to 7 
days from 
week 8a 
visit(6) 
-3 to + 5 
days 
-3 to + 7 
days 
+ 5 
days 
-3 to + 5 days 
Dispense Subject Diary(25) 
X 
 
 
 
 
 
 
 
 
 
 
Subject Diary Completion 
and Compliance Review (26) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X(27)  
 
 
 
 
 
 
 
 
Study Drug Dispensing  
 
 
X 
X 
X 
 
X 
 
 
 
 
In Clinic Dosing - Study 
Drug Dosing(28)  
 
 
X 
 
X 
 
X 
 
X 
 
 
Non-Site Study Procedures (Calculations for Programming/Statisticians and applicable suppliers) 
partial Mayo score and 
PRO2 scores calculation  
 
X  
X 
X 
X 
X 
 
X 
X 
X 
X 


Table 2: 
Schedule of Study Procedures – Induction and Extended Induction Studies 
 
 
INDUCTION VISITS 
EXTENDED INDUCTION VISITS(33) 
 
 
Procedures 
Screening 
Period  
Day 
1 
Week 
2 
Week 4 
Week 8a 
(1) 
Week 
8b(2),(3) 
Week 12 
(2) 
Week 16 
(2)(4) 
Early 
Study 
Drug 
D/C(5) 
End of Study 
(4 weeks post 
last study 
dose)  
Study Day/Week 
Day -28 to – 
1 
 
 
Stage 
1 
Stage 
2 
Window 
 
 
 
± 3 
days 
± 3 
days 
-3 to + 5 
days 
+ 1 to 7 
days from 
week 8a 
visit(6) 
-3 to + 5 
days 
-3 to + 7 
days 
+ 5 
days 
-3 to + 5 days 
adapted and total Mayo 
score calculations 
 
 
X 
 
 
X 
 
 
X 
 
 
Abbreviations: D/C, discontinue; ECG, electrocardiogram; EOS, End of Study; FSH, follicle stimulating hormone; 
; PK, pharmacokinetic; 
PRO2, two-item patient reported outcome; 
; 
 
; 
; 
; EOS, End 
of Study 
 
Induction Studies: 
1. 
Subjects will continue on study drug at the same Induction dose until they return to clinic for post-central read endoscopy results visit.  
Depending on the week 8a adapted Mayo score (using centrally read endoscopy), the subject will proceed with one of the following: 
 
Week 8b visit if subject did not achieve clinical response, or  
 
Maintenance Week 0 (mWeek 0) if subject achieved clinical response  
Subject to be reminded not to take study drug on the morning of this next clinic visit, whether Week 8b or mWeek 0, to allow for re-randomization 
and initiation of study drug of either Extended Induction or Maintenance Study, whichever he or she qualifies for 
2. 
Week 8b, Week 12, and Week 16 visits pertain only to subjects who undergo extended induction (i.e., who do not demonstrate clinical response 
based on the adapted Mayo score from Week 8a visit) 
3. 
Subject should be instructed not to take study drug from their Induction study drug bottles at home to allow for re-randomization and to receive the 
first dose of extended induction in the clinic. 


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4. 
Week 16 visit may be done over a period of 1 to 3  visits to complete: a) the Week 16 endoscopy, b) Week 16 clinical assessments (e.g., vital signs, 
weight, laboratory testing, and Quality-of-Life assessments), and c) an optional visit to bring subjects back (or could be done over the phone) to 
inform them that they should stop study drug and proceed to EOS visit if they did not achieve clinical response (those who achieve clinical response 
will proceed to mWeek 0 visit).  The Week 16 clinical response will be determined using the adapted Mayo score utilizing the centrally read 
endoscopic subscore from the Week 16 endoscopy. 
5. 
Early Study Drug Discontinuation visit is for subjects who prematurely discontinue the Study drug during the Induction Study. Visit to 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 four weeks after last study drug.  An EOS visit will be required for all subjects 4 weeks following their last dose of study drug, 
regardless if they completed the full duration of study drug treatment.  
6. 
Seven-day window provided to allow time to receive results from the central reading of endoscopy performed at Week 8a. 
7. 
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.  Vital sign 
measurements should be obtained prior to scheduled blood draws. 
8. 
Obtain blood pressure and heart rate pre-dose and approximately 1-hour post-dose on Day 1. 
9. 
ECGs should be performed after the subject has been resting in a supine position for at least 10 minutes. 
10. Physical Exam will be performed as per local standard practice. 
11. 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 of 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 by the investigator) will be obtained. Subjects who have had a chest X-ray or 
equivalent chest imaging within 90 days prior to screening will not require a repeat X-ray unless subject is deemed to be at high risk of recent 
pulmonary infection.  If a chest X-ray is indicated, it may be performed anytime between Screening Stage 1 and Screening Stage 2 visits.   
12. 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 TB testing, respectively, unless subject is deemed by the investigator to be at high risk of recent pulmonary infection.  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. 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 protocol are met. 
13. PK sampling will be performed in subjects at the following time points: 
 
Day 1 (n= 3 samples): one sample collected pre-dose (within 1 hour prior to study drug administration) and one sample collected anytime between 
0.25 to 0.5 hours post-dose; and one sample collected anytime between 1 to 6 hours post-dose; 
 
Week 4 (n= 2 samples): one pre-dose and one post-dose sample collected anytime between 1 to 6 hours post-dose 
 
Week 8b (n = 2 samples): one pre-dose and one post-dose sample collected anytime between 1 to 6 hours post-dose; samples may be obtained 
up to -7 days from the Week 8a endoscopy visit, but cannot be obtained within 24 hours of endoscopy prep 


 
Week 12 (n= 1 sample): One sample to be collected anytime between 0.5 to 6 hours post-doses 
 
Week 16 (n=2 samples):  one pre-dose and one post-dose sample collected anytime between 0.5 to 6 hours. The Week 16 sample may be 
obtained -3 to + 7 days from the endoscopy visit 
 
NOTE: Post-dose sampling times are defined relative to the time of Study drug administration on the day of collection. All PK sampling times will 
be accurately recorded by collection date, hour, and minute. Study drug dosing time on the day before each PK collection will also be accurately 
recorded by dosing date, hour, and minute by the subject; Study drug dosing time on the day of each PK collection will be accurately recorded by 
dosing date, hour, and minute by the Study staff.  
14. For stool infectious analysis: Including C. difficile, other bacterial pathogens (including Shigella, Salmonella, Yersinia, E. coli O157, and 
Campylobacter), and ova and parasite.  This can be done any time after written consent and prior to Screening Stage 2 visit, and results 
reviewed before Screening Stage 2 visit. 
15. 
 
 
 
16. Serology testing: 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.  Serologies do not need to be repeated during 
re-screening if results from the first screening were negative and within 90 days of re-screening. 
17. B-hCG testing (serum for Screening and urine for all other visits) will be performed for females of childbearing potential to confirm absence of 
pregnancy.  If urine b-hCG test is positive, confirm with serum b-hCG test. 
18. Required for postmenopausal females. 
19. Screening Labs including urinalysis may be obtained anytime during the 28-day window for Screening, but results must be available before 
Screening Stage 2 endoscopy with the exception of 
 and fasting lipid panel.  *NOTE: Subjects must not be requested to 
come in fasting for study specific assessments prior to signing the informed consent. Exception: The overnight fasting lipid panel may be obtained 
on Day -28 if subjects are fasting as per institutions standard of care procedure, which must be clearly documented in the source documents.  
20. Endoscopy with biopsies will be performed at the Screening Stage 2 visit after subject’s eligibility from Screening Stage 1 is confirmed.  This 
screening endoscopy must occur at ≥ 5 days before Day 1 to allow ≥ 3 days of symptom reporting for adapted Mayo score calculation on Day 
1. This Screening Stage 2 endoscopic subscore, determined by central reading, will be used to calculate any clinical score for Day 1 that requires the 
endoscopic subscore.   The centrally read endoscopic subscore will be used for all endpoints and for eligibility criteria to enroll a subject into the 
Induction and Maintenance Studies.  Local reading of the endoscopic subscore will also be collected. The aMS will be calculated by the electronic 
tablet at all applicable visits.  
21. Centrally read endoscopic subscore from Week 8a visit will used to calculate adapted Mayo score to determine whether subject should undergo 
extended induction or continue into Maintenance Study depending on whether the subject meets criteria for clinical response at Week 8a.  Centrally 


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read endoscopic subscore from Week 16 visit will used to calculate adapted Mayo score to determine whether subject should continue into 
Maintenance Study or discontinue study drug and proceed to EOS visit depending on whether the subject meets criteria for clinical response at 
Week 16. Local reading of the endoscopic subscore will also be collected.  
22. All concomitant UC and non-UC 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. 
23. AE assessments are to include collection and reporting of AEs, SAEs, and AEs of Special Interest (AESIs). 
24.  PGA from Screening Stage 1 visit will be used for the partial Mayo score calculation as a guide to assess if subject should proceed with endoscopy 
at Screening Stage 2 visit. It is suggested that subjects with a partial Mayo score ≥ 3 (reflecting disease that is at least moderate in severity) should 
proceed with endoscopy screening. This partial Mayo Score can be assessed at any time between Screening Stage 1 visit and Screening Stage 2 visit 
as long as there are ≥ 3 days of symptom reporting. The pMS is calculated by the electronic tablet at the Screening Stage 2 visit page and it is 
recommended that this is completed before the subject proceeds with the Screening Stage 2 visit endoscopy. 
25. Subjects will be provided with an electronic diary at the Screening (Stage 1) visit and instructed on diary completion, including symptom 
monitoring and Study drug dosing details.  Diaries of symptoms will be collected daily from Screening through the EOS visit.   
26. Diary completion will be monitored for completeness at each Study visit.  Subjects will be counseled on missed Study drug doses and missed diary 
entries. Subjects who discontinue study drug early due to AE are permitted to optionally complete their daily diary through to the EOS visit. 
27. Subject will be randomized on Day 1 after all pre-dose procedures have been completed and subject is confirmed to be eligible for the Study.  The 
adapted Mayo score criteria for randomization on Day 1 may be calculated within 48 hours of Day 1.  
28. Study drug administration will be in-clinic on Day 1, Week 4, Week 8b and Week 16.  All study procedures must be done prior to drug 
administration with the exception of the post-dose PK sample and 
 samples.  Refer to footnote 13 for the post-dose instructions 
for PK collections and footnote 15 for the 
 collection window. All other days, subjects will take study drug at home for the rest of 
the Induction period. 
29. Procedures may be done -3 to +7 days after week 8a visit (i.e., at the next visit, either Week 8b or mWeek0). 
30. 
  
