Clinical trial NCT04596293
Conditions: Ulcerative Colitis
Sponsor: Bridge Biotherapeutics, Inc.
Start date: 2021-06-11; Completion date: 2022-07-12
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomised, double-blind, placebo-controlled, proof of clinical principle study to explore the efficacy and safety of orally administered BBT-401-1S in subjects with ulcerative colitis.

Detailed description:

Arms: arm 1: * Induction Phase: BBT-401 800mg for 8 weeks
* Extension Phase: After 8 weeks,

  * Participants who achieved clinical remission in the induction phase will continue the same treatment for 8 weeks
  * Participants who did not achieve clinical remission in the induction phase will receive BBT-401 1600mg for 8 weeks arm 2: * Induction Phase: BBT-401 1600mg for 8 weeks
* Extension Phase: After 8 weeks, Participants will continue the same treatment for 8 weeks arm 3: * Induction Phase: Placebo for 8 weeks
* Extension Phase: After 8 weeks,

  * Participants who achieved clinical remission in the induction phase will continue the same treatment for 8 weeks
  * Participants who did not achieve clinical remission in the induction phase will receive BBT-401 800mg for 8 weeks
Interventions: intervention 1: BBT-401-1S or Placebo
Intervention descriptions: intervention 1: Administered by 200mg capsules of BBT-401-1S or placebo

Protocol documents:
Prot_000.pdf: 
TITLE PAGE 
Protocol 
A Randomised, Double-blind, Placebo-controlled Study of Orally 
Administered BBT-401-1S in Subjects with Moderate to Severe Ulcerative 
Colitis, Incorporating a Response-Adaptive, Double-blind Extension Phase 
Protocol Status: Final 
Protocol Date: 02 August 2021 
Protocol Version: 5 
Investigational Medicinal Product: BBT-401-1S 
Protocol Reference Number: BBT401-UC-005 
Sponsor: 
Bridge Biotherapeutics, Inc. 
C’s Tower #303 
58, Pangyo-ro 255beon-gil, Bundang-gu 
Seongnam-si, Gyeonggi-do 
Republic of Korea 
Sponsor Signatory: 
 
Medical Director 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 


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STUDY IDENTIFICATION 
Sponsor 
Bridge Biotherapeutics, Inc. 
C’s Tower #303 
58, Pangyo-ro 255beon-gil, Bundang-gu 
Seongnam-si, Gyeonggi-do 
Republic of Korea 
Sponsor’s Study Contact 
 
Director of Clinical Operations 
Bridge Biotherapeutics, Inc. 
C’s Tower #303 
58, Pangyo-ro 255beon-gil, Bundang-gu 
Seongnam-si, Gyeonggi-do 
Republic of Korea 
Sponsor’s Medical Contact 
 
Medical Director 
Bridge Biotherapeutics, Inc. 
C’s Tower #303 
58, Pangyo-ro 255beon-gil, Bundang-gu 
Seongnam-si, Gyeonggi-do 
Republic of Korea 
Statistician 
 
Senior Principal Biostatistician 
Labcorp Drug Development 


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SYNOPSIS 
Study Title 
A randomised, double-blind, placebo-controlled study of orally administered BBT-401-1S in 
subjects with moderate to severe ulcerative colitis, incorporating a response-adaptive, 
double-blind extension phase.  
Objectives 
The primary objective of this study is to explore the efficacy of orally administered 
BBT-401-1S in inducing a clinical response in subjects with active ulcerative colitis (UC). 
The secondary objectives of the study are: 
• to assess the safety and tolerability of orally administered BBT-401-1S 
• to explore additional measurements of the efficacy of orally administered 
BBT-401-1S in inducing endoscopic and clinical remission.  
The exploratory objectives of this study are to evaluate the effects of BBT-401-1S on 
endoscopic response, subject-reported outcomes, histological improvement, biomarkers, and 
long-term clinical remission. 
Endpoints 
Primary Efficacy: 
• clinical response rate at Day 57, as measured by a reduction of ≥3 points and ≥30% 
improvement from baseline of total Mayo score, which includes a decrease in rectal 
bleeding subscore of ≥1 point or an absolute rectal bleeding subscore ≤1.  
Secondary Efficacy: 
• clinical remission at Day 57, as measured by a total Mayo score of ≤2 points, with no 
individual subscore exceeding 1 point 
• achievement of endoscopic remission at Day 57, as measured by a Mayo endoscopic 
subscore of 0 or 1. 
Exploratory Efficacy: 
• endoscopic response rate at Day 57, as defined by a ≥2-point reduction from baseline 
in Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score 
• endoscopic response rate at Day 57, as defined by a reduction of ≥1 grade in the 
Mayo endoscopic subscore 
• Inflammatory Bowel Disease Questionnaire (IBDQ) total score, as measured by 
change from baseline 
• histological improvement, as guided by change from baseline in Geboes score 


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• biomarkers, including C-reactive protein and faecal calprotectin, as measured by 
change from baseline 
• clinical remission at Day 112, as measured by a total Mayo score of ≤2 points, with 
no individual subscore exceeding 1 point 
• percentage of subjects with sustained remission at Day 112 
• clinical response rate at Day 112. 
Primary Safety: 
• adverse events and serious adverse events. 
Study Design 
This study will comprise 2 periods: a randomised, double-blind, placebo-controlled induction 
phase; and a response-adaptive, double-blind extension phase. 
Induction Phase 
Subjects will be screened for inclusion in the study within 28 days of Day 1. Eligible subjects 
will be randomised in a 1:1:1 ratio; 12 subjects will receive 800 mg BBT-401-1S once daily 
(QD) and placebo QD, 12 subjects will receive 800 mg BBT-401-1S twice daily (BID), and 
12 subjects will receive placebo BID. Subjects will receive the first dose of study drug at the 
study site on Day 1 and will administer study drug away from the study site for 56 days, 
during which they will attend 2 study site visits on Days 29 and 57. Additionally, subjects 
will be contacted by telephone on Day 8 for safety and compliance monitoring; however, at 
the discretion of the investigator, subjects may be requested to attend a study site visit on this 
day. 
Subjects who do not agree to participate in the extension phase will attend the study site for a 
follow-up visit on Day 71. 
Extension Phase 
Subjects who complete the induction phase will be offered the opportunity to enter the 
extension phase after the Day 57 visit. Subjects who agree to participate in the extension 
phase will continue study drug administration while awaiting their clinical remission status 
from the local reader. Subjects will be assigned to the treatment for the extension phase 
treatment upon receipt of their clinical remission status. 
• Subjects who achieved clinical remission in the induction phase will continue the 
same treatment. 
• Subjects who did not achieve clinical remission in the induction phase and: 
o who received placebo BID will receive 800 mg BBT-401-1S QD and 
placebo QD 
o who received 800 mg BBT-401-1S QD and placebo QD will receive 
800 mg BBT-401-1S BID  
o who received 800 mg BBT-401-1S BID will continue the same treatment. 


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Subjects will attend the study site on Days 85 and 112 (follow-up visit). Additionally, 
subjects will be contacted by telephone on Day 71 for safety and compliance monitoring; 
however, at the discretion of the investigator, subjects may be requested to attend a study site 
visit on this day. 
Number of Subjects 
Approximately 36 subjects will be randomised. 
Diagnosis and Main Criteria for Inclusion 
Male and female subjects aged ≥18 and ≤60 years who have been diagnosed with active UC 
for ≥3 months prior to Day 1, and have a total Mayo score ≥6, an endoscopic subscore ≥2, a 
rectal bleeding subscore ≥1, and a stool frequency subscore ≥1. 
Investigational Medicinal Products, Dose, and Mode of Administration 
200 mg BBT-401-1S capsules for oral administration. Dose levels of 800 mg QD and BID 
will be studied. 
Reference Product and Mode of Administration 
Reference product: placebo capsules for oral administration. 
Duration of Subject Participation in the Study 
Planned Screening duration: up to 4 weeks. 
Induction phase: approximately 10 weeks. 
Extension phase: approximately 8 weeks. 
Total planned study duration (screening to follow-up): approximately 20 weeks for subjects 
who are enrolled into the extension phase and approximately 14 weeks for subjects who are 
not enrolled into the extension phase. 
Study Populations 
The intent-to-treat population will include all subjects who received at least 1 dose of study 
drug, have a partial Mayo score recorded on Day 1, and at least 1 post-baseline Mayo score 
recorded. 
The safety population will include all subjects who received at least 1 dose of study drug. 
Statistical Methods 
Primary and Secondary Efficacy Analyses 
Descriptive summaries will be presented for clinical response, clinical remission, and 
endoscopic remission rates. The estimate and 95% confidence interval (CI) of clinical 
response, clinical remission, and endoscopic remission rates at Day 57 will be calculated 


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using the exact binomial method for each treatment. The Fisher’s exact test will be used to 
evaluate any differences between treatments. 
Exploratory Efficacy Analysis 
The estimate and 95% CI of endoscopic response rate and histological improvement at 
Day 57, and clinical response rate and the percentage of subjects with clinical remission at 
Day 112 will be calculated using the exact binomial method for each treatment. Actual values 
and change from baseline in Mayo scores, UCEIS scores, IBDQ total score, C-reactive 
protein, and faecal calprotectin over time will be summarised descriptively. No formal 
hypothesis will be tested on the exploratory efficacy endpoints. 
Safety Analysis  
Adverse events will be presented using descriptive statistics. 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................5 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF ABBREVIATIONS ..................................................................................................11 
1. 
INTRODUCTION ...........................................................................................................12 
1.1. 
Overview ................................................................................................................12 
1.2. 
Benefit-risk Assessment.........................................................................................12 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................13 
2.1. 
Objectives ..............................................................................................................13 
2.2. 
Endpoints ...............................................................................................................13 
2.2.1. 
Primary Endpoints .......................................................................................13 
2.2.2. 
Secondary Endpoints ...................................................................................13 
2.2.3. 
Exploratory Endpoints .................................................................................14 
3. 
INVESTIGATIONAL PLAN ..........................................................................................14 
3.1. 
Overall Study Design and Plan ..............................................................................14 
3.2. 
Discussion of Study Design ...................................................................................17 
3.3. 
Selection of Doses in the Study .............................................................................17 
4. 
SELECTION OF STUDY POPULATION .....................................................................17 
4.1. 
Inclusion Criteria ...................................................................................................17 
4.2. 
Exclusion Criteria ..................................................................................................18 
4.3. 
Subject Number and Identification ........................................................................19 
4.4. 
Rescreening ............................................................................................................19 
4.5. 
Screen Failures .......................................................................................................20 
4.6. 
Subject Withdrawal ................................................................................................20 
4.7. 
Study Termination .................................................................................................20 
5. 
STUDY TREATMENTS .................................................................................................21 
5.1. 
Description, Storage, Packaging, and Labelling ....................................................21 
5.2. 
Study Treatment Administration............................................................................21 
5.3. 
Randomisation .......................................................................................................21 
5.4. 
Blinding..................................................................................................................21 
5.5. 
Treatment Compliance ...........................................................................................22 
5.6. 
Rescue Therapy ......................................................................................................22 
5.7. 
Drug Accountability...............................................................................................23 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................23 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................23 