31. The adapted Mayo Score at these visits will be calculated by the electronic tablet using the symptoms in the applicable days prior to Day 1, Week8a 
or Week 16 and the centrally read endoscopy score. This will be available once the centrally read endoscopy score has been received by the site and 
entered into the electronic tablet.  
32. ECG at Day 1 is only required during the Phase 2b Dose-finding Induction study.  
33. If the Week 8b visit occurs out of window, the dates of subsequent visits will be based on the Week 8b visit start date to ensure a full 8 weeks of 
treatment in Extended Induction. 


1.5. 
Sample Size Determination 
A sample size of 60 subjects per group is estimated to give approximately 90% power to detect a 
2 point improvement relative to placebo in total Mayo score at all three doses, under the 
following assumptions: 
 Hochberg step-up procedure adjustment for multiple comparisons (2-sided 
tests) 
 
Family-wise type 1 error rate to be controlled at 5% 
 
Residual change standard deviation (SD) of 3 points 
The estimated power to detect a 2-point improvement relative to placebo for at least one of the 
three doses is greater than 98%. 
Assuming a slightly larger residual change SD of 3.5 points, the estimated power to detect a 2 
point active dose group vs. placebo improvement in total Mayo score at all three doses was 
approximately 73% and the estimated power to detect a 2 point improvement at one or more of 
the doses was approximately 94%. 
Estimates were obtained using East software, with 10,000 simulations per case.   


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2. 
ANALYSIS SETS 
 
Table 3: 
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 
Safety* 
The Safety analysis set will include all subjects who 
received at least one dose of study drug (TD-1473 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 into the Phase 2b study.  
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.  
The mITT set is the primary analysis set for efficacy 
summaries and analyses. 
Randomized 
treatment 
Modified ITT-
16w* 
The modified Intent-to-Treat for extended induction 
(mITT-16w) analysis set comprises all randomized 
into the Phase 2b study, who did not meet the 
criteria for clinical response by adapted Mayo score 
at Week 8, and, continued dosing during extended 
induction. 
Randomized 
treatment 
PP* 
The Per-Protocol (PP) analysis set comprises all 
subjects in the mITT analysis set who complete their 
Week 8 visit and have no major analysis protocol 
deviations 
Randomized 
treatment 
 Due to confirmed data integrity violations the data for site 36044 (deviation report 
GCP-23) and site 38915 (deviation report GCP-11) will be excluded from all analysis 
sets. 


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 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 predose.  
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 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. 
3.1.3. 
Visit Windows 
All assessments (including unscheduled assessments) will be summarized using analysis 
windows. The exception is the End of Study 4 week follow up visit  which will not be 
windowed. 
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.  
 


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Confidential – Property of Theravance Biopharma, Inc. 
 
Table 4: 
Visit Analysis Windows 
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: 
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. 
Nominal 
Visit 
Nominal Day 
Start (days) 
Stop (days) 
Screening 
NA 
-28 
-1 
Day 1 
1 
1 
1 
Week 2 
14 
7 
21 
Week 4 
28 
22 
35 
Week 8a/8b 
56 
46 
Minimum of: 
 
Day 71, or  
 
8 Week Induction period 
end date  
Week 12 
Extended Induction day 
28 
Extended Induction day 22 
Extended Induction day 35 
Week 16 
Extended Induction day 
56 
Extended Induction day 46 
Minimum of: 
 
Extended Induction day 
71, or 
 
Extended  Induction 
period end date  


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 
Unless stated otherwise the following are the definitions for Induction and Extended Induction 
treatment periods for analysis and summaries. 
3.1.5.1. 
Induction Treatment Period 
All data collected for each subject from first dose up until the earliest event between first dose at 
Week 8b, first dose at mWeek 0 or End of  Treatment + 5 days will be presented. 
3.1.5.2. 
Extended Induction Treatment Period 
All data collected for each subject from first dose at Week 8b up until the End of Treatment + 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 (Induction, Extended Induction or overall) that the 
incorrect treatment was dispensed and returned. 
Mean Dose 
Actual Treatment 
>0 mg and <=50 mg 
20mg 
>50 mg and <=140 mg 
80mg 
>140 mg 
200mg 
Mean dose is calculated over a period as the summation of each dose taken (where placebo is 
considered 0mg) and divided by total number of doses taken.   
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. Where specified additional summaries on the mITT-16w 
will also be presented. 


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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 on all randomized subjects and mITT-16w analysis set 
separately 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 disposition summary will be provided on the ITT set for Induction period: 
 Number of subjects who completed the Week 8a Visit 
 Number of subjects who discontinued prior to the Week 8a Visit 
 Primary reasons for discontinuation prior to the Week 8a Visit, with frequencies 
A listing of subject disposition will include analysis set flags (ITT, Safety, mITT, mITT-16w, PP 
[Yes/No]),  dates of first and last dose of study drug, primary reason for subject discontinuation 
of study treatment, study completion status, primary reason for study termination, and date of 
last contact. 
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 
Unless otherwise stated all Demographic and Baseline Characteristic tables will be summarized 
on the both the ITT and the mITT-16w analysis set. All listings will be presented for the Safety 
analysis set. 
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.  
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 
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.  
Ulcerative Colitis Disease State Clinical Characteristics 
A summary of Ulcerative Colitis Clinical Characteristics taken at baseline or screening will be 
provided. A listing will also be provided. 
Parameter 
Units/Response category 
Severity of Disease 
Moderate: 6≤ tMS ≤ 10,  
Severe: tMS >10 
Time Since Diagnosis  
Years 
Time Since Diagnosis categories 
≤ 5years; 
>5 to <=15 years; 
> 15 years 
Time since start of symptoms 
Years 
Extent or location of Disease 
Proctosigmoiditis,  
Left-sided colitis,  
Extensive,  
Unknown 
Presence of Complications 
Yes, No 
Normal stool count in remission or 
prior to diagnosis 
Stools 
  
 
 
 
 
  
 
 
 
 
 
Prior Ulcerative Colitis Therapy Characteristics 
A summary of Prior Ulcerative Colitis Therapy Characteristics will be provided. A listing will 
also be provided. 
Parameter 
Units/Response category 


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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 
Inadequate Response 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,  non-response or 
intolerance 
Yes, No 
Prior immunomodulator use 
Yes, No 
History of immunomodulator non-response or 
intolerance 
Yes, No 
Prior aminosalicylate use 
Yes, No 
Aminosalicylate use at enrolment 
Yes, No 
History of aminosalicylate non-response 
Yes, No 
Prior Jak-inhibitor use 
Yes, No 
 
Complications of Ulcerative Colitis at Baseline 
A summary of complications of ulcerative colitis at Baseline will be provided, the number and 
percentage of subjects with each complication collected on the Ulcerative Colitis History page 
will be presented. A listing will also be provided. 
Baseline Mayo Scores 
A summary of baseline Mayo scores and components will include the following items.  A listing 
will also be provided. 
Parameter 
Units/Response category 
Baseline tMS 
Points 
Baseline pMS  
Points 
Baseline aMS  
Points 
Baseline PRO2  
Points 
Baseline Mayo Stool Frequency subscore  0, 1, 2, 3 
Baseline Mayo Rectal Bleeding subscore  0, 1, 2, 3 
Baseline Mayo Endoscopy Findings 
subscore 
0, 1, 2, 3 
Baseline Mayo Physician Global 
Assessment subscore 
0, 1, 2, 3 
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. 
Major analysis protocol deviations include: 
1. Subjects who received the wrong treatment prior to Week 8a visit, 


2. Study drug compliance defined as compliance < 80% or ≥ 120% during 8 Week 
Induction study, 
3. Subject did not meet efficacy-related inclusion criteria (inclusion criterion 4 and 5), 
4. Subject took a prohibited medication prior to Day 1 (exclusion criteria 7a-j),   
5. Subject required prohibited concomitant medications that are deemed to have an 
impact on the efficacy outcomes 
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 # 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. Medications that stopped 
more than 60 days prior to screening will not be included in the prior medication summaries. The 
number and percentage of subjects who have taken each medication will be provided by study 
treatment. 
On-going Ulcerative Colitis Medications of Interest at Baseline will also be presented. Ulcerative 
Colitis Medications of Interest include aminosalicylates and corticosteroids. 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 medications to 
treat UC or AE of worsening UC and are categorized as : 
 Initiation of oral corticosteroids or aminosalicylates  


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 Increase in oral corticosteroids or aminosalicylates dose 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 Total Mayo score at 
Week 8. 
3.3.2. 
Total Mayo Score (tMS) 
The Total Mayo score (0-12 points) (Table 5) is the sum of four components: stool frequency (0-
3 pts), rectal bleeding (0-3 pts), Mayo endoscopic (0-3 pts) and Physician Global Assessment 
(0-3 pts) subscores. 
Additional information on derivation of stool frequency and rectal bleeding components from 
diary data can be found in Section 5.4. 
If at least one component of the Total Mayo score is available then the score will be calculated. 
Missing components will be imputed through last observation carried forward (LOCF). 
 