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7.1. 
Efficacy Assessments.............................................................................................24 
7.1.1. 
Endoscopy with Biopsy ...............................................................................24 
7.1.2. 
Ulcerative Colitis Endoscopic Index of Severity .........................................24 
7.1.3. 
Mayo Score ..................................................................................................24 
7.1.4. 
Inflammatory Bowel Disease Questionnaire ...............................................25 
7.1.5. 
Histopathology .............................................................................................25 
7.2. 
Biomarkers .............................................................................................................25 
7.3. 
Pharmacokinetic Assessments ...............................................................................26 
7.4. 
Safety Assessments ................................................................................................26 
7.4.1. 
Adverse Events ............................................................................................26 
7.4.2. 
Clinical Laboratory Evaluations ..................................................................26 
7.4.3. 
Vital Signs ....................................................................................................26 
7.4.4. 
12-Lead Electrocardiogram .........................................................................27 
7.4.5. 
Physical Examination...................................................................................27 
7.5. 
Guidelines, Study Assessments, and Procedures During the Coronavirus 
Disease-19 Pandemic .............................................................................................27 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................28 
8.1. 
Determination of Sample Size ...............................................................................28 
8.2. 
Analysis Populations ..............................................................................................28 
8.3. 
General Principles ..................................................................................................28 
8.4. 
Efficacy Analyses ..................................................................................................28 
8.4.1. 
Primary and Secondary Efficacy Analysis ..................................................28 
8.4.2. 
Exploratory Efficacy Analysis .....................................................................28 
8.5. 
Safety Analysis ......................................................................................................29 
8.6. 
Interim Analysis .....................................................................................................29 
9. 
REFERENCES ................................................................................................................29 
10. APPENDICES .................................................................................................................30 
Appendix 1: Adverse Event Reporting ..............................................................................31 
Appendix 2: Clinical Laboratory Evaluations ...................................................................34 
Appendix 3: Contraception Guidance ................................................................................35 
Appendix 4: Regulatory, Ethical, and Study Oversight Considerations ............................38 
Appendix 5: Ulcerative Colitis Endoscopic Index of Severity ..........................................41 
Appendix 6: Total Mayo Score ..........................................................................................42 
Appendix 7: Partial Mayo Score ........................................................................................43 
Appendix 8: Modified Mayo Score ...................................................................................44 
Appendix 9: Geboes Score.................................................................................................45 
Appendix 10: Inflammatory Bowel Disease Questionnaire ..............................................46 
Appendix 11: Schedule of Assessments ............................................................................57 
Appendix 12: Summary of Changes ..................................................................................59 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
BID 
twice daily 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
COVID-19 
coronavirus disease-19 
CRO 
contract research organisation 
DSS 
Drug Safety Services 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
GCP 
Good Clinical Practice 
HRQoL 
health-related quality of life 
IB 
investigator’s brochure 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
JAK 
Janus kinase 
IL 
interleukin 
PGA 
physician’s global assessment 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse events 
TNF 
tumour necrosis factor 
UC 
ulcerative colitis 
UCEIS 
Ulcerative Colitis Endoscopic Index of Severity 
ULN 
upper limit of normal 
 
 


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1. INTRODUCTION 
Refer to the investigator’s brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile 
of the investigational medicinal product (study drug). 
1.1. 
Overview 
Ulcerative colitis (UC) is a chronic disorder characterised by inflammation of intestinal 
mucosa, primarily the colon, as well as the rectum in approximately 95% of cases. The goals 
of treatment of UC are to induce and maintain remission of symptoms. Oral aminosalicylate 
(eg, sulfasalazine) therapy comprises the conventional standard of care in the 
pharmacological treatment of mild to moderate active UC. Corticosteroids or 
immunosuppressants may also be used to treat symptoms. Subjects unable to be treated with 
conventional therapies or those with moderate to severe disease might receive biological 
therapy (ie, an anti-tumour necrosis factor [TNF]-α agent).1 
Conventional therapies are broadly limited by safety and tolerability issues, such as thinning 
of the skin, effects on bone contributing to osteoporosis, increased risks of infection, and 
psychological effects with corticosteroid therapy, and headache, nausea, hypersensitivity 
reactions, and potential for nephrotoxicity with sulfasalazine therapy.2,3 Biologic therapy is 
known to have immunocompromising effects that increase patient risks to other diseases and 
a range of infections (mycobacterial, fungal, viral).4 Reported treatment failures further limit 
the utility of biologic therapies.5 New therapies with novel mechanisms may help address the 
unmet needs in the treatment of UC. 
BBT-401 was derived from Smad6 and developed to modulate inflammatory disorders. 
BBT-401 directly interacts with Pellino-1 protein, competitively binding in a dose-dependent 
manner, thus inhibiting the proinflammatory activity of Pellino-1. Given the inflammatory 
pathophysiology of UC and the effects of BBT-401 on inhibiting inflammatory processes, 
there is a pharmacological rationale to evaluate BBT-401 in the treatment of UC.  
. A Phase 1 clinical study of orally administered 
BBT-401-1S 
 showed no systemic 
exposure and an excellent safety and tolerability profile, with no serious adverse events 
(SAEs). Mild diarrhoea (usually transient in nature and generally not interfering with normal 
activities) was the most observed AE in the 1600-mg single- and multiple-ascending-dose 
cohorts. Additionally, orally administered BBT-401-1S was generally well tolerated at doses 
of 400 mg/day in an exploratory study of efficacy in subjects with UC. Conclusions on 
efficacy have not yet been made. 
This clinical study of BBT-401-1S is designed to explore the safety and efficacy of 
BBT-401-1S administered orally in subjects with active UC.
 
 
 
1.2. 
Benefit-risk Assessment 
Subjects participating in this study may experience therapeutic benefit to symptoms of UC.  


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Given the excellent safety and tolerability profile in the Phase 1 study and the overall 
favourable safety profile seen in the nonclinical toxicology studies, BBT-401-1S is expected 
to demonstrate safety and tolerability with minimal systemic absorption in subjects with 
active UC. However, as there may be unknown and potential risks with administration of 
BBT-401-1S because of its pharmacological action and based on clinical experience with 
compounds that have inhibitory effects on proinflammatory pathways, all subjects will be 
closely monitored for safety and tolerability. 
There is low risk of drug-drug interactions between BBT-401-1S and common 
comedications, based on the low systemic exposure and benign safety profiles demonstrated 
in the nonclinical and clinical studies. 
More information about the known and expected benefits, risks, and reasonably anticipated 
AEs associated with BBT-401-1S may be found in the IB. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of this study is to explore the efficacy of orally administered 
BBT-401-1S in inducing a clinical response in subjects with active UC. 
The secondary objectives of the study are: 
• to assess the safety and tolerability of orally administered BBT-401-1S 
• to explore additional measurements of the efficacy of orally administered 
BBT-401-1S in inducing endoscopic and clinical remission.  
The exploratory objectives of this study are to evaluate the effects of BBT-401-1S on 
endoscopic response, subject-reported outcomes, histological improvement, biomarkers, and 
long-term clinical remission. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary efficacy endpoint is the clinical response rate at Day 57, as measured by a 
reduction of ≥3 points and ≥30% improvement from baseline of total Mayo score, which 
includes a decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding 
subscore ≤1. 
The primary safety endpoints are AEs and SAEs. 
2.2.2. 
Secondary Endpoints 
The secondary efficacy endpoints are: 
• clinical remission at Day 57, as measured by a total Mayo score of ≤2 points, with no 
individual subscore exceeding 1 point 


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• achievement of endoscopic remission at Day 57, as measured by a Mayo endoscopic 
subscore of 0 or 1. 
2.2.3. 
Exploratory Endpoints 
The exploratory efficacy endpoints are: 
• endoscopic response rate at Day 57, as defined by a ≥2-point reduction from baseline 
in Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score 
• endoscopic response rate at Day 57, as defined by a reduction of ≥1 grade in the 
Mayo endoscopic subscore 
• Inflammatory Bowel Disease Questionnaire (IBDQ) total score, as measured by 
change from baseline 
• histological improvement, as guided by change from baseline in Geboes score 
• biomarkers, including C-reactive protein and faecal calprotectin, as measured by 
change from baseline 
• clinical remission at Day 112, as measured by a total Mayo score of ≤2 points, with 
no individual subscore exceeding 1 point 
• percentage of subjects with sustained remission at Day 112 
• clinical response rate at Day 112. 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This study will comprise 2 periods: a randomised, double-blind, placebo-controlled induction 
phase; and a response-adaptive, double-blind extension phase. 
Induction Phase 
Subjects will be screened for inclusion in the study within 28 days of Day 1.  
Eligible subjects will be randomised in a 1:1:1 ratio; 12 subjects will receive 800 mg 
BBT-401-1S once daily (QD) and placebo QD, 12 subjects will receive 800 mg BBT-401-1S 
twice daily (BID), and 12 subjects will receive placebo BID. Subjects will receive the first 
dose of study drug at the study site on Day 1 and will administer study drug away from the 
study site for 56 days, during which they will attend 2 study site visits on Days 29 and 57. 
Additionally, subjects will be contacted by telephone on Day 8 for safety and compliance 
monitoring; however, at the discretion of the investigator, subjects may be requested to attend 
a study site visit on this day. 
Subjects who do not agree to participate in the extension phase will attend the study site for a 
follow-up visit on Day 71. 


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Extension Phase 
Subjects who complete the induction phase will be offered the opportunity to enter the 
extension phase after the Day 57 visit. Subjects who agree to participate in the extension 
phase will continue study drug administration while awaiting their clinical remission status 
from the local reader. Subjects will be assigned to the treatment for the extension phase 
treatment upon receipt of their clinical remission status. 
• Subjects who achieved clinical remission in the induction phase will continue the 
same treatment. 
• Subjects who did not achieve clinical remission in the induction phase and: 
o who received placebo BID will receive 800 mg BBT-401-1S QD and 
placebo QD 
o who received 800 mg BBT-401-1S QD and placebo QD will receive 
800 mg BBT-401-1S BID  
o who received 800 mg BBT-401-1S BID will continue the same treatment. 
Subjects will attend the study site on Days 85 and 112 (follow-up visit). Additionally, 
subjects will be contacted by telephone on Day 71 for safety and compliance monitoring; 
however, at the discretion of the investigator, subjects may be requested to attend a study site 
visit on this day. 
The study design is presented in Figure 1 and a schedule of assessments is presented in 
Appendix 11. The total planned study duration (screening to follow-up) is approximately 
20 weeks for subjects who are enrolled into the extension phase and approximately 14 weeks 
for subjects who are not enrolled into the extension phase. 


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Figure 1: Study Design 
 
Abbreviations:  BID = twice daily; QD = once daily; R = randomisation.  


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3.2. 
Discussion of Study Design 
This study will be double-blind and placebo-controlled to avoid bias in the collection and 
evaluation of data during its conduct. Placebo has been chosen as the control treatment to 
assess whether any observed effects are treatment related or simply reflect the study 
conditions. 
The study will exclude confounding effects, as is practically possible, by selecting a limited 
study population and concomitant medications. Additionally, subjects with only mild UC, as 
determined by the Mayo score, are excluded to provide scope for improvement in symptoms. 
3.3. 
Selection of Doses in the Study 
Once and twice daily doses of 800 mg have been selected for this study. 
Nonclinical pharmacological assays showed a less than dose-proportional increase in efficacy 
(up to 400 mg/kg/day in mice and 100 mg/kg/day in rats, which correspond to human 
equivalent doses of 2000 and 970 mg/day, respectively). 
 
 
  
Clinical studies of single doses of up to 1600 mg and multiple doses of up to 1600 mg/day for 
7 days in healthy subjects indicated that BBT-401-1S is not absorbed systemically (plasma 
concentrations were below the lower limit of quantification [<1 ng/mL]). No SAEs were 
reported in this study. Additionally, in an exploratory study of the efficacy in subjects with 
UC, orally administered BBT-401-1S was generally well tolerated at 400 mg/day for up to 
12 weeks. 
4. SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must satisfy all the following criteria at the screening visit, unless otherwise stated: 
1. Male or female, of any race, ≥18 and ≤60 years of age. 
a. Females will not be pregnant or lactating. 
b. Females of childbearing potential will agree to abide by the contraception 
requirements from the time of signing the informed consent form (ICF) until 
3 months after the last dose of study drug (Appendix 3).  
c. Males will agree to abide by the contraception requirements from Day 1 until 
3 months after the follow-up visit (Appendix 3). 
2. Have been diagnosed with active UC for ≥3 months prior to Day 1, as determined by 
clinical and endoscopic evidence and documented in a histopathology evaluation.  
3. Have a total Mayo score ≥6, an endoscopic subscore ≥2, rectal bleeding subscore ≥1, 
and a stool frequency subscore ≥1, regardless of standard of care history. 


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4. Able to comprehend and willing to voluntarily sign an ICF and to abide by the study 
restrictions. 
4.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they satisfy any of the following criteria at the 
screening visit, unless otherwise stated: 
1. Have received: 
a. intravenous or rectally administered corticosteroids within 3 weeks, or 
b. Janus kinase (JAK) inhibitors within 2 weeks, or 
c. cyclosporine, mycophenolate, tacrolimus, or methotrexate within 5 weeks, or 
d. anti-TNF-α biologics within 9 weeks, or  
e. any other biologics (including ustekinumab and vedolizumab) for the 
treatment of UC within 12 weeks. 
2. Have received orally administered azathioprine or 6-mercaptopurine that has been 
stable for <8 weeks. Doses of oral drugs must remain stable until the last dose of 
study drug. 
3. Have received orally or rectally administered 5-aminosalicylic acid, or orally 
administered sulphasalazine or low-dose corticosteroids (prednisolone ≤20 mg/day or 
equivalent), that have been stable for <5 weeks. Doses must remain stable until the 
last dose of study drug. 
4. Have received any other concomitant medications for UC that have been stable (ie, 
have not started dosing with a new drug or had a change to their dosing regimen) for 
<7 days or 5 half-lives, whichever is longer. 
5. Have Crohn’s disease, indeterminate colitis, ischaemic colitis, fulminant colitis, toxic 
megacolon, chronic (as determined by the investigator) pancolitis, confined proctitis 
(distal, ≤15 cm), or symptomatic intestinal stenosis. 
6. Have a history of extensive colonic resection (subtotal or total colectomy) or are 
anticipated to require surgical intervention for UC. 
7. Have an ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine. 
8. Have a positive test for Clostridium difficile, or have evidence of treatment for 
Clostridium difficile infection or other pathogenic bowel infection within 60 days or 
for another intestinal pathogen within 30 days prior to Day 1. 
9. Have active infection with the human immunodeficiency virus or hepatitis B or C 
viruses. 
10. Have clinically significant active extraintestinal infection (eg, pneumonia, 
pyelonephritis). 
11. Have, in the opinion of the investigator, clinically significant abnormal vital signs, 
physical examination findings, or 12-lead electrocardiograms (ECGs) at screening or 
Day 1. 


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12. Have a history of any disease or condition (including mental and emotional 
conditions) that, in the opinion of the investigator (or designee), would affect 
participation in this study. 
13. Have clinically significant abnormal liver function tests, including: 
a. estimated glomerular filtration rate ≤50 mL/min/1.73m2 
b. alanine aminotransferase or aspartate aminotransferase >2 × the upper limit of 
normal (ULN) 
c. direct bilirubin >1.5 × ULN. 
Note: Liver function tests may be repeated once, at the discretion of the investigator 
(or designee). 
14. Have other clinically significant abnormal clinical laboratory results that, in the 
opinion of the investigator, preclude participation in the study, including: 
a. platelet count <100,000/μL 
b. haemoglobin <8.5 g/dL 
c. neutrophils <1500/μL 
d. lymphocytes <500/mm3 
e. absolute white blood cells count <3000/μL. 
Note: Clinical laboratory evaluations may be repeated once, at the discretion of the 
investigator (or designee). 
15. Have participated in a clinical study involving administration of an investigational 
drug in the past 30 days prior to Day 1. 
16. Have previously participated in any study of BBT-401-1S. 
17. In the opinion of the investigator (or designee) or the sponsor, should not participate 
in this study. 
4.3. 
Subject Number and Identification 
Subjects will be assigned a subject number prior to the first dosing occasion. Subjects will be 
identified only by a subject number on all study documentation. A list identifying the subjects 
by subject number will be kept in the site master file. 
4.4. 
Rescreening 
Subjects may be rescreened once, at the discretion of the investigator (or designee), providing 
that the reason for screen failure was not due to a safety concern or non-eligibility based on 
exclusion criteria related to clinical laboratory evaluations. If a subject is considered to be 
eligible for rescreening, this will be discussed with the sponsor prior to rescreening. Subjects 
who are rescreened will be identified by a new subject number. 


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4.5. 
Screen Failures 
Subjects who consent to participate in the study but are not subsequently enrolled will be 
considered screen failures. A minimal set of screen failure information, including 
demographics, eligibility criteria, SAEs, and details of the screen failure, will be collected to 
ensure transparent reporting of screen failures and to respond to queries from regulatory 
authorities. 
4.6. 
Subject Withdrawal 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn from dosing if any of the following criteria are met: 
• change in compliance with any inclusion/exclusion criterion that is clinically relevant 
and affects subject safety as determined by the investigator (or designee) 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the investigator (or designee) 
• any clinically relevant sign or symptom (including disease worsening) that, in the 
opinion of the investigator (or designee), warrants subject withdrawal. 
If a subject is withdrawn from dosing, the sponsor will be notified and the date and reason(s) 
for the withdrawal will be documented in the subject’s electronic case report form. If a 
subject is withdrawn from the study, efforts will be made to perform all early termination 
assessments, if possible (Appendix 11). Other procedures may be performed at the 
investigator’s (or designee’s) and/or sponsor’s discretion. The investigator (or designee) may 
also request that the subject return for an additional follow-up visit. All withdrawn subjects 
will be followed until resolution of all their AEs or until the unresolved AEs are judged by 
the investigator (or designee) to have stabilised. 
4.7. 
Study Termination 
The study may be discontinued at the discretion of the sponsor if any of the following criteria 
are met: 
• AEs unknown to date (ie, not previously reported in any similar investigational study 
drug trial with respect to their nature, severity, and/or duration) 
• increased frequency, severity, and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined predose on Day 1 as baseline signs 
and symptoms) 
• medical or ethical reasons affecting the continued performance of the study 
• difficulties in the recruitment of subjects 
• cancelation of drug development. 


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5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labelling 
BBT-401-1S and placebo will be supplied by the sponsor (or designee) in bottles, along with 
the batch/lot numbers and certificates of analysis.  
 
 
 
 
Study drug will be stored according to the instructions on the label, and when stored at the 
site, will be stored in a location that is locked with restricted access. 
5.2. 
Study Treatment Administration 
Study drug will be administered orally. At each dosing occasion, subjects will receive a total 
of 4 capsules, comprising a combination of BBT-401-1S and/or placebo capsules to maintain 
the blind (Table 1). Subjects will receive study drug in the morning and evening during the 
induction and extension phases.  
Table 1: Study Drug Administration 
Dose Level 
Morning Dose 
Evening Dose 
Number of 
BBT-401-1S 
Capsules 
Number of 
Placebo 
Capsules 
Number of 
BBT-401-1S 
Capsules 
Number of 
Placebo 
Capsules 
Placebo BID 
0 
4 
0 
4 
800 mg BBT-401-1S QD 
and placebo QD 
4 
0 
0 
4 
800 mg BBT-401-1S BID 
4 
0 
4 
0 
Abbreviations: BID = twice daily; QD = once daily.
5.3. 
Randomisation 
Subjects will be randomised to placebo BID, 800 mg BBT-401-1S QD and placebo QD, or 
800 mg BBT-401-1S BID during the induction phase using an interactive voice/web response 
system. 
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study:  
• The placebo capsules will be identical in appearance to BBT-401-1S.  
• The same number of capsules will be administered at each dosing occasion. 
• There will be the same number of dosing occasions within the induction and extension 
phases. 