Table 5: 
Components of Total Mayo Score 
Stool Frequency  
0 point:  Normal number of stools for patient 
1 point:  1 to 2 stools per day more than normal 
2 points:  3 to 4 stools more than normal 
3 points:  ≥ 5 stools more than normal 
Rectal Bleeding 
0 point:  No blood seen 
1 point:  Streaks of blood with stool less than half the time 
2 points:  Obvious blood with stool most of the time 
3 points:  Blood alone passes 
Endoscopic Findings  
0 point:  Normal or inactive disease 
1 point:  Mild Disease (erythema, decreased vascular pattern) 
2 points:  Moderate Disease (marked erythema, lack of vascular pattern, friability, erosions) 


3 points:  Severe Disease (spontaneous bleeding, ulceration) 
Physician's Global Assessment (PGA)  
0 point:  Normal 
1 point:  Mild disease 
2 points:  Moderate disease 
3 points:  Severe disease 
 
3.3.3. 
Statistical Hypotheses 
The primary estimate of interest, change from baseline in total Mayo score at Week 8, is used to 
evaluate the effectiveness of TD-1473 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 TD-1473 (active) and the mean response on the placebo 
treatment in the change from baseline in total Mayo score at Week 8.   
The alternative hypothesis will be that there is a difference.   
Symbolically, this is expressed as follows: 
 
0
placebo
1
placebo
:
:






Active
Active
H
H
  
In order to control for the comparison of 3 active treatment groups versus placebo for the 
primary endpoint, a multiplicity procedure is planned.   
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 
patients regardless of use of rescue medication.  
Population:  
The study population consists of treated subjects with moderately-to-severely active UC as 
defined by an adapted Mayo score between 4 and 9 with a Mayo endoscopic subscore ≥ 2 who 
are corticosteroid-dependent or had intolerance or demonstrate an inadequate response or loss of 
response to conventional therapy (aminosalicylates, corticosteroids or immunomodulators) [i.e., 
as azathioprine or 6-mercaptopurine] or biologics [i.e., anti-TNF-therapy, anti-integrin, or anti-
IL-12/23  ]. Randomized and treated subjects with inclusion or exclusion protocol deviations will 
be included in the analysis. 


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Variable: 
Change from baseline in Total Mayo Score at Week 8.Subjects with any of the following 
intercurrent events (ICE) prior to Week 8 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 UC or adverse event of worsening UC  
2. Documented ostomy, colectomy or any other major intestinal resection for UC during the 
treatment period 
3. Increase in dose of oral corticosteroids or aminosalicylates above baseline dose  
4. Initiation of oral corticosteroids or aminosalicylates where they were not ongoing at 
baseline 
5. Discontinuation of study treatment due to lack of clinical benefit or AE of worsening UC 
Other ICE: 
6. Discontinuation of study treatment due to COVID-19 
7. Discontinuation of study treatment due to reasons other than COVID-19, lack of clinical 
benefit or AE of worsening UC 
Population-level summary: 
The mean difference in change from baseline in Total Mayo Score at Week 8 between each TD-
1473 group and placebo. 
3.3.4.2. 
Analysis Methods 
The primary endpoint of change from baseline in Total Mayo Score at Week 8 will be analyzed 
based on the Primary Estimand by fitting an ANCOVA model incorporating the change from 
baseline tMS measurement at Week 8 as the dependent variable in the model. The model will 
include fixed-effect class terms for treatment group, prior biologic failure status (yes/no), 
corticosteroid use at baseline (yes/no).  A covariate for baseline tMS will be included. 
Summaries will be on the mITT population and include observed values, change from baseline 
values, and least square (LS) means estimate. 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. Unadjusted p-values will also be reported.   
A 4-group forest plot will summarize the LS mean change from baseline in Total Mayo Score at 
Week 8 with 95% confidence interval. An additional 3-group forest plot will summarize the 
difference from placebo in LS mean change from baseline in Total Mayo Score at Week 8 with 
95% confidence interval. The 3-group 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 equal slopes, linearity of regression, equal variances and the 
independence and normality of errors. In the event that the ANCOVA assumptions are not met 
then p-values will be generated from the nonparametric randomization-based analysis of 
covariance methodology of Koch et al. (1998). 
3.3.4.3. 
Missing Data Handling  
After accounting for intercurrent events and individual missing components (outlined in Section 
3.3.2) all missing data (including data missing due to COVID-19) will be assumed missing 
completely at random (MCAR) and not imputed. 
3.3.5. 
Sensitivity Analyses 
A sensitivity analysis of the MCAR assumption for the primary endpoint will be performed 
where missing data will be assumed Missing at Random (MAR). Missing components of the 
Total Mayo Score will be imputed through multiple imputation. Details on the multiple 
imputation methodology are outlined in Section 5.9.  
3.3.6. 
Supplementary Analyses 
3.3.6.1. 
Supplementary Estimand 1 
This estimand uses a hybrid strategy where subjects meeting intercurrent events for treatment 
failure follow a composite strategy and subjects meeting intercurrent events other than treatment 
failure follow a hypothetical  strategy.  
Population:  
The study population consists of treated subjects with moderately-to-severely active UC as 
defined by an adapted Mayo score between 4 and 9 with a Mayo endoscopic subscore ≥ 2 who 
are corticosteroid-dependent or had intolerance or demonstrate an inadequate response or loss of 
response to conventional therapy (aminosalicylates, corticosteroids or immunomodulators) [i.e., 
as azathioprine or 6-mercaptopurine] or biologics [i.e., anti-TNF-therapy, anti-integrin, or anti-
IL-12/23  ]. Randomized and treated subjects with inclusion or exclusion protocol deviations will 
be included in the analysis. 
Variable: 
Change from baseline Total Mayo Score at Week 8. Subjects meeting intercurrent events (1-5) 
will have their change from baseline in Total Mayo Score at Week 8 equal to zero. 
Intercurrent events: 
Intercurrent events outlined in Section 3.3.4.1. 
Population-level summary: 
The mean difference in change from baseline in Total Mayo Score at Week 8 between each TD-
1473 group and placebo. 


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Analysis Methods: 
Subjects meeting intercurrent events (1-5) follow a composite strategy with baseline observation 
carried forward (BOCF). Subjects affected by remaining intercurrent events follow a 
hypothetical strategy where data following the intercurrent event is set to missing and assumed 
MAR. All other missing data following application of intercurrent event strategies will be also be 
assumed to be MAR. For all data assumed MAR multiple imputation will be performed to a 
generate a group of imputed datasets (n=20 imputed datasets per Mayo subscore component). 
Details on the multiple imputation are outlined in Section 5.9.  
The following covariates will be included in the imputation model to impute the missing 
components:  treatment group, prior biologic failure status (yes/no), corticosteroid use at baseline 
(yes/no) and the individual baseline Total Mayo subscore components. The tMS will then be 
calculated by summing together the individual components for each imputation.  
The change from baseline in Total Mayo Score at Week 8 will be analyzed after applying 
multiple imputation using the same ANCOVA model as outlined for the primary estimand on 
each imputed dataset. The SAS procedure MIANALYZE is then used to combine the results 
from the ANCOVA analysis of each imputation. 
3.3.6.2. 
Supplementary Estimand 2 
This estimand has the same variable, analysis, ICE and population level summary as primary 
estimand however the population differs and is defined below. 
Population:  
Treated subjects who reach the Week 8 visit without any major protocol deviations and who 
enter the study with moderately-to-severely active UC as defined by an adapted Mayo score 
between 4 and 9 with a Mayo endoscopic subscore ≥ 2 who are corticosteroid-dependent or had 
intolerance or demonstrate an inadequate response or loss of response to conventional therapy 
(aminosalicylates, corticosteroids or immunomodulators) [i.e., as azathioprine or 6-
mercaptopurine] or biologics [i.e., anti-TNF-therapy, anti-integrin, or anti-IL-12/23  ].  
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 an interaction term of treatment*subgroup 
category and baseline*subgroup category into the primary analysis model. If a subgroup 
determines the level of a class effect included in the primary analysis model, the redundant term 
will be omitted (e.g., prior biologic failure status subgroup analyses will not include the status 
term). Treatment group LS means for each subgroup will be calculated by setting the baseline 
score to the subgroup mean (for the subjects included in the analysis). 
The following subgroups are pre-defined: 
 Biologic Failure Status:  [a] Yes, [b] No  


 Biologics experience categories:  [a] Primary non-responder, Secondary non-responder or 
intolerant, [b] naïve, [c] bio-experienced [but not documented failure] 
 Number of prior biologics failed [a] 0 [b] 1 [c] ≥2 
 Number of biologic classes failed [a] 0 [b] 1 [c] ≥2 
 Inadequate response to at least one biologic:  [a] Yes, [b] No 
 Intolerant to at least one biologic:  [a] Yes, [b] No 
 Steroid use status at enrollment: [a] Yes, [b] No 
 Baseline Tobacco use Status: [a] no use [b] prior use [c] current use 
 Extent of disease: [a] Proctosigmoiditis,[b] Left-sided colitis, [c] extensive 
 Duration of disease: [a] ≤ 5 years, > 5 to ≤ 15 years, > 15 years 
 
 
 
 
 Baseline total Mayo score: [a] ≤ 10 [b] > 10  
 Baseline adapted Mayo score: [a] ≤ 7 [b] > 7  
 Baseline Mayo Endoscopy subscore [a] 2 [b] 3 
 Baseline Rectal Bleeding subscore [a] 0 [b] ≥1 
 Geographic Region: [a] North America [b] Eastern Europe [c] Europe (excluding Eastern 
Europe)[d] Asia/Pacific [e] Other;  
 Country: [a] Japan [b] United States [c] Rest of the world 
 Refractory or intolerant to 6-MP/AZA: (yes, no) 
 Refractory, dependent or intolerant to oral or IV corticosteroids: (yes, no) 
 Evidence of inadequate response, recurrent disease or relapse 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 
3.3.6.4. 
Total Mayo Score Component Analysis 
Summaries of each individual Total Mayo Score component will be presented by treatment 
group and visit over time. The components will be presented as both a continuous and 
categorical variables separately, displaying summary statistics and then a shift table for 
percentage of subjects with each score (0, 1, 2, 3) at baseline and Week 8.  
3.3.6.5. 
Total Mayo Score Completeness and Intercurrent Event Summaries 
Summaries of the completeness of Total Mayo Score components at Week 8 will be performed 
where the number of patients missing 1, 2, 3 or all components will be presented. For subjects 
with all components missing the summary will be further broken down by those of discontinue 
prior to Week 8 and those who missed the Week 8 visit.  