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• Subjects, investigators, and other members of staff involved with the study (including 
those involved in clinical operations and study site monitoring) will remain blinded to 
the treatment randomisation. Note: Sponsor representatives who are not involved in 
monitoring of the study may be unblinded. 
The interactive voice/web response system will be programmed with unblinding instructions. 
The study blind may be broken if, in the opinion of the investigator, it is in the subject’s best 
interest to know the assigned treatment. Whenever possible, and providing it does not 
interfere with or delay any decision in the best interest of the subject, the investigator will 
discuss the intended unblinding with the sponsor. If it becomes necessary to unblind during 
the study, the date, time, and reason will be recorded in the subject’s source data. 
5.5. 
Treatment Compliance 
Where doses are administered at the study site, all doses will be administered under the 
supervision of suitably qualified study site staff and treatment administration will be 
documented at the study site. 
Where doses are administered away from the study site, subjects will document treatment 
administration using subject diaries that will be reviewed at study site visits. Additionally, 
unused study drug will be returned to the study site for assessment of treatment compliance. 
5.6. 
Rescue Therapy 
A rescue treatment is defined as any procedure or medication (new medications or 
medications that have been increased in dose) used for the treatment of new or persistent 
symptoms of UC. 
If a subject who does not exhibit a clinical response experiences worsening of disease (ie, 
worsening of clinical status or symptoms of UC that require rescue treatment) or disease 
relapse, study drug must be discontinued, and subjects should be treated as clinically 
appropriate with conventional treatments for active disease, as determined by the 
investigator. These subjects should continue in the study for safety assessments but will be 
considered treatment failures with respect to the intent-to-treat population.  
A subject will be considered to have disease relapse when they meet all of the following 
criteria: 
• an increase in UC disease activity after achievement of a clinical response, defined as 
an increase from nadir or Day 57 in partial Mayo score of ≥2 points and an absolute 
partial Mayo score ≥4 points, and 
• an endoscopic subscore of ≥2 points, and 
• exclusion of other causes of increased disease activity that are unrelated to UC (eg, 
infections or changes in medication). 
The date and time of rescue medication administration as well as the name and dosage 
regimen of the rescue medication must be recorded. 


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5.7. 
Drug Accountability 
The investigator (or designee) will maintain an accurate record of the receipt of study drug. In 
addition, an accurate drug accountability record will be kept, specifying the amount 
dispensed to each subject and the date of dispensing. This drug accountability record will be 
available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the sponsor upon request. 
At the completion of the study, all unused study drug will be returned to the sponsor or 
disposed of by the study site, per the sponsor’s written instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
Allowed concomitant medications for UC should be maintained at a stable dose until the last 
dose of study drug. 
The following medications are specifically excluded: 
• cyclosporine, mycophenolate, tacrolimus, methotrexate, JAK inhibitors, and 
intravenous and rectally administered corticosteroids 
• anti-TNF-α biologics or any other biologics (including ustekinumab and 
vedolizumab) for the treatment of UC 
• orally administered azathioprine or 6-mercaptopurine that has been stable for 
<8 weeks prior to screening 
• orally or rectally administered 5-aminosalicylic acid, or orally administered 
sulphasalazine or low-dose corticosteroids (prednisolone ≤20 mg/day or equivalent), 
that have been stable for <5 weeks prior to screening 
• any other medications for UC that have been stable for <7 days or 5 half-lives, 
whichever is longer, prior to screening 
• over-the-counter and prescription antidiarrhoeals and probiotics 
• treatments for Clostridium difficile. 
Oral, implantable, injectable, or intrauterine contraceptives are acceptable concomitant 
medications.  
Any medication administered by a subject during the study and the reason for its use will be 
documented in the source data.  
7. STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time provided in Appendix 11, giving considerations to appropriate posture 
conditions, practical restrictions, and the other procedures to be performed at the same 
timepoint. 


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At the discretion of the investigator, subjects may be requested to attend unscheduled visits 
for additional assessments or procedures, including, but not limited to, safety assessments and 
prescription of rescue medications. 
7.1. 
Efficacy Assessments 
7.1.1. 
Endoscopy with Biopsy 
All details regarding endoscopic examination, standardised performing procedures, video 
recordings, assessment, biopsy sampling procedures, storage, and shipping will be provided 
in the laboratory manual.  
Endoscopic examination will be required in order to establish the Mayo endoscopic subscore. 
Mayo endoscopic subscores will be assessed by both a local reader and a qualified central 
reader. Locally read Mayo endoscopic subscores will be used to determine the subject’s 
clinical remission status, and treatment to be assigned in the extension phase. Centrally read 
Mayo endoscopic subscores will be used to evaluate the subject’s eligibility and the 
objectives of the study. Further details of the endoscopy procedures and their standardisation 
will be documented in a separate charter. 
Subjects will be required to undergo a full colonoscopy at screening; a flexible 
proctosigmoidoscopy will not be an option.  Subsequent endoscopies may comprise a full 
colonoscopy or a flexible proctosigmoidoscopy; this will be at the investigator’s discretion, 
based on the extent of disease. 
An appropriately trained endoscopist should perform the flexible 
proctosigmoidoscopy/colonoscopy. Where possible, the same endoscopist should perform the 
endoscopy at all visits. It should be clearly documented who performed each endoscopy 
procedure.  
On each occasion, every attempt should be made to collect biopsy samples from the same 
area. Biopsies will be collected from 2 locations, from the rectum and from the most 
proximal lesion in the colon (if the disease extends beyond the sigmoid colon). For biopsies 
collected from the rectum, if the disease extends <20 cm from the anal verge, the biopsy will 
be collected at the most proximal lesion of the disease. If the disease extends >20 cm from 
the anal verge, the biopsy will be collected at 15 to 20 cm from the anal verge. 
7.1.2. 
Ulcerative Colitis Endoscopic Index of Severity  
The UCEIS is the first validated index for the assessment of overall endoscopic activity 
(Appendix 5). The final model incorporates the vascular pattern, the presence of bleeding, 
and the presence of ulcerations with accurate definitions and 3 or 4 levels of severity as 
measurable parameters, which explain almost 90% of variations in determining overall 
activity. 
7.1.3. 
Mayo Score 
The total Mayo score (Appendix 6) is an instrument designed to measure disease activity of 
UC, with scores ranging from 0 to 12 points. The total Mayo score consists of 4 subscores, 
each graded from 0 to 3 with higher scores indicating more severe disease. For the 


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endoscopic subscore, the modified Mayo endoscopic score will be used to exclude any 
friability from Grade 1. 
• stool frequency (0 to 3) 
• rectal bleeding (0 to 3) 
• findings on endoscopy (0 to 3) 
• physician’s global assessment (PGA; 0 to 3). 
The total Mayo score (including the findings on endoscopy subscore) measured at screening 
will be used as the total Mayo baseline score. 
The partial Mayo score (Appendix 7) consists of 3 subscores (stool frequency, rectal 
bleeding, and PGA).  
The modified Mayo score (Appendix 8) consists of 3 subscores (stool frequency, rectal 
bleeding, and findings on endoscopy).  
Where applicable, the subscores of stool frequency and rectal bleeding will be answered by 
the subject, subscores of PGA will be assessed by the investigator who has observed the 
subject, and findings on endoscopy will be assessed by designated reader. 
7.1.4. 
Inflammatory Bowel Disease Questionnaire 
The IBDQ is a health-related quality-of-life (HRQoL) tool measuring bowel, systemic, 
emotional, and social function (Appendix 10). Scores for each question range between 1 and 
7, reflecting poor to good HRQoL, for a range of possible total scores from 32 to 224. 
7.1.5. 
Histopathology 
Mucosal biopsy samples will be collected during endoscopy for the histologic assessment of 
disease and healing. Measurements of histologic improvement will be performed by a central 
reader guided by the Geboes score (Appendix 9). Further details of the histologic procedures 
and their standardisation will be documented in a separate charter. 
Biopsy samples will be used to explore the efficacy and safety of BBT-401-1S using gene 
expression and profiling; tissue blocks may be used for RNA analysis and/or 
immunohistochemistry. The biomarkers to be investigated will include, but will not be 
limited to: interleukin (IL)-8, granulocyte-macrophage colony-stimulating factor, IL-6, IL1-β, 
TNF-α, IL-23, IL-17, and retinoic acid receptor-related orphan receptor C.  
7.2. 
Biomarkers 
Serum C-reactive protein and faecal calprotectin will be measured to support the efficacy 
assessments.  


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7.3. 
Pharmacokinetic Assessments 
Biopsy samples will be collected for analysis of tissue concentrations of BBT-401-1S. 
Procedures for the collection and shipping of tissue samples will be detailed in a separate 
document. 
7.4. 
Safety Assessments 
7.4.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to final 
discharge from the study. Subjects will be observed for any signs or symptoms and asked 
about their condition by open questioning, such as “How have you been feeling since you 
were last asked?”, at each study visit. Subjects will also be encouraged to spontaneously 
report AEs occurring at any other time during the study. 
Any AEs and remedial action required will be recorded in the subject’s source data. The 
nature, time of onset, duration, and severity will be documented, together with an 
investigator’s (or designee’s) opinion of the relationship to study drug. 
Adverse events recorded during the study that are possibly related or related to the study drug 
or study procedures will be followed up, where possible, to resolution or until the unresolved 
AEs are judged by the investigator (or designee) to have stabilised. This will be completed at 
the investigator’s (or designee’s) discretion. 
7.4.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations. Clinical 
laboratory evaluations are listed in Appendix 2. For all subjects, a Clostridium difficile test 
will be performed at screening. For all female subjects of childbearing potential, a serum 
pregnancy test will be performed at screening and urine pregnancy tests performed at all 
other timepoints. An investigator (or designee) will perform a clinical assessment of all 
clinical laboratory data. 
7.4.3. 
Vital Signs 
Supine or sitting blood pressure, supine or sitting pulse rate, and tympanic temperature will 
be assessed. Vital signs may also be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of vital 
signs is required. All measurements will be performed singly and repeated once if outside the 
relevant clinical reference range. 
Subjects must be supine or sitting for at least 5 minutes before blood pressure and pulse rate 
measurements. For individual subjects, the same posture and same arm should be used for all 
measurements throughout the study. Vital signs should be assessed prior to blood sampling. 


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7.4.4. 
12-Lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at 
least 5 minutes. Single 12-lead ECGs will be repeated once if either of the following criteria 
apply: 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) >500 ms 
• QTcF change from the baseline (predose) is >60 ms. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The investigator (or designee) will perform an assessment of each 12-lead ECG 
to determine any clinically significant findings. 
7.4.5. 
Physical Examination 
Physical examinations will be performed. Body weight will be measured as part of physical 
examinations. 
7.5. 
Guidelines, Study Assessments, and Procedures During the Coronavirus 
Disease-19 Pandemic 
In view of the coronavirus disease -19 (COVID-19) worldwide pandemic, the safety and 
wellbeing of study subjects is of primary importance. Study sites must comply with local 
public health rules. 
Although every effort should be made to follow the protocol, subject safety is paramount and 
the investigator should continue to reassess the risks and benefits of continued study 
participation for each subject.  
If a subject is diagnosed with COVID-19 or is suspected to have COVID-19, they should 
follow the local treatment and quarantine guidances. 
• All diagnoses, procedures, assessments, dosing interruptions, and sequelae should be 
recorded in the electronic case report form (eCRF). 
• Adverse events and SAEs should be reported in accordance with instructions in 
Appendix 1. If an AE or SAE related to COVID-19 is reported, the investigator 
should determine whether study drug administration should continue, be interrupted, 
or stopped. 
If a subject is unable to attend study site visits and/or receive study drug, site staff should 
keep contact with the subject, preferably via telephone calls, to maintain awareness of subject 
status. If the subject is unable to attend the site, the following options may be considered: 
• Subjects may be visited at their home by study staff or other trained professionals 
(where possible due to social distancing requirements). 
• Visits may be performed by telephone or telemedicine to provide continuous medical 
care and oversight and to identify AEs. 


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• Blood samples may be collected and analysed at an alternative healthcare facility, at 
the discretion of the investigator. Although results of these analyses may not 
necessarily be collected or documented in the study database, it will allow the 
investigator to assess subject safety. 
• If the endoscopy at the end-of-treatment visit can not be performed, the partial Mayo 
score may be collected by telephone or telemedicine (preferred). 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
There has not been any formal statistical assessment of the sample size. However, the number 
of subjects is common in early clinical studies and is considered sufficient to achieve the 
objectives of the study. 
8.2. 
Analysis Populations 
The intent-to-treat population will include all subjects who received at least 1 dose of study 
drug, have a partial Mayo score recorded on Day 1, and at least 1 post-baseline Mayo score 
recorded. 
The safety population will include all subjects who received at least 1 dose of study drug. 
8.3. 
General Principles  
Continuous variables will be summarised by the standard descriptive statistics: number of 
subjects (n), mean, standard deviation, median, minimum, and maximum. Frequency of 
subjects or events and percentages will be summarised in categorical variables.  
8.4. 
Efficacy Analyses 
8.4.1. 
Primary and Secondary Efficacy Analysis 
All subjects in the intent-to-treat population will be included in the primary and secondary 
efficacy analyses. Descriptive summaries will be presented for clinical response, clinical 
remission, and endoscopic remission rates. The estimate and 95% confidence interval (CI) of 
clinical response, clinical remission, and endoscopic remission rates at Day 57 will be 
calculated using the exact binomial method for each treatment. The Fisher’s exact test will be 
used to evaluate any differences between treatments.  
Missing data will be deemed as “unresponsive”. If any event that was not initially anticipated 
demands to reconsider data handling, then the method of handling the relevant data will be 
established in the statistical analysis plan. 
8.4.2. 
Exploratory Efficacy Analysis 
All subjects in the intent-to-treat population will be included in the exploratory efficacy 
analysis. The estimate and 95% CI of endoscopic response rate and histological improvement 
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Day 112 will be calculated using the exact binomial method for each treatment. Actual values 
and change from baseline in Mayo scores, UCEIS scores, IBDQ total score, C-reactive 
protein, and faecal calprotectin over time will be summarised descriptively. No formal 
hypothesis will be tested on the exploratory efficacy endpoints. 
8.5. 
Safety Analysis 
All subjects in the safety population will be included in the safety analysis. All AEs will be 
listed and summarised using descriptive methodology. Each AE will be coded using the 
Medical Dictionary for Regulatory Activities. Observed values for clinical laboratory test 
data, 12-lead ECGs, vital signs, and physical examination findings will be listed. 
8.6. 
Interim Analysis 
No formal interim analyses are planned for this study. However, an assessment of clinical 
remission will be performed at Day 57 to determine whether a subject will progress into the 
extension phase and the dose to be administered. 
9. REFERENCES 
1.  Kornbluth A, Sachar DB. Ulcerative Colitis Practice Guidelines in Adults: American 
College of Gastroenterology, Practice Parameters Committee: Am J Gastroenterol. 2010 
Mar;105(3):501–23.  
2.  D’Haens G. Systematic review: second-generation vs. conventional corticosteroids for 
induction of remission in ulcerative colitis. Aliment Pharmacol Ther. 2016;44(10):1018–
29.  
3.  Curkovic I, Egbring M, Kullak-Ublick GA. Risks of Inflammatory Bowel Disease 
Treatment with Glucocorticosteroids and Aminosalicylates. Dig Dis. 2013;31(3–4):368–
73.  
4.  Andersen NN, Jess T. Risk of infections associated with biological treatment in 
inflammatory bowel disease. World J Gastroenterol. 2014;20(43):16014.  
5.  Gordon JP, McEwan PC, Maguire A, Sugrue DM, Puelles J. Characterizing unmet 
medical need and the potential role of new biologic treatment options in patients with 
ulcerative colitis and Crohn’s disease: a systematic review and clinician surveys. Eur J 
Gastroenterol Hepatol. 2015 Jul;27(7):804–12.  
 
 


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10. APPENDICES 


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Appendix 1: Adverse Event Reporting 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product, which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavourable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not related to the study 
drug. 
Assessment of Severity 
The investigator will be asked to provide an assessment of the severity of the AE using the 
following categories:  
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
• Severe: Interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
Relationship to Study Treatment 
The investigator (or designee) will decide the relationship of the AE to the study drug using a 
4-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions. 
• Unlikely Related: The temporal association between the AE and the drug is such that 
the drug is not likely to have any reasonable association with the AE. 
• Possibly Related: The AE follows a reasonable temporal sequence from the time of 
drug administration, but could have been produced by the subject’s clinical state or 
the study procedures/conditions. 
• Related: The AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesised 
cause-effect relationship, and (if appropriate) reappears when the drug is reintroduced.  
Follow-up of Adverse Events 
Every reasonable effort will be made to follow up with subjects who have AEs. Any subject 
who has an ongoing AE that is possibly related or related to the study drug or study 
procedures at the follow-up visit will be followed up, where possible, until resolution or until 
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completed at the investigator’s (or designee’s) discretion. Any subject who has an ongoing 
AE that is not related or unlikely related to the study drug or study procedures at the 
follow-up visit can be closed out as ongoing at the investigator’s discretion.  
Adverse Drug Reactions 
All noxious and unintended responses to a study drug (ie, where a causal relationship 
between a study drug and an AE is at least a reasonable possibility) related to any dose 
should be considered adverse drug reactions. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (eg, investigator’s 
brochure for an unapproved study drug). 
Serious Adverse Events 
A serious AE (SAE) is defined as any untoward medical occurrence that at any dose either: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalisation may be considered SAEs when, based upon appropriate medical judgement, 
they may jeopardise the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
Instances of death or congenital abnormality, if brought to the attention of the investigator at 
any time after cessation of the study drug and considered by the investigator to be possibly 
related to the study drug, will be reported to the sponsor. 
Definition of Life-threatening 
An AE is life-threatening if the subject was at immediate risk of death from the event as it 
occurred (ie, does not include a reaction that might have caused death if it had occurred in a 
more serious form). For instance, drug-induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life-threatening even though drug-induced hepatitis 
can be fatal. 
Definition of Hospitalisation 
Adverse events requiring hospitalisation should be considered serious. In general, 
hospitalisation signifies that the subject has been detained (usually involving an overnight 


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stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the study site. When in doubt as to whether hospitalisation occurred or 
was necessary, the AE should be considered as serious. 
Hospitalisation for elective surgery or routine clinical procedures, which are not the result of 
an AE, need not be considered AEs and should be recorded on a clinical assessment form and 
added to the electronic case report form. If anything untoward is reported during the 
procedure, this must be reported as an AE and either ‘serious’ or ‘nonserious’ attributed 
according to the usual criteria. 
Serious Adverse Event Reporting 
The investigator will complete an SAE report form and forward it by facsimile or email to 
Labcorp Drug Safety Services (DSS) and the sponsor immediately (within 24 hours) upon 
becoming aware of an SAE. 
The responsibilities of Labcorp DSS include the following: 
• Prepare an AE reporting plan prior to the start of the study. Where this plan differs 
from the applicable study site standard operating procedure on SAE reporting, the 
Safety Management Plan will always take precedence. 
• Receive and review SAE report forms from the study site and inform the sponsor of 
the SAE within 1 working day of the initial notification to Labcorp DSS. Drug Safety 
Services will delete any information from the SAE report forms that may identify the 
subject. 
• Write case narratives and enter the case into Labcorp’s safety database as defined in 
the AE reporting plan. 
• Produce appropriate reports of all suspected unexpected serious adverse reactions and 
forward to the ethics committee, principal investigator, and the sponsor.  
The responsibility for reporting SAEs will be transferred to the sponsor 28 days after the end 
of the study. 
Pregnancy 
Pregnancy (maternal or paternal exposure to study drug) does not meet the definition of an 
AE. However, to fulfil regulatory requirements any pregnancy should be reported following 
the SAE process to collect data on the outcome for both mother and foetus. A separate 
consent form will be signed by the pregnant female partner in order to gather information on 
the pregnancy and foetus. 
 