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The number of subjects who experience an intercurrent event prior to Week 8 and those who 
don’t will also be presented for the subset of subjects with at least one Total Mayo Score 
component missing at Week 8.  
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. 
Key Secondary Endpoint 
The key secondary endpoint  is: 
 Clinical remission by adapted Mayo score components at Week 8 
3.4.2. 
Statistical Hypotheses 
The key secondary estimate of interest, clinical remission by adapted Mayo score components at 
Week 8, 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 secondary endpoint:   
The null hypothesis for the treatment comparison will be that there is no difference between the 
proportion of subjects in remission at a given dose level of TD-1473 (active) and the proportion 
of subjects in remission on the placebo treatment.   
The alternative hypothesis will be that there is a difference.   
Symbolically, this is expressed as follows: 
                                      𝐻0: 𝑃𝐴𝑐𝑡𝑖𝑣𝑒= 𝑃placebo 
                                      𝐻1: 𝑃𝐴𝑐𝑡𝑖𝑣𝑒≠𝑃placebo 
In order to control for the comparison of 3 active treatment groups versus placebo for the 
secondary endpoint, a multiplicity procedure is planned (See Section 3.6).   
3.4.3. 
Definition of Key Secondary Endpoint 
The adapted Mayo score (0-9 points) is the sum of three components: stool frequency (0-3 pts), 
rectal bleeding (0-3 pts), and Mayo endoscopic (0-3 pts) subscores. 
Clinical remission by Adapted Mayo Score requires each of the subscores to meet the criteria 
defined in Table 6. If at least one component of the adapted Mayo score (aMS) is available then 
the score will be calculated. Missing components will be imputed through last observation 
carried forward. 


Table 6: 
Clinical Remission by aMS Definition 
Mayo Definition 
Stool 
Frequency 
Rectal 
Bleeding 
Endoscopic 
Findings 
Adapted Mayo Score (aMS) 
0 or 1 
0 
0 or 1 
3.4.4. 
Key Secondary Efficacy Analyses  
3.4.4.1. 
Estimands 
Clinical remission by adapted Mayo Score 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). Subjects meeting criteria 
for ICE, with the exception of ICE criteria 6, will have their remission status at Week 
8 set to not in remission. 
 Intercurrent Events: Intercurrent events outlined in Section 3.3.4.1.  
 Population-level summary: The difference in proportion in clinical remission by 
adapted Mayo Score between each TD-1473 group and placebo. 
3.4.4.2. 
Analysis Methods  
Subjects meeting criteria for ICE, with the exception of ICE criteria 6, will follow a composite 
strategy with their remission status at Week 8 set to not in remission. Subjects meeting ICE 
criteria 6 will have their Week 8 remission status missing and not imputed and assumed MCAR. 
The proportions of subjects with clinical remission by aMS definitions will be compared 
between each TD-1473 treatment group and the placebo group using a Cochran-Mantel-Haenszel 
(CMH) chi-square test stratified by biologic failure status (yes or no) and corticosteroid use at 
baseline (yes or no).  In order to derive the weighed difference in proportions, CMH weights (wj) 
will be used: 
𝑤̂𝑗=
(
𝑛1𝑗𝑛2𝑗
𝑛1𝑗+𝑛2𝑗)
∑
(
𝑛1𝑗𝑛2𝑗
𝑛1𝑗+𝑛2𝑗)
4
𝑗=1
  For j=1…4 stratum  
To derive the difference in proportions within a stratum, the standard difference in proportions is 
used, 𝑑̂𝑗= 𝑝̂2𝑗−𝑝̂1𝑗 where the difference over all strata is 𝑑̂𝐶𝑀𝐻= ∑
𝑤̂𝑗𝑑̂𝑗
4
𝑗=1
. 
A Wald-type CI is constructed as follows: 
𝑑̂𝐶𝑀𝐻± (𝑧𝛼2
⁄  × 𝜎̂(𝑑̂𝑐𝑚ℎ)) 
Where 𝜎̂(𝑑̂𝑐𝑚ℎ) is estimated with the Sato variance estimator (Sato, 1989). 
Summaries of the proportion of subjects in remission will be presented by treatment group, the 
adjusted treatment difference in proportions between each TD-1473 group and placebo will also 
be presented along with associated 95% CIs calculated based on the Wald method outlined 
above. P-values from the CMH Chi-square test for the comparison of each dose of TD-1473 
versus placebo will also be presented. 


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Separate 3-group forest plots for the difference in proportion versus placebo at Week 8 will 
display the CMH weighted difference in proportions and associated 95% CI. 
3.4.4.3. 
Missing Data Handling  
Following the application of ICE strategy, missing data will be imputed as not in remission . 
3.4.5. 
Sensitivity Analyses 
No sensitivity analysis will be performed for secondary endpoints. 
3.4.6. 
Supplementary Analyses 
3.4.6.1. 
Change in aMS 
Change in aMS at Week 8 will be analyzed by fitting an ANCOVA model incorporating the 
change from baseline aMS measurement at Week 8 as the dependent variable in the model. The 
model will include independent fixed-effect class terms for treatment group, prior biologic 
failure status (yes/no), corticosteroid use at baseline (yes/no).  A covariate for baseline aMS will 
also be included. 
The analysis population, intercurrent events and missing data will be analyzed in the same way 
as for the primary estimand. Summaries will 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 4-group forest plot will summarize the LS mean change from baseline in aMS at Week 8 with 
95% confidence interval. An additional 3-group forest plot will summarize the difference from 
placebo in LS mean change from baseline in aMS at Week 8 with 95% confidence interval.  
3.4.6.2. 
Subgroup Analyses 
All subgroup analyses outlined for the primary endpoint will be performed on clinical remission 
by aMS at Week 8 and change from baseline in aMS at Week 8. 
3.4.6.3. 
Adapted Mayo Score Completeness  
Summaries of the completeness of Adapted Mayo Score components at Week 8 will be 
performed where the number of patients missing 1, 2 or all components will be presented. For 
subjects with all components missing the summary will be further broken down by those of 
discontinue prior to Week 8 and those who missed the Week 8 visit.  
The number of subjects who experience an intercurrent event prior to Week 8 and those who 
don’t will also be presented for the subset of subjects with at least one Adapted Mayo Score 
component missing at Week 8. 


3.5. 
Multiplicity Adjustment 
Adjustment for multiplicity on the primary endpoint will follow the step-down Hochberg 
procedure. The resulting nominal p-values for the primary endpoint will be ordered, largest to 
smallest.   
 If the largest p-value < 0.05, then all treatment groups will be declared as statistically 
significant. 
 If the largest p-value is > 0.05, then the next largest p-value will be compared to 0.025. If 
this p-value is < 0.025, then the last 2 treatment groups will be declared as statistically 
significant. 
 If the second largest p-value is > 0.025 and the largest is > 0.05, the smallest p-value will 
be compared to 0.0167.  If this p-value < 0.0167, then the last treatment group 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 will be considered not met. 
The key secondary endpoint will only be tested if all three active treatment groups are declared 
statistically significant for the primary endpoint, if that occurs then adjustment for multiplicity of 
the key secondary endpoint will also follow the step-down Hochberg procedure. 
3.6. 
Exploratory Endpoint(s) Analyses 
3.6.1. 
Exploratory Endpoint(s) 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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3.6.2. 
Definition of Exploratory Endpoint(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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3.6.3. 
Exploratory Efficacy Analyses  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 


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3.6.4. 
Supplementary Analyses  
3.6.4.1. 
Subgroup analysis 
To characterize the consistency of the treatment effect for clinical response by aMS and tMS, 
endoscopic healing, and endoscopic remission, subgroup analyses will be performed for each of 
the subgroups in Section 3.3.6.3. 
3.7. 
Safety Analyses 
The analysis of safety data includes an overall summary of adverse event preferred terms by 
body/organ system, drug exposure (duration of treatment), dosing information/compliance, 
clinical laboratory results, vital signs and ECGs.  Tables summarizing the adverse events 
reported by subjects who died, experienced non-fatal serious adverse events (SAE), or 
prematurely discontinued the study due to adverse event (AEs) will be prepared.  Summaries of 
potentially clinically notable laboratory results and vital sign abnormalities are presented.   
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 phase 2b induction study 
overall, data will be presented separately for the following groups: 
1. Subjects treated with placebo in induction period 
2. Subjects treated with TD-1473 20mg in Induction period and Extended Induction period 
if they enter 
3. Subjects treated with TD-1473 80mg in Induction period and Extended Induction period 
if they enter 
4. Subjects treated with TD-1473 80mg in Extended Induction period who were randomized 
to placebo in Induction period 
5. Combined data on TD-1473 80mg from groups (2) and (3) 
Subjects treated with TD-1473 200mg in Induction period and Extended Induction period 
if they enter 
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 the Week 8 visit dose administration date for those that reach the Week 
8 visit or equal to date of last study drug return for those who discontinue prior to Week 8 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: 
 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 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: 
Label 
≥ 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. 


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Adverse events (AEs) are recorded from signing of the informed consent form through the final 
follow-up assessment. Adverse events observed prior to first dose are non-treatment emergent. 
Treatment emergent adverse events are defined as follows for induction period and overall: 
 TEAEs are AEs with onset on or after the first initiation of study drug up to the date 
of last dose of study drug + 28 days. 
Only treatment-emergent AEs will be summarized in the tables.  
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 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 
 Cardiovascular Event (e.g. myocardial infarction or cerebrovascular accident) 
The incidence of AESI’s will be summarized overall and by AESI category and preferred term. 
3.7.3. 
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.  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  
 
Leukoocytes 
 
Lymphocytes  
 
Hemoglobin  
 
Lipids [LDL cholesterol, HDL cholesterol, Cholesterol, and Triglyceride]  
 
Liver Function Test's [ALT, AST, Bilirubin]  
 
Creatinine   
 
Creatinine Kinase 
The number and percentage of subjects with clinically abnormal lab values will also be 
summarized by timepoint for the following criteria:  
 absolute neutrophil count of < 1.0 x 109/L 
 white blood cell count of < 2.0 x 109/L  
 absolute lymphocyte count of < 0.5 x 109/L 
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 8 and through Week 16.  
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 9 will be flagged in the listing. 