 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Haematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatine kinase 
Creatinine 
Direct bilirubin  
Gamma-glutamyl transferase 
Glucose 
Lipase 
Potassium  
Sodium  
Total bilirubin 
Total protein 
Triglycerides 
Uric acid 
Hematocrit  
Haemoglobin 
Mean cell haemoglobin 
Mean cell haemoglobin 
concentration 
Mean cell volume 
Platelet count 
Red blood cell count 
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
 
Bilirubin 
Blood 
Colour and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination  
Serology: 
Hormone panel - females only: 
Coagulation 
Hepatitis B surface antigen 
Hepatitis B virus surface antibody 
Hepatitis B virus core antibody 
Hepatitis C antibody 
Human immunodeficiency (HIV-1 
and HIV-2) antibodies and p24 
antigen 
Follicle-stimulating hormone 
(postmenopausal females only) 
Serum pregnancy test (human 
chorionic gonadotropin; screening 
only; females of childbearing 
potential only) 
Urine pregnancy test (all 
timepoints except screening; 
females of childbearing potential 
only) 
Prothrombin time  
Activated partial thromboplastin 
time  
International normalized ratio 
Other: 
Clostridium difficile test 


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Appendix 3: Contraception Guidance 
Definitions 
Females of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Females of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy by reported medical history and/or 
medical records. Surgical sterilisation to have occurred a minimum of 6 weeks, or at 
the investigator’s discretion, prior to screening. 
2. Postmenopausal: females at least 45 years of age with amenorrhoea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating hormone 
levels of ≥40 mIU/mL. The amenorrhoea should not be induced by a medical 
condition, such as anorexia nervosa, hypothyroid disease, or polycystic ovarian 
disease, or by extreme exercise. It should not be due to concomitant medications that 
may have induced the amenorrhoea, such as oral contraceptives, hormones, 
gonadotropin-releasing hormones, anti-oestrogens, or selective oestrogen receptor 
modulators. 
Fertile male: a male that is considered fertile after puberty. 
Infertile male: permanently sterile male via: 
• bilateral orchiectomy, or  
• vasectomy performed at least 90 days prior to the screening visit with confirmation of 
surgical success. 
Contraception Guidance 
Female Subjects 
Female subjects who are of nonchildbearing potential will not be required to use 
contraception.  
Female subjects of childbearing potential who have a fertile male partner must be willing to 
use 2 methods (1 primary and 1 secondary method) of birth control from the time of signing 
the informed consent form (ICF) until 3 months after the last dose of study drug. Primary 
(non-barrier) methods of contraception include: 
• hormonal injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• surgical method performed at least 3 months prior to the screening visit: 
o 
bilateral tubal ligation 


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o 
Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes 
• hormonal implant 
• hormonal or non-hormonal intrauterine device. 
Secondary (barrier) methods of contraception include: 
• male condom 
• female condom 
• diaphragm (as prescribed). 
Female subjects of childbearing potential who have an infertile male partner are not required 
to use contraception, providing that the infertile male is the sole partner of the female subject. 
A barrier method of contraception may be encouraged but is not required. 
Female subjects of childbearing potential should refrain from donation of ova from Day 1 
until 3 months after the last dose of study drug. 
Male Subjects 
Infertile male subjects must use a barrier method of contraception from Day 1 until 3 months 
after the follow-up visit. 
Fertile male subjects with partners of childbearing potential must use a barrier method of 
contraception in addition to a second method of acceptable contraception from Day 1 until 
3 months after the follow-up visit.  
Barrier methods of contraception include: 
• male condom 
• female condom 
• diaphragm (as prescribed). 
Acceptable secondary methods of contraception for female partners include: 
• hormonal injection 
• combined oral contraceptive pill or progestin/progestogen-only pill 
• combined hormonal vaginal ring 
• surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
• hormonal implant 
• hormonal or non-hormonal intrauterine device. 


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For male subjects, sexual intercourse with female partners who are pregnant or breastfeeding 
should be avoided unless condoms are used from Day 1 until 3 months after the follow-up 
visit.  
Male subjects are required to refrain from donation of sperm from Day 1 until 3 months after 
the follow-up visit. 
Sexual Abstinence and Same-sex Relationships 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (ie, the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a 
subject who is abstinent at the time of signing the ICF becomes sexually active, they must 
agree to use contraception as described previously.  
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 


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Appendix 4: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
• Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, informed consent form (ICF), investigator’s brochure, 
and other relevant documents must be submitted to an ethics committee (EC) by the 
investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any nonsubstantial changes, as defined by 
regulatory requirements.  
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the EC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the EC. 
• Notifying the EC of serious adverse events or other significant safety findings as 
required by the EC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the EC, 
European Directive 2001/20/EC for clinical studies (if applicable), and all other 
applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the investigator (or 
designee) and that their participation is voluntary and that they are free to withdraw from the 
study at any time. Subjects will be given an opportunity to ask questions about the study prior 
to providing consent for participation. 


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Following discussion of the study with study site personnel, subjects will sign 2 copies of the 
ICF in the presence of a suitably trained member of staff to indicate that they are freely 
giving their informed consent. One copy will be given to the subject, and the other will be 
maintained in the subject’s records. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in eCRFs, 
study-related forms, study reports, or any related publications. Subject and investigator 
personal data will be treated in compliance with all applicable laws and regulations. In the 
event the study protocol, study report, or study data are included in a public registry, all 
identifiable information from individual subjects or investigators will be redacted according 
to applicable laws and regulations.  
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. The subject must also be informed that his/her study-related data 
may be examined by the sponsor or contract research organisation (CRO) auditors or other 
authorised personnel appointed by the sponsor, by appropriate EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the study, will be regarded as confidential. The investigator (or designee) 
agrees not to disclose such information in any way without prior written permission from the 
sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All relevant subject data relating to the study will be recorded on eCRFs, unless 
directly transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF.  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Predefined agreed risks, monitoring thresholds, 
quality tolerance thresholds, controls, and mitigation plans will be documented in a 
risk management register. Additional details of quality checking to be performed on 
the data may be included in a data management plan.  


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• A study monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorised site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator in the study site archive for at least 5 years after 
the end of the study unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.  
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR 
Part 11-compliant electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and 
transmitted to the sponsor or designee electronically, will be integrated with the subject’s 
eCRF data in accordance with the data management plan. 
An eCRF must be completed for each enrolled subject who undergoes any screening 
procedures, according to the eCRF completion instructions. The sponsor, or CRO, will 
review the supporting source documentation against the data entered into the eCRFs to verify 
the accuracy of the electronic data. The investigator will ensure that corrections are made to 
the eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the investigator reviewed and approved the data 
on the eCRF, data queries, and site notifications. 
Publications 
• Publications will be addressed in a separate agreement.The results of this study may 
be published or presented at scientific meetings. If this is foreseen, the investigator 
agrees to submit all manuscripts or abstracts to the sponsor before submission. This 
allows the sponsor to protect proprietary information and to provide comments. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicentre studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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Appendix 5: Ulcerative Colitis Endoscopic Index of Severity 
Descriptor 
Likert scale  
(anchor points) 
Definition 
Vascular 
pattern  
Normal (0)  
Normal vascular pattern with arborisation of capillaries clearly defined, or 
with blurring or patchy loss of capillary margins  
Patchy obliteration (1)  
Patchy obliteration of vascular pattern  
Obliterated (2)  
Complete obliteration of vascular pattern  
Bleeding  
None (0)  
No visible blood  
Mucosal (1)  
Some spots or streaks of coagulated blood on the surface of the mucosa 
ahead of the scope, which can be washed away  
Luminal mild (2)  
Some free liquid blood in the lumen  
Luminal moderator 
severe (3)  
Frank blood in the lumen ahead of endoscope or visible oozing from 
mucosa after washing intraluminal blood or visible oozing from a 
haemorrhagic mucosa  
Erosions and 
ulcers  
None (0)  
Normal mucosa, no visible erosions or ulcers  
Erosions (1)  
Tiny (≤5 mm) defects in the mucosa, of a white or yellow colour with a 
flat edge  
Superficial ulcer (2)  
Larger (>5 mm) defects in the mucosa, which are discrete fibrin-covered 
ulcers in comparison with erosions, but remain superficial  
Deep ulcer (3)  
Deeper excavated defects in the mucosa with a slightly raised edge  
Adapted from Travis SP, Schnell D, Krzeski P et al.  Reliability and initial validation of the Ulcerative Colitis Endoscopic 
Index of Severity. Gastroenterology 2013;145:987–95. 


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Appendix 6: Total Mayo Score 
Question 
Subject-reported 
Investigator-reported 
Stool frequency* 
Rectal bleeding* 
Physician’s Global 
Assessment† 
Findings on 
endoscopy 
Score 
 
 
 
 
0 
Normal number of 
stools 
No blood seen 
Normal 
Normal or inactive 
disease 
1 
1-2 stools more than 
normal 
Streaks of blood with 
stool less than half the 
time 
Mild disease 
Mild disease 
(erythema, decreased 
vascular pattern) 
2 
3-4 stools more than 
normal 
Obvious blood (more 
than just streaks) or 
streaks of blood with 
stool most of time 
Moderate disease 
Moderate disease 
(marked erythema, 
absent vascular 
pattern, friability, 
erosions) 
3 
≥ 5 stools more than 
normal 
Blood alone passed 
Severe disease 
Severe disease 
(spontaneous 
bleeding, ulceration) 
 
* Subject will document the stool frequency and the rectal bleeding score daily in the subject diary. The stool frequency and 
rectal bleeding subscores will use the average of the last 3 non-missing assessments recorded in the subject diary. If an 
endoscopy is performed, the average of the last 3 non-missing assessments recorded in the subject diary prior to bowel 
preparation should be used. If the subscore is not an integer, the subscore should be rounded to the nearest integer. 
† Physician’s Global Assessment acknowledges the subscores, the daily records of abnormal discomfort and functional 
assessment, and other observations such as physical findings and the subject’s performance status. 
Adapted from Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately 
active ulcerative colitis. A randomised study. N Engl J Med. 1987;317(26):1625.