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Table 9: 
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 
correction. 
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 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 10 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. 
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 10: 
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 


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) 
 
 
 
 
 
≥ 450 
 
 
 
 
 
 
≥ 470 
 
 
 
 
 
 
≥ 480 
 
 
 
 
 
 
≥ 500 
 
 
 
 
 
 
Females: 
 
 
 
 
 
 
< 450 
 
 
 
 
 
 
≥ 450 
 
 
 
 
 
 
≥ 470 
 
 
 
 
 
 
≥ 480 
 
 
 
 
 
 
≥ 500 
 
 
3.8. 
Other Analyses 
 
 
 
  
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 


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3.9. 
Interim Analyses 
The study will have an interim freeze to perform the primary analysis after the last subject 
ongoing in induction period reaches the Week 8b/mWk0 timepoint or discontinues. 
3.9.1. 
Maintenance of blind following interim analysis 
Study team members with access to subject level data during the interim analysis that reveals a 
subjects dose (i.e. 20mg, 80mg or 200mg) during the Extended Induction period cannot 
participate in study-related activities that involve direct site interaction from Week 8 unblinding 
onwards.  
3.9.2. 
Data Monitoring Committee 
 
 
 
 


4. 
REFERENCES 
Devine, B.J. (1974). Gentamicin therapy. Drug Intelligence and Clinical Pharmacy 8:650-655. 
 
 
LaVange LM, Koch GG (2008). Randomization-Based Nonparametric Analysis of Covariance 
(ANCOVA)." In RB D'Agostino, L Sullivan, J Massaro (eds.), Wiley Encyclopedia of 
Clinical Trials. John Wiley & Sons, Hoboken. 
Mosli MH, Feagan BG, Zou G, Sandborn WJ, D'Haens G, Khanna R, Shackelton LM, Walker CW, 
Nelson S, Vandervoort MK, Frisbie V, Samaan MA, Jairath V, Driman DK, Geboes K, Valasek MA, Pai 
RK, Lauwers GY, Riddell R, Stitt LW, Levesque BG. Development and validation of a histological index 
for UC. Gut. 2017 Jan;66(1):50-58. doi: 10.1136/gutjnl-2015-310393. Epub 16 Oct 2015  
Guyatt GH, Mitchell A, Irvine EJ, Singer J, Williams BA, Goodacre R, Tompkins C. A new measure of 
health status for clinical trials in inflammatory bowel disease.Gastroenterology. 1989; 96: 804-810 
SAS Institute Inc. 2017. Base SAS® 9.4 Procedures Guide, Seventh Edition. Cary, NC: SAS Institute Inc. 
Sato, T. (1989). On the variance estimator for the Mantel-Haenszel risk difference. Biometrics, 45(4), 
1323-1324.   
 
 


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5. 
SUPPORTING DOCUMENTATION 
5.1. 
Appendix 1: Changes to Protocol-Planned Analyses 
The endpoints and analysis have been updated follow the advice in ICH E9 (R1) addendum on 
estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for 
clinical trials. As a result, endpoints following a treatment policy strategy no longer omit data 
meeting treatment failure criteria as outlined in the protocol section 8.9. 
5.2. 
Appendix 2: Data Conventions and Transformations 
5.2.1. 
Derived and Transformed Data 
5.2.1.1. 
Study Day 
If the date of interest occurs on or after the first dose/randomization date then study day will be 
calculated as (date of interest – date of first dose/randomization) + 1. 
If the date of interest occurs prior to the first dose/randomization date then study day will be 
calculated as (date of interest – date of first dose/randomization). 
There is no Study Day 0. 
5.2.1.2. 
Change from baseline 
Change from baseline is calculated as (postbaseline result – baseline result). 
Percent change from baseline is calculated as ((change from baseline/baseline result) × 100) or 
equivalently as 100(postbaseline value/baseline value - 1). 
If either the baseline or the postbaseline result is missing, the change from baseline and 
percentage change from baseline values are missing. 
5.2.1.3. 
BMI 
BMI is calculated as: 





2
2
/
.
weight kg
BMI kg m
height m

 
5.2.1.4. 
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. 
 
5.2.1.5. 
QTcF 
QTcF is calculated as: 
QTcF = 
𝑄𝑇
( 𝑅𝑅
1𝑠𝑒𝑐)
1
3
. 
 
 
5.2.1.6. 
Time Since Ulcerative Colitis Diagnosis 
Time since UC diagnosis (years) as of the first dose date is calculated as (first dose date - 
diagnosis date )/365.25. It is left unrounded for calculation of summary statistics but rounded to 
1 decimal place for display. 
5.2.1.7. 
Prior Biologic Failure  
Subjects who have entered primary non-response, secondary non-response or intolerant to at 
least one biologic treatment are defined as failing prior biologic treatment. All other subjects 
regardless of receiving prior biologic treatment are not considered failures. 
Subjects who have not received a biologic are considered “biologic-naïve”. 
Subjects who have received a biologic but have not met the criteria for failure above are 
considered “bio-experienced [but not documented failure]”. 
5.2.1.8. 
Prior Biologic Mechanism of Actions 
Anti-tumor necrosis factor-alpha therapies: 
 
Adalimumab  
 
Golimumab  
 
Infliximab  
Anti-integrin therapy: 
 
Vedolizumab 
Anti-interleukin-12 and interleukin-23 therapy 
 
Ustekinumab  
5.2.1.9. 
Creatinine Clearance 
Creatinine clearance (mL/min) will be estimated using the Cockcroft-Gault equation, as follows: 


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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) 
 
Ideal body weight =  
50 kg + 2.3 kg for each  
2.54 cm over 152.4 cm  
, if male  
Ideal body weight =  
45.5 kg + 2.3 kg for each  
2.54 cm over 152.4 cm  
, if female 
Serum Creatinine (mg/dL) = 
Serum Creatinine (umol/L)/88.4 
 
 
5.2.2. 
Missing Date Imputation 
5.2.2.1. 
Missing/Incomplete AE/Start Date 
Imputation of dates with missing day and/or month is only applied to TEAEs. TEAE start dates 
with missing day or month will be imputed as follows: 
 If day and month are missing but year is available, then the imputed day and month 
will be 01 Jan 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 injection date if they have the same month and 
year, whichever is later. 
5.2.2.2. 
Missing/Incomplete AE/Medication End Date/Time 
Imputation of dates with missing day and/or month is only applied to TEAEs when AE duration 
is calculated. TEAE end dates with missing day or month will be imputed as following: 
 If day and month are missing but year is available, then the imputed day and month 
will be 31 Dec [with a time of 23:59 if applicable’] or the 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. 


5.2.2.3. 
Missing/Incomplete Start for Medication 
To determine whether medications were used prior to initiation of dosing and whether they were 
used after initiation of dosing, missing or partial dates for medications will be imputed according 
to the following rule: 
Missing medication start date/time: 
 If day and month are missing but year is available, then the imputed day and month 
will be 31 Dec [with a time of 23:59 if applicable] or the study exit date if they have 
the same year, whichever is earlier. 
 If day is missing but the month and year are available, then the imputed day will be 
the first day [or 1 minute after midnight if applicable] of the month or the first dose 
date if they have the same month and year, whichever is later. 
 If day, month and years are completely missing, impute as date and time of first dose 
if 1) end date is not missing and occurs on and after date of first dose, or 2) end date 
is missing but marked as “ongoing”. 
5.2.3. 
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, e.g., specimen hemolyzed. 
Laboratory data that are continuous in nature but are less than the lower limit of 
quantitation/limit of detection (LOD) will be, in general, imputed as follows: 
 A value that is 1 unit less than the LOD will be used for calculation of descriptive 
statistics if the data are reported in the form of “< x” (x is considered as the LOD).  
More specifically, x−1 is used for data summarization if the data are reported in the 
form of “< x”; and x.e where e = d−1, will be used for analysis if the data are reported 
in the form of “< x.d”; 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 more than the LOD will be used for calculation of descriptive 
statistics if the data are reported in the form of “> x” (x is considered as the LOD).  
More specifically, x+1 is used for data summarization if the data are reported in the 
form of “> x”; and x.e where e = d+1, will be used for analysis if the data are reported 
in the form of “< x.d”; 
 
5.2.4. 
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. 


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For graded adverse event summaries, AEs with no grade reported will be graded as severe. 
5.3. 
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: 
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". 
5.4. 
Diary Data derivations 
5.4.1. 
Selection of diary days to use in calculation 
Derivation of rectal bleeding and stool frequency subscores will consider the 7 days prior to: 
 
Treatment start date for calculation Baseline score. 
 
Start date of study visit for Week 2, 4, 8a, 12 and 16. 
Days of endoscopy prep, days of endoscopy and the day after endoscopy are set to missing as 
endoscopy affects rectal bleeding (and stool frequency) 
To select the appropriate 3 days in the calculation: 
 
Find 3 most recent consecutive days in 7 day period 
 
If 3 days of consecutive diary data are not available then use 3 most recent days 
 If there are not 3 days of data available then missing 


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5.4.2. 
Rectal Bleeding 
Score calculated by averaging the 3 days and rounding to closest whole number i.e. scores of 1, 
2, 2, then average=  1.67, round to score of 2 
5.4.3. 
Stool Frequency 
Score calculated through the following steps: 
 Average stool score calculated by taking average of the 3 days selected scores and 
rounding to closest whole number (from Evening Diary) 
 
Average stool score then has the subjects normal stool count subtracted (from Normal 
Stool Frequency)  from it to give number of stools above normal 
 
Then this new score ( number of stools above normal) is mapped as follows 
5.4.4. 
Diary Weeks 
Analysis of endpoints by diary weeks will be mapped according to the table below: 
Table 11: 
Diary Weeks 
Nominal Period 
Start (days) 
Stop (days) 
Diary Week 1 
1 
7 
Diary Week 2 
8 
14 
Diary Week 3 
15 
21 
Diary Week 4 
22 
28 
Diary Week 5 
29 
35 
Diary Week 6 
36 
42 
Diary Week 7 
43 
49 
Diary Week 8 
50 
56 
Diary Week 9 
57 
63 
Diary Week 10 
64 
70 
Diary Week 11 
71 
77 
Diary Week 12 
78 
84 
Diary Week 13 
85 
91 
Diary Week 14 
92 
98 
Diary Week 15 
99 
105 
Diary Week 16 
106 
112 
 


 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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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 
≥65 - <80 
<65 
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 
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 


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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] 
Creatine Kinase 
Increase 
>ULN - ≤2.5 
xULN 
>2.5 xULN - ≤5.0 
xULN 
>5.0 xULN - ≤10.0 
xULN 
>10.0 xULN 
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-
124 mmol/L 
regardless of 
symptoms 
<120 
Triglycerides 
(mmol/L) 
Increase 
1.71 - ≤3.42 
>3.42 - ≤5.7  
>5.7 - ≤11.4  
>11.4 
 
5.9. 
Multiple Imputation 
Missing data after application of the appropriate intercurrent event strategy for (a) the primary 
estimand sensitivity analysis and (b) all supplementary estimand 1 analyses, is assumed missing 


at random (MAR). A Multiple Imputation (MI) method will be used to impute missing data 
where the MI procedure will be used.  
The MI procedure in the SAS Software is a multiple imputation procedure that creates multiply 
imputed data sets for incomplete p-dimensional multivariate data. It uses methods that 
incorporate appropriate variability across the m number of imputations. Once the m complete 
data sets are analyzed by using standard procedures, the MIANALYZE procedure can be used to 
generate valid statistical inferences about these parameters by combining results from the m 
complete data sets.  
 The missing data are filled in m times to generate m complete data sets.  
 The m complete data sets are analyzed by using standard procedures.  
 The results from the m complete data sets are combined for the inference. 
The following 5 step process will be followed for the primary estimand sensitivity analysis and 
all supplementary estimand 1 analyses:  
1. To explore missing data patterns the MI procedure will be performed with 0 imputations 
and presented by treatment group for the following list of variables: 
a. Prior biologic failure,  
b. Corticosteroid use at enrolment,  
c. Stool frequency, Rectal Bleeding and PGA scores at Baseline, Week 2, Week 4 
and Week 8 
d. Endoscopy score at Baseline and Week 8. 
[Note: stratification factors and baseline variables are expected to be non-missing due to study 
eligibility criteria] 
2. Generate 20 sets of imputed datasets separately for each treatment group using a fully 
conditional specification (FCS) with the logistic method (i.e. FCS LOGISTIC). The FCS 
statement will specify each of the total Mayo score components at Week 8 and both the 
CLASS and VAR statements will specify all variables listed in step 1.  
3. The total Mayo score and respective change from baseline score will be calculated for 
each subject on each set of imputed datasets.  
4. The statistical analysis plan specified ANCOVA model will be performed on each of the 
20 imputed datasets.  
5. Finally, the MIANALYZE procedure combines the results and provides valid statistical 
inferences.  


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{Study/Report Number} 
{Sponsor Name} 
 
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STATISTICAL ANALYSIS PLAN 
PHASE II-III 
Protocol Title:  
A Phase 2b/3 Multi-Center, Randomized, Double-Blind, 
Multi-Dose, Placebo-Controlled, Parallel-Group Set of 
Studies to Evaluate the Efficacy and Safety of Induction and 
Maintenance Therapy with TD˗1473 in Subjects with 
Moderately-to-Severely Active Ulcerative Colitis  
Protocol Number:   
0157 
Compound Number: 
TD-1473 
Short Title 
Rhea: Efficacy and Safety of TD-1473 in Ulcerative Colitis  
Sponsor Name:  
Theravance Biopharma Ireland Limited 
Legal Registered Address: 
Connaught House  
1 Burlington Road  
Dublin 4  
D04 C5Y6  
Ireland 
 
EudraCT No. 
2018-002136-24  
 
   
 
This study will be conducted in compliance with Good Clinical Practice. 
CONFIDENTIAL 
This document is confidential and property of Theravance Biopharma, Inc. It may not be copied 
or provided to any other party without the express written consent of Theravance Biopharma, Inc 
 
© Theravance Biopharma (Unpublished Work). All rights reserved. 


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SIGNATURE PAGE 
TD-1473 
 
0157 
 
Author: 
 
 
 
Theravance Biopharma Ireland Limited. 
 
Date 
 
 
 
 
Reviewer:
 
 
 
Theravance Biopharma US, Inc. 
 
Date 
 
 
 
 
Reviewer:
 
 
 
Theravance Biopharma Ireland Limited. 
 
Date 
 
11 November 2021 | 05:49 PST
11 November 2021 | 09:18 PST
12 November 2021 | 07:40 PST


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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................7 
SAP VERSION HISTORY..............................................................................................................9 
1. 
INTRODUCTION ......................................................................................................10 
1.1. 
Objectives and Endpoints ...........................................................................................11 
1.1.1. 
Primary Objective(s) and Endpoint(s) ........................................................................11 
1.1.2. 
Secondary Objective(s) and Endpoint(s) ....................................................................11 
 
 
1.2. 
Study Design ...............................................................................................................12 
1.3. 
Treatment Assignment and Blinding ..........................................................................14 
1.4. 
Schedule of Assessments ............................................................................................15 
1.5. 
Sample Size Determination ........................................................................................16 
2. 
ANALYSIS SETS ......................................................................................................17 
3. 
STATISTICAL ANALYSES .....................................................................................18 
3.1. 
General Considerations ...............................................................................................18 
3.2. 
Study Subjects ............................................................................................................18 
3.2.1. 
Subject Disposition and Completion Status ...............................................................18 
3.2.2. 
Demographic and Baseline Characteristics ................................................................19 
3.2.3. 
Protocol Deviations ....................................................................................................19 
3.2.4. 
Medical History ..........................................................................................................19 
3.2.5. 
Prior/Concomitant Medications ..................................................................................19 
3.3. 
Primary Endpoint(s) Analysis .....................................................................................19 
3.3.1. 
Definition of Primary Endpoint ..................................................................................19 
3.3.2. 
Statistical Hypotheses .................................................................................................19 
3.3.3. 
Main Analysis Methods ..............................................................................................19 
3.3.3.1. 
Missing Data Handling ...............................................................................................20 
3.3.4. 
Sensitivity Analyses ....................................................................................................20 
3.3.5. 
Supplementary Analyses ............................................................................................20 
3.4. 
Secondary Endpoint(s) Analyses ................................................................................20 
3.4.1. 
Definition of Secondary Endpoint(s) ..........................................................................20 
3.4.2. 
Statistical Hypotheses .................................................................................................20 


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3.4.3. 
Main Analysis Methods ..............................................................................................20 
3.4.3.1. 
Missing Data Handling ...............................................................................................21 
3.4.4. 
Sensitivity Analyses ....................................................................................................21 
3.4.5. 
Supplementary Analyses ............................................................................................21 
3.5. 
Multiplicity Adjustment (if applicable) ......................................................................21 
 
 
3.7. 
Safety Analyses ..........................................................................................................21 
3.7.1. 
Extent of Exposure .....................................................................................................21 
3.7.1.1. 
Treatment Compliance ................................................................................................22 
3.7.2. 
Adverse Events ...........................................................................................................22 
3.7.2.1. 
Adverse Events of Special Interest .............................................................................23 
3.7.3. 
Additional Safety Assessments (if applicable) ...........................................................23 
3.7.3.1. 
Clinical Laboratory Parameters ..................................................................................23 
3.7.3.2. 
Vital Signs ..................................................................................................................24 
3.7.3.3. 
Electrocardiogram .......................................................................................................24 
3.8. 
Other Analyses ............................................................................................................25 
3.8.1. 
Subgroup Analyses .....................................................................................................25 
3.9. 
Interim Analyses .........................................................................................................25 
3.9.1. 
Data Monitoring Committee .......................................................................................26 
4. 
REFERENCES ...........................................................................................................27 
5. 
SUPPORTING DOCUMENTATION ........................................................................28 
5.1. 
Appendix 1: Changes to Protocol-Planned Analyses .................................................28 
5.2. 
Appendix 3: Date Conventions and Transformations ................................................28 
5.2.1.1. 
Derived and Transformed Data ..................................................................................28 
5.2.2. 
Missing Data Imputation ............................................................................................28 
5.2.2.1. 
Missing/Incomplete AE/Start Date .............................................................................29 
5.2.2.2. 
Missing/Incomplete AE/Medication End Date/Time .................................................29 
5.2.2.3. 
Missing/Incomplete Start for Medication ...................................................................29 
5.2.2.4. 
Laboratory Data ..........................................................................................................29 
5.2.2.5. 
AE Severity .................................................................................................................30 
 
LIST OF TABLES 


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Table 1: 
List of Abbreviations ....................................................................................................7 
Table 2: 
SAP Version History Summary ....................................................................................8 
Table 3: 
Analysis Sets ...............................................................................................................16 
Table 4: 
Clinical Remission by aMS Definition .......................................................................18 
Table 5: 
Criteria for Marked Abnormalities in Vital Signs ......................................................23 
Table 6: 
ECG Interval Categories .............................................................................................24 
 
LIST OF FIGURES 
Figure 1: 
Protocol Schema .........................................................................................................12 
 
 


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LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
BMI 
body mass index 
CI 
confidence interval 
CSR 
clinical study report 
DMC 
data monitoring committee 
ITT 
intent-to-treat 
LLoQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
SD 
standard deviation 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMQs 
standardized MedDRA queries 
ULN 
upper limit of normal 
 


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1. 
INTRODUCTION 
This document outlines the plan for the summarization and analysis of clinical data 
collected in the Phase 3 Maintenance Study of Protocol 0157 for TD-1473.  
Protocol 0157 comprises 3 separate studies within a single protocol. The purpose of 
multiple studies within a single protocol is to increase operational efficiency and 
reduce operational costs.  
The 0157 maintenance study was terminated early due to lack of efficacy in the 0157 
Phase 2b Induction study, all subjects date of last dose occurred by 11 September 
2021 date and end of study visit by 20 October 2021 date. 
The 0157 CSR will be an abbreviated CSR incorporating data from the Phase 2b 
Induction and Phase 3 Maintenance study and as a result all protocol defined analyses 
will not be performed.