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Appendix 7: Partial Mayo Score 
Question 
Subject-reported 
Investigator-reported 
Stool frequency* 
Rectal bleeding* 
Physician’s Global 
Assessment† 
Score 
 
 
 
0 
Normal number of stools 
No blood seen 
Normal 
1 
1-2 stools more than normal 
Streaks of blood with stool 
less than half the time 
Mild disease 
2 
3-4 stools more than normal 
Obvious blood (more than 
just streaks) or streaks of 
blood with stool most of time 
Moderate disease 
3 
≥5 stools more than normal 
Blood alone passed 
Severe disease 
 
* Subject will document the stool frequency and the rectal bleeding score daily in the subject diary. The stool frequency and 
rectal bleeding subscores will use the average of the last 3 non-missing assessments recorded in the subject diary. If an 
endoscopy is performed, the average of the last 3 non-missing assessments recorded in the subject diary prior to bowel 
preparation should be used. If the subscore is not an integer, the subscore should be rounded to the nearest integer. 
† Physician’s Global Assessment acknowledges the subscores, the daily records of abnormal discomfort and functional 
assessment, and other observations such as physical findings and the subject’s performance status. 
Adapted from Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately 
active ulcerative colitis. A randomised study. N Engl J Med. 1987;317(26):1625.


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Appendix 8: Modified Mayo Score 
Question 
Subject-reported 
Investigator-reported 
Stool frequency* 
Rectal bleeding* 
Findings on endoscopy 
Score 
 
 
 
0 
Normal number of 
stools 
No blood seen 
Normal or inactive disease 
1 
1-2 stools more than 
normal 
Streaks of blood with 
stool less than half the 
time 
Mild disease (erythema, decreased 
vascular pattern) 
2 
3-4 stools more than 
normal 
Obvious blood (more 
than just streaks) or 
streaks of blood with 
stool most of time 
Moderate disease (marked erythema, 
absent vascular pattern, friability, 
erosions) 
3 
≥5 stools more than 
normal 
Blood alone passed 
Severe disease (spontaneous bleeding, 
ulceration) 
 
* Subject will document the stool frequency and the rectal bleeding score daily in the subject diary. The stool frequency and 
rectal bleeding subscores will use the average of the last 3 non-missing assessments recorded in the subject diary. If an 
endoscopy is performed, the average of the last 3 non-missing assessments recorded in the subject diary prior to bowel 
preparation should be used. If the subscore is not an integer, the subscore should be rounded to the nearest integer. 
Adapted from Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately 
active ulcerative colitis. A randomised study. N Engl J Med. 1987;317(26):1625.


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Appendix 9: Geboes Score 
Grade 0: Architectural changes   
0.0 No abnormality 
0.1 Mild abnormality 
0.2 Mild/moderate diffuse or multifocal abnormalities 
0.3 Severe diffuse or multifocal abnormalities   
Grade 1: Chronic inflammatory infiltrate  
1.0 No increase 
1.1 Mild but unequivocal increase 
1.2 Moderate increase 
1.3 Marked increase  
Grade 2A: Eosinophils in lamina propria  
2A.0 No increase 
2A.1 Mild but unequivocal increase 
2A.2 Moderate increase 
2A.3 Marked increase  
Grade 2B: Neutrophils in lamina propria  
2B.0 No increase 
2B.1 Mild but unequivocal increase 
2B.2 Moderate increase 
2B.3 Marked increase  
Grade 3: Neutrophils in epithelium  
3.0 None 
3.1 < 5% crypts involved 
3.2 < 50% crypts involved 
3.3 > 50% crypts involved  
Grade 4: Crypt destruction  
4.0 None 
4.1 Probable: local excess of neutrophils in part of the crypts 
4.2 Probable: marked attenuation 
4.3 Unequivocal crypt destruction  
Grade 5: Erosions and ulcerations  
5.0 No erosion, ulceration or granulation tissue 
5.1 Recovering epithelium + adjacent inflammation 
5.2 Probable erosion: focally stripped 
5.3 Unequivocal erosion 
5.4 Ulcer or granulation tissue  
Adapted from Geboes K Riddell R Ost A Jensfelt B Persson T Lofberg R. A reproducible grading scale for histological 
assessment of inflammation in ulcerative colitis. Gut 2000;47:404–9. 


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Appendix 10: Inflammatory Bowel Disease Questionnaire 


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Appendix 11: Schedule of Assessments 
 
Induction Phase 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6a 
Screening 
Baseline 
 
 
EOT/ET 
Follow-up 
≤28 days 
prior to 
Day 1 
Day 1 
Day 8b 
(± 3 d) 
Day 29 
(± 3 d) 
Day 57 
(± 3 d) 
Day 71 
(± 7 d) 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion 
X 
P 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
P 
 
 
 
 
Concomitant medication 
X 
Subject diary completion 
X 
 
Study drug 
Randomisation 
 
X 
 
 
 
 
Study drug administration 
 
X 
 
Compliance review 
 
 
X 
X 
X 
 
Safety  
Follicle-stimulating hormonec 
X 
 
 
 
 
 
Pregnancy testd 
X 
P 
 
X 
X 
 
Viral serology 
Xe 
 
 
 
 
 
Clostridium difficile test 
X 
 
 
 
 
 
Chemistry, haematology, 
coagulation, and urinalysis 
X 
P 
 
X 
X 
X 
Vital signs 
X 
P 
 
X 
X 
X 
12-lead ECGs 
X 
P 
 
X 
X 
X 
Physical examination 
X 
 
 
X 
X 
X 
Adverse event monitoring 
X 
Endoscopic and clinical assessments 
UCEIS  
X 
 
 
 
X 
 
Total Mayo scoref 
X 
 
 
 
X 
 
Partial Mayo scoref,g 
X 
P 
 
X 
X 
 
Modified Mayo scoref,h 
X 
 
 
 
X 
 
Health-related quality of life 
IBD questionnaire 
 
P 
 
X 
X 
 
Biomarkers 
C-reactive protein 
X 
P 
 
X 
X 
 
Faecal calprotectin 
X 
P 
 
X 
X 
 
Endoscopy/biopsy 
Endoscopy 
Xi 
 
 
 
Xj 
 
Histopathology 
X 
 
 
 
X 
 
Tissue concentration 
 
 
 
 
X 
 
Abbreviations: d = days; ECG = electrocardiogram; EOT = end of treatment; ET = early termination; IBD = inflammatory 
bowel disease; P = predose; UCEIS = Ulcerative Colitis Endoscopic Index of Severity.
 
a Only for subjects who do not agree to participate in the extension phase. 
b Telephone visit; however, at the discretion of the investigator, subjects may be requested to attend the study site. 
c Postmenopausal females only. 
d Females of childbearing potential only. A serum pregnancy test will be performed at screening and urine pregnancy tests 
performed at all other timepoints. 
e At a minimum comprises HBV (includes HBV surface antigen, HBV surface antibody, and HBV core antibody), 
antibodies to hepatitis C virus, and human immunodeficiency virus.  
f Mayo scores collected from 1 week prior to each visit (including endoscopy visit). 
g Rectal bleeding, stool frequency, and Physician’s global assessment. 
h Rectal bleeding, stool frequency, and findings on endoscopy. 
i Conducted within 7 days of Day 1. 
j Endoscopy will be performed ≤7 days prior to the Day 57 visit or on the same day as the other Day 57 
procedures/assessments. 


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Extension Phase 
Visit 7 
Visit 8 
Visit 9 
 
 
EOS/ET visit 
Day 71 (± 3 d)a 
Day 85 (± 3 d) 
Day 112 (± 3 d) 
Concomitant medication 
X 
Subject diary completion 
X 
Study drug 
Study drug administration 
X 
Compliance review 
X 
X 
X  
Safety  
Urine pregnancy testb 
 
X 
X 
Chemistry, haematology, coagulation, and urinalysis 
 
X 
X 
Vital signs 
 
X 
X 
12-lead ECGs 
 
X 
X 
Physical examination 
 
X 
X 
Adverse event monitoring 
X 
Endoscopic and clinical assessments 
UCEIS 
 
 
Xd 
Total Mayo scorec 
 
 
Xd 
Partial Mayo scorec,e 
 
X 
X 
Modified Mayo scorec,f 
 
 
Xd 
Health-related quality of life 
IBD questionnaire 
 
X 
X 
Biomarkers 
C-reactive protein 
 
X 
X 
Faecal calprotectin 
 
X 
X 
Endoscopy/biopsy 
Endoscopy 
 
 
Xg 
Histopathology 
 
 
Xd 
Abbreviations: d = days; ECG = electrocardiogram; EOS = end of study; ET = early termination; IBD = inflammatory bowel 
disease; UCEIS = Ulcerative Colitis Endoscopic Index of Severity.
 
a Telephone visit; however, at the discretion of the investigator, subjects may be requested to attend the study site for safety 
assessments. 
b Females only. 
c Mayo scores collected from 1 week prior to each visit (including endoscopy visit). 
d If endoscopy is performed. 
e Rectal bleeding, stool frequency, and Physician’s global assessment. 
f Rectal bleeding, stool frequency, and findings on endoscopy. 
g Endoscopy performed at the discretion of the investigator. If an endoscopy is performed, it should be performed ≤7 days 
prior to the EOS/ET visit or on the same day as the other EOS/ET procedures/assessments. 