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1.1. 
Objectives and Endpoints 
1.1.1. 
Primary Objective(s) and Endpoint(s) 
The primary objectives of the study are as follows:  
• 
Assess the clinical remission rates associated with TD-1473 compared to placebo treatment at 
mWeek 44  
• 
Assess the safety and tolerability of TD-1473 with up to 44 additional weeks of treatment  
 
The primary endpoint is clinical remission by adapted Mayo score components at mWeek 44  
1.1.2. 
Secondary Objective(s) and Endpoint(s) 
The key secondary objectives of the Study are to assess the rates of the following associated with 
TD-1473 compared to placebo treatment:  
• 
Clinical response, endoscopic healing, symptomatic remission, and mucosal healing at 
mWeek 44  
• 
Corticosteroid-free remission at mWeek 44  
• 
Maintenance of clinical remission at mWeek 44 in those who were in clinical remission at 
mWeek 0 
As the study was terminated early only the following secondary endpoints will be analyzed:  
• 
Clinical response by adapted Mayo score at mWeek 44 
• 
Endoscopic healing at mWeek 44  
• 
Symptomatic remission at mWeek 44  
• 
 
 
 
  
 
  
 
  
 
 
 
1.2. 
Study Design 
This single protocol includes three studies: a Phase 2b dose-finding Induction Study, a Phase 3 
dose-confirming Induction Study, and a Phase 3 randomized-withdrawal Maintenance Study 
(Figure 1).  
Figure 1: Protocol Schema 


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Each of the three studies will utilize a multi-center, randomized, double-blind, 
placebo-controlled, parallel-group design to evaluate various doses of TD-1473 compared to 
placebo in subjects with moderately-to-severely active ulcerative colitis (UC).  
The Induction Studies will target subjects with moderately-to-severely active UC who 
demonstrate an inadequate response or failure to tolerate conventional or biologic therapy.  
The Maintenance Study will be a randomized withdrawal study targeting subjects with 
moderately-to severely-active UC who demonstrate a clinical response to induction treatment 
with TD-1473. 
Maintenance Study 
In summary, subjects who demonstrate clinical response to a total of 8 weeks of TD-1473 induction 
therapy, either at Week 8 or Week 16, will be re-randomized. Those who demonstrate response to 
placebo at Week 8 or those who demonstrate response to a total of 16 weeks of TD-1473 treatment at 
Week 16 will enter the Maintenance Study on the same study drug treatment as during Induction for 
the purpose of maintaining blinding. The Maintenance Study consists of treatment for 44 weeks. 
During the Maintenance Study, subjects must taper their corticosteroid dose using the regimen 
outlined in Section 6.5.3 if they entered the study on corticosteroids. 
The randomization will be stratified by clinical remission status at mWeek 0 using adapted Mayo 
score component definition, and corticosteroid use at enrollment into the Phase 3 Maintenance Study. 
In addition, randomization will also be stratified by subjects who reach clinical response after 
receiving 8 weeks of TD-1473 versus subjects who reach clinical response after receiving placebo 
during the first 8 weeks and then TD-1473 80 mg during extended induction. 
  


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1.3. 
Treatment Assignment and Blinding  
Randomization of the Maintenance Study will be stratified by 3 stratification factors (8 strata): 1) 
clinical remission status using adapted Mayo score component definition, 2) corticosteroid use at 
enrollment into the Maintenance Study (4 strata), and 3) subjects who achieved clinical response on 
TD-1473 during Induction at Week 8 versus subjects who reach clinical response after receiving 
placebo during the first 8 weeks and then TD-1473 80 mg during extended induction. 
 
 


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1.4. 
Schedule of Assessments  
The schedule of assessments is presented in the protocol. 


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1.5. 
Sample Size Determination 
Upon completion of the analyses based on the Phase 2b Induction data, the sample size may be 
refined. Currently, it is estimated that 120 subjects per dose group (360 subjects total) will 
provide at least 90% disjunctive power to demonstrate at least one of the two TD-1473 doses is 
effective compared to placebo for the primary endpoint of clinical remission at Maintenance 
Week 44 under the following assumptions:  
• 
Hochberg step-up procedure adjustment for multiple comparisons  
• 
Family-wise type 1 error rate to be controlled at 5% (2-sided)  
• 
Clinical remission rate of 15% for placebo at Week 44  
• 
Clinical remission rates of 30% and 40% for the two active TD-1473 doses at Maintenance 
Week 44 
 
A total of 360 subjects total will provide 80% conjunctive power to demonstrate both doses of 
TD-1473 are effective compared to placebo for clinical remission at Maintenance. In addition, 
360 subjects total will also provide adequate power (at least 80%) to demonstrate that at least one 
of the two TD-1473 doses is effective compared to placebo for the key secondary endpoints of 
symptomatic remission and endoscopic healing at Maintenance Week 44.  
 
It is estimated that with 880 subjects enrolled in the Induction studies, approximately 400 
subjects will be eligible for re-randomization into the Maintenance study. However, about 30 of 
these 400 subjects will be assigned to the dose that is de-selected based on the analyses of the 
Phase 2b Induction Study data and therefore not included in the primary efficacy analysis 
population of the Phase 3 Maintenance Study. In addition, approximately 170 subjects will also 
enter Maintenance and continue to receive the same treatment as assigned in the Induction study 
in order to maintain blind. These subjects will also not be included in the primary efficacy 
analysis population of the Phase 3 Maintenance Study. 


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2. 
ANALYSIS SETS 
Table 3: 
Analysis Sets 
Analysis Set 
Definition 
Treatment 
Assignment 
Safety 
The Safety analysis set will include all subjects who 
received at least one dose of study drug (TD-1473 or 
placebo) in the Maintenance study.  
The Safety analysis set is the primary analysis set for 
safety analyses. 
Actual Treatment 
received 
ITT 
The ITT set comprises all randomized into the Phase 
3 Maintenance study.  
Note: Subjects who demonstrate clinical response to a 
total of 8 weeks of TD-1473 induction therapy, either 
at Week 8 or Week 16 are eligible to be re-randomized 
into the maintenance study. 
Randomized 
treatment 
mITT 
The mITT set comprises all randomized into the 
Phase 3 Maintenance study who were also treated.  
Note: Subjects who demonstrate clinical response to a 
total of 8 weeks of TD-1473 induction therapy, either 
at Week 8 or Week 16 are eligible to be re-randomized 
into the maintenance study. 
Randomized 
treatment 
 


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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 visits will be included in the 
summaries, statistical analysis, and calculation of derived parameters. All assessments will be 
summarized using CRF visits.  
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. 
For safety assessments, summary statistics will be reported by treatment. 
Analyses and tabulations will generally be prepared using SAS, version 9.4 or later. 
3.2. 
Study Subjects 
Unless otherwise noted, the safety analysis set is the main analysis set used in the summarization 
of general (Study Population) analyses. Disposition and Demographics tables will be presented 
also on the ITT population. 
3.2.1. 
Subject Disposition and Completion Status 
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 subjects who completed treatment 
 Number of subjects who discontinued treatment early 
 Primary reasons for early treatment discontinuation, with frequencies 
 


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3.2.2. 
Demographic and Baseline Characteristics 
Demographic data including age, sex, race, ethnicity, weight, height, and body mass index (BMI) 
will be summarized overall and by treatment group. Sex, race, and ethnicity frequency 
distributions will be provided.  
3.2.3. 
Protocol Deviations 
A listing of important protocol deviations will be presented. 
3.2.4. 
Medical History 
A listing of subjects medical history will be provided. 
3.2.5. 
Prior/Concomitant Medications 
A listing of all concomitant medications will be presented. 
3.3. 
Primary Endpoint(s) Analysis 
3.3.1. 
Definition of Primary Endpoint 
The primary endpoint  is: 
• 
Clinical remission by adapted Mayo score components at mWeek 44 
The adapted Mayo score (0-9 points) is the sum of three components: stool frequency (0-3 pts), 
rectal bleeding (0-3 pts), and Mayo endoscopic (0-3 pts) subscores. 
Clinical remission by adapted Mayo score requires each of the subscores to meet the criteria 
defined in Table 4. There will be no imputation of missing components, if a component is 
missing then the endpoint is missing. 
Table 4: 
Clinical Remission by aMS Definition 
Mayo Definition 
Stool 
Frequency 
Rectal 
Bleeding 
Endoscopic 
Findings 
Adapted Mayo Score (aMS) 
0 or 1 
0 
0 or 1 
3.3.2. 
Statistical Hypotheses 
The primary estimate of interest, clinical remission by adapted Mayo score components at 
mWeek 44, is used to evaluate the effectiveness of  therapy relative to the placebo comparator in 
the mITT population.  
As the 0157 maintenance study was terminated early the study is not powered to detect a 
difference between the active groups and placebo, all analysis and p-values will be interpreted 
in a purely descriptive manner. 
3.3.3. 
Main Analysis Methods  
The proportions of subjects with clinical remission by aMS definitions will be compared 
between each TD-1473 treatment group and the placebo group using a fishers exact test. 


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Summaries of the proportion of subjects in remission will be presented by treatment group and p-
values from the fishers exact test for the comparison of each dose of TD-1473 versus placebo. 
3.3.3.1. 
Missing Data Handling  
There will be no imputation of missing data. 
3.3.4. 
Sensitivity Analyses 
There will be no sensitivity analyses performed. 
3.3.5. 
Supplementary Analyses 
There will be no supplementary analyses performed. 
3.4. 
Secondary Endpoint(s) Analyses 
3.4.1. 
Definition of Secondary Endpoint(s) 
As the study was terminated early only the following secondary endpoints will be analyzed: 
 Endoscopic healing at mWeek 44 
 Clinical response by adapted Mayo at mWeek44 
 Symptomatic remission at mWeek44 
Endoscopic Healing 
Mayo endoscopic findings subscore ≤ 1. 
Symptomatic Remission 
Symptomatic remission is defined as stool frequency subscore ≤ 1 and rectal bleeding subscore = 
0. 
Clinical Response by adapted Mayo score 
Clinical response is defined as a reduction from baseline in adapted Mayo score of ≥ 2 points and 
≥ 30% relative to baseline. It also requires ≥ 1 reduction in the rectal bleeding subscore or an 
absolute subscore ≤ 1.  
3.4.2. 
Statistical Hypotheses 
As the study was terminated early there will be no hypothesis testing of secondary endpoints, all 
p-values will be interpreted in a purely descriptive manner. 
3.4.3. 
Main Analysis Methods  
Analysis for the secondary endpoints will be performed similar to the primary endpoint outlined 
in Section 3.3.3. 
3.4.3.1. 
Missing Data Handling  
Refer to Section 3.3.3.1.  


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3.4.4. 
Sensitivity Analyses 
Refer to Section 3.3.4. 
3.4.5. 
Supplementary Analyses 
There will be no supplementary analyses. 
3.5. 
Multiplicity Adjustment  
As the study was terminated early there will be no hypothesis testing and associated multiplicity 
adjustment.: 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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.   
For all safety analyses, the safety analysis population will be used. 
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 for the study will be displayed in weeks and calculated as: 
(𝑙𝑎𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑟𝑒𝑡𝑢𝑟𝑛 𝑑𝑎𝑡𝑒 - 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑑𝑎𝑡𝑒 +  1) 
7
 


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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 100 × 0.5 × (number of capsules dispensed - number 
of capsules returned)/(date of last dose - date of first dose + 1). 
Study drug compliance over the interval from first to last dose will be assessed using the 
following categories: 
 ≥ 100% 
 ≥ 90% to < 100% 
 ≥ 80% to < 90% 
 < 80% 
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 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. 
Treatment emergent adverse events are defined as AEs with onset on or after the first initiation 
of study drug up to the date of study follow visit. Subjects who do not complete study follow-up 
visit will include AE’s up to date of last dose study drug + 28 days.  
Only treatment-emergent AEs will be summarized in the tables. Listings of both 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. 
The number and percentage of subjects with TEAEs [in each study drug group/during the study] 
will be tabulated separately by  
 Preferred term 
 System organ class and preferred term  
 System organ class, preferred term, and severity 
The number and percentage of subjects with treatment-related TEAEs [in each study drug 
group/during the study] will be tabulated by system organ class and preferred term. 
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. 


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Summary tables will also be provided for: 
 TESAEs by SOC and PT 
 TEAEs leading to discontinuation of study drug by SOC and PT 
 Drug related TEAEs by SOC, PT and severity 
 Drug related TESAEs by SOC and PT 
 TEAEs resulting in death by PT 
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 
 Cardiovascular Event (e.g. myocardial infarction or cerebrovascular accident) 
The incidence of AESI’s will be summarized overall and by SOC and PT. 
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.  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.  


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The number and percentage of subjects with clinically abnormal lab values will also be 
summarized by timepoint for the following criteria:  
 absolute neutrophil count of < 1.0 x 109/L 
 white blood cell count of < 2.0 x 109/L  
 absolute lymphocyte count of < 0.5 x 109/L 
A summary of maximum National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) toxicity grade (Appendix 5.3) for postbaseline laboratory values.  
A listing of all abnormal lab values will 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 below and will be flagged in the 
listing. 
Table 5: 
Criteria for Marked Abnormalities in Vital Signs 
Heart Rate (bpm) 
Systolic Blood Pressure 
(mm Hg) 
Diastolic Blood Pressure 
(mm Hg) 
< 40 
< 85 
< 45 
> 110 
> 160 
> 100 
3.7.3.3. 
Electrocardiogram 
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 
correction. 
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 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 below will be presented in Electrocardiogram Categorical Summary by 
Visit and Time Point. 


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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. 
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 6: 
ECG Interval Categories 
Heart Rate 
(bpm) 
Heart Rate 
Change 
from 
Baseline 
(bpm) 
PR 
 Interval 
(msec) 
PR 
Percentage 
Change 
From 
Baseline 
(%) 
QRS 
 Interval 
(msec) 
QTcF 
(msec) 
QTcF 
change 
from 
Baseline 
(msec) 
> 120 
≥ 20 
≥ 200 
≥ 15 
≥ 120 
Males: 
≤ 30 
> 130 
≥ 30 
≥ 220 
≥ 25 
 
< 430 
>30, ≤ 60 
 
 
 
 
 
≥ 430 
> 60 
 
 
 
 
 
≥ 450 
 
 
 
 
 
 
≥ 470 
 
 
 
 
 
 
≥ 480 
 
 
 
 
 
 
≥ 500 
 
 
 
 
 
 
Females: 
 
 
 
 
 
 
< 450 
 
 
 
 
 
 
≥ 450 
 
 
 
 
 
 
≥ 470 
 
 
 
 
 
 
≥ 480 
 
 
 
 
 
 
≥ 500 
 
3.8. 
Other Analyses 
3.8.1. 
Subgroup Analyses 
Not applicable due to early termination of study. 
3.9. 
Interim Analyses 
There is no interim analysis planned. 


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3.9.1. 
Data Monitoring Committee 
 
 
 
 
 


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


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5. 
SUPPORTING DOCUMENTATION 
5.1. 
Appendix 1: Changes to Protocol-Planned Analyses  
The major changes to the analyses specified in the protocol, dated 14 May 2020, are as follows 
due to early termination of the study: 
 deletion of secondary efficacy parameters corticosteroid free remission, maintenance 
of clinical remission and mucosal healing. The only exploratory efficacy parameter to 
be displayed is endoscopic remission. 
 Changes in the statistical methodology for the primary, secondary efficacy and 
exploratory parameters from  CMH to fishers exact test due to small sample size 
 
5.2. 
Appendix 3: Date Conventions and Transformations  
5.2.1.1. 
Derived and Transformed Data  
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. 
Change from Baseline 
Change from baseline is calculated as (postbaseline result – baseline result). 
Percent change from baseline is calculated as ((change from baseline/baseline result) × 100) or 
equivalently as 100(postbaseline value/baseline value - 1). 
If either the baseline or the postbaseline result is missing, the change from baseline and 
percentage change from baseline values are missing. 
5.2.2. 
Missing Data Imputation  
 


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5.2.2.1. 
Missing/Incomplete AE/Start Date 
Imputation of dates with missing day and/or month is only applied to TEAEs. TEAE start dates 
with missing day or month will be imputed as follows: 
 If day and month are missing but year is available, then the imputed day and month 
will be 01 Jan 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 injection date if they have the same month and 
year, whichever is later. 
5.2.2.2. 
Missing/Incomplete AE/Medication End Date/Time 
Imputation of dates with missing day and/or month is only applied to TEAEs when AE duration 
is calculated. TEAE end dates with missing day or month will be imputed as following: 
 If day and month are missing but year is available, then the imputed day and month 
will be 31 Dec [with a time of 23:59 if applicable’] or the 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. 
5.2.2.3. 
Missing/Incomplete Start for Medication 
To determine whether medications were used prior to initiation of dosing and whether they were 
used after initiation of dosing, missing or partial dates for medications will be imputed according 
to the following rule: 
Missing medication start date/time: 
 If day and month are missing but year is available, then the imputed day and month 
will be 1 Jan [with a time of 01-01T00:01 if applicable] or the study exit date if they 
have the same year, whichever is earlier. 
 If day is missing but the month and year are available, then the imputed day will be 
the first day [or 1 minute after midnight if applicable] of the month or the first dose 
date if they have the same month and year, whichever is later. 
 If day, month and years are completely missing, impute as date and time of first dose 
if 1) end date is not missing and occurs on and after date of first dose, or 2) end date 
is missing but marked as “ongoing”. 
5.2.2.4. 
Laboratory Data   
For non-efficacy laboratory data, a missing baseline value will be replaced with the last available 
assessment, generally the screening assessment. A retest value will be used if the original test 
result is invalid (e.g., specimen hemolyzed). 


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5.2.2.5. 
AE Severity 
For graded adverse event summaries, AEs with no grade reported will be graded as severe. 
5.3. 
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 
≥65 - <80 
<65 
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 
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] 


Theravance Biopharma 
 
20OCT2021 
Statistical Analysis Plan - Protocol 0157 
 
Page 14 of 61 
 
Confidential – Property of Theravance Biopharma, Inc. 
Creatine Kinase 
Increase 
>ULN - ≤2.5 
xULN 
>2.5 xULN - ≤5.0 
xULN 
>5.0 xULN - ≤10.0 
xULN 
>10.0 xULN 
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-
124 mmol/L 
regardless of 
symptoms 
<120 
Triglycerides 
(mmol/L) 
Increase 
1.71 - ≤3.42 
>3.42 - ≤5.7  
>5.7 - ≤11.4  
>11.4 
 
 
 
  
 
 
 


Theravance Biopharma 
 
20OCT2021 
Statistical Analysis Plan - Protocol 0157 
 
Page 14 of 61 
 
Confidential – Property of Theravance Biopharma, Inc.