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Appendix 12: Summary of Changes 
The following changes were implemented in Protocol Version 2: 
• It was clarified that the Mayo endoscopic subscore will be assessed by both a local 
and qualified central reader. Locally read Mayo endoscopic subscores will be used to 
determine the subject’s eligibility, clinical remission status, and treatment to be 
assigned in the extension phase. Centrally read Mayo endoscopic subscores will be 
used to evaluate the objectives of the study. 
• Measurements of the tissue concentration of BBT-401-1S at screening were removed. 
• The time window for the Day 57 endoscopy was updated. 
• The time windows for visits in the extension phase were updated. 
• The fasting requirements were removed. 
• It was clarified that stool frequency and rectal bleeding will be documented daily by 
the subject. 
• The unit of glomerular filtration rate was corrected. 
The following changes were implemented in Protocol Version 3: 
• Protocol Version 2 incorrectly stated that locally read Mayo endoscopic subscores 
would be used to determine the subject’s eligibility. This was corrected to state that 
centrally read Mayo endoscopic subscores will be used to evaluate the objectives of 
the study. 
The following changes were implemented in Protocol Version 4: 
• Clarified that subjects who test positive for Clostridium difficile at screening will be 
excluded. 
• Added that clinical laboratory evaluations, including liver function tests, may be 
repeated once, at the discretion of the investigator (or designee), to determine 
eligibility. 
• Added that subjects may be rescreened once, at the discretion of the investigator (or 
designee), providing that the reason for screen failure was not due to a safety concern 
or non-eligibility related to clinical laboratory evaluations. 
• Updated that the study treatments will be provided in bottles. 
• Added locations from which biopsies will be collected. 
• Added that the total Mayo score measured at screening will be used as baseline. 
• Clarified that subscores of physician’s global assessment component of the Mayo 
score will be assessed by the investigator who has observed the subject 
• Updated the definition of ‘obvious blood’ for subject-reported rectal bleeding within 
the total, partial, and modified Mayo scores according to Food and Drug 


Protocol 
CONFIDENTIAL 
 
Protocol Reference: BBT401-UC-005 
Protocol Version 5, 02 August 2021  
Page 60 of 60 
Administration (FDA) interpretation of the FDA Guidance on Clinical Trial 
Endpoints of Ulcerative Colitis. 
• Clarified that the subject will document stool frequency and the rectal bleeding score 
daily in the subject diary and subscores will be calculated as the average of the last 
3 non-missing assessments. 
• Added histopathology on Day 112, if endoscopy is performed. 
• Minor editorial and formatting changes were made. 
The following changes were implemented in Protocol Version 5: 
• Updated the sponsor’s medical contact. 
• The name of the organisation Covance was changed to Labcorp. 
• Updated that rectally administered 5-aminosalicylic acid that has been stable for 
<5 weeks is exclusionary. 
• Clarified in Section 6 that concomitant medications for ulcerative colitis should be 
maintained at a stable dose until the last dose of study drug for consistency with the 
exclusion criteria in Section 4.2. 
• Added that over-the-counter and prescription antidiarrhoeals and probiotics are 
excluded for the duration of the study. 
• Added guidelines for performing assessments and procedures during the coronavirus 
disease-19 pandemic. 
• Minor editorial and formatting changes were made. 

SAP_001.pdf: 
Statistical Analysis Plan 
Sponsor Name: Bridge Biotherapeutics, Inc. 
Sponsor Protocol ID: BBT401-UC-005 
 
 
 
CONFIDENTIA 
Page 1 of 30 
Statistical Analysis Plan  
Bridge Biotherapeutics, Inc. 
BBT401-UC-005 
 
 
 
Document Version: Final 1.0 
Document Date: 26JAN2021 
 
 
 
 
 
 
 
Labcorp Inc. CDCS 
Clinical Development Commercialization Services 


Statistical Analysis Plan 
Sponsor Name: Bridge Biotherapeutics, Inc. 
Sponsor Protocol ID: BBT401-UC-005 
 
 
 
CONFIDENTIA 
Page 2 of 30 
Table of Contents 
1. 
Source Documents ............................................................................... 6 
2. 
Protocol Details .................................................................................... 6 
2.1 
Study Objectives ............................................................................... 6 
2.2 
Overall Study Design .......................................................................... 6 
2.3 
Sample Size and Power ...................................................................... 7 
3. 
Efficacy and Safety Variables .................................................................. 7 
3.1 
Primary Endpoint(s) ........................................................................... 7 
3.2 
Secondary Endpoints .......................................................................... 8 
3.3 
Exploratory Endpoints ........................................................................ 8 
4. 
Analysis populations ............................................................................. 9 
4.1 
Intent-to-treat Population ................................................................... 9 
4.2 
Safety Population ............................................................................... 9 
4.3 
Pharmacokinetic Population ................................................................. 9 
4.4 
Per Protocol Population ....................................................................... 9 
5. 
Data Handling ...................................................................................... 9 
5.1 
Time points and Visit Windows ............................................................. 9 
5.2 
Handling of Dropouts, Missing Data, and Outliers ................................. 10 
6. 
Statistical Methods ............................................................................. 11 
6.1 
General Principles ............................................................................ 11 
6.2 
Subject Disposition and Data Sets Analyzed ........................................ 13 
6.3 
Protocol Deviations .......................................................................... 13 
6.4 
Demographics and Other Baseline Characteristics ................................. 13 
6.4.1 
Medical History ................................................................................................................... 14 
6.4.2 
Previous and Concomitant Medications ............................................................................. 14 
6.4.3 
Concomitant Procedure ...................................................................................................... 15 
6.4.4 
Rescue Therapy ................................................................................................................... 15 
6.5 
Measurements of Treatment Compliance ............................................. 16 
6.6 
Efficacy .......................................................................................... 17 
6.6.1 
Primary Efficacy Analysis ..................................................................................................... 17 
6.6.2 
Secondary Efficacy Analysis ................................................................................................ 18 


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Document Date: 26JAN2022 
 
 
 
6.6.3 
Sensitivity Analysis .............................................................................................................. 19 
6.6.4 
Subgroup Analysis ............................................................................................................... 19 
6.6.5 
Exploratory Analysis ............................................................................................................ 19 
6.7 
Safety ............................................................................................ 23 
6.7.1 
Extent of Exposure .............................................................................................................. 23 
6.7.2 
Adverse Events .................................................................................................................... 24 
6.7.3 
Laboratory Evaluations ....................................................................................................... 26 
6.7.4 
Vital Signs ............................................................................................................................ 27 
6.7.5 
12-Lead Electrocardiograms ............................................................................................... 27 
6.7.6 
Physical Examination ........................................................................................................... 28 
6.8 
PK Analysis ..................................................................................... 28 
6.9 
Interim Analysis .............................................................................. 28 
7. 
Changes in Planned Analysis ................................................................ 28 
8. 
Data Issues ....................................................................................... 29 
9. 
References ........................................................................................ 29 
10. 
Appendices ........................................................................................ 29 
Appendix 1: Document History ........................................................... 29 
Appendix 2: Sample SAS Code for MMRM ............................................. 29 
 
 
 


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CONFIDENTIAL 
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Document Date: 26JAN2022 
 
 
 
Reviewers 
The following reviews of the SAP were conducted: 
 
Glossary of Abbreviations 
Abbreviation 
Term 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice daily 
CI 
Confidence interval 
CRF 
Case report form 
ECG 
Electrocardiogram 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICF 
Inform consent form 
ITT 
Intention-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
PR 
Pulse rate 
PT 
Preferred term 
QD 
Once a day 
QTcF 
Fridericia corrected QT interval 
RBS 
Rectal Bleeding Score 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SFS 
Stool Frequency Score 
SI 
International system of units 
SOC 
System organ class 
STEAE 
Serious treatment emergent adverse event 
Name and Title  
 Role 
Version Last 
Reviewed 
Company/ 
Organization 
 
Lead Programmer 
  
 
 
Peer Statistician 
 
 
 
Medical Writer 
 
 
 
Project Physician 
 
 
 
Lead Data Manager 
 
 
 
Project Manager 
 
 
  
Statistical Consultant 
 
 
 
Head of Clinical Development 
and Strategy 
 
 
  
Global Project Manager 
 
 


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Document Date: 26JAN2022 
 
 
 
TEAE 
Treatment emergent adverse event 
TFLs 
Tables, figures and listings 
UC 
Ulcerative colitis 
UCEIS 
Ulcerative Colitis Endoscopic Index of Severity 
mMCS 
Modified Mayo Clinical Score 
mESS 
Modified Mayo Endoscopic Score 
 
 


Statistical Analysis Plan 
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CONFIDENTIAL 
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Document Date: 26JAN2022 
 
 
 
1. Source Documents 
The Statistical Analysis Plan (SAP) was written based on the following 
documentation: 
Document 
Date 
Version 
Protocol for Korea 
02-Aug-2021 
5.1 (Korea) 
Protocol for other countries  
02-Aug-2021 
5.0 (Other countries) 
 
 
  
2. Protocol Details 
2.1 Study Objectives 
The primary objective of this study is to explore the efficacy of orally administered 
BBT-401-1S in inducing a clinical response in subjects with active ulcerative colitis 
(UC) which is defined as have been diagnosed with active UC for ≥3 months prior to 
Day 1, have an inadequate response or disease relapse despite treatment of UC based 
on the local standard of care prior to screening, or have a total Mayo score ≥6, and 
endoscopic subscore ≥2, rectal bleeding subscore ≥1, and a stool frequency subscore 
≥1, regardless of standard of care history. 
The secondary objectives of the study are: 
• 
to assess the safety and tolerability of orally administered BBT-401-1S 
• 
to explore additional measurements of the efficacy of orally administered BBT-
401-1S in inducing endoscopic and clinical remission. 
The exploratory objectives of this study are to evaluate the effects of BBT-401-1S on 
endoscopic 
response, 
subject-reported 
outcomes, 
histological 
improvement, 
biomarkers, and long-term clinical remission. 
2.2 Overall Study Design 
This study will comprise 2 periods: a randomised, double-blind, placebo-controlled 
induction phase; and a response-adaptive, double-blind extension phase. 
Induction Phase 
Subjects will be screened for inclusion in the study within 28 days of Day 1. Eligible 
subjects will be randomised in a 1:1:1 ratio; 12 subjects will receive 800 mg BBT-
401-1S once daily (QD) and placebo QD, 12 subjects will receive 800 mg BBT-401-
1S twice daily (BID), and 12 subjects will receive placebo BID. Subjects will receive 
the first dose of study drug at the study site on Day 1 and will administer study drug 
away from the study site for 56 days, during which they will attend 2 study site visits 
on Days 29 and 57. Additionally, subjects will be contacted by telephone on Day 8 
for safety and compliance monitoring; however, at the discretion of the investigator, 
subjects may be requested to attend a study site visit on this day. 


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Document Date: 26JAN2022 
 
 
 
Subjects who do not agree to participate in the extension phase will attend the study 
site for a follow-up visit on Day 71. 
Extension Phase 
Subjects who complete the induction phase will be offered the opportunity to enter 
the extension phase after the Day 57 visit. Subjects who agree to participate in the 
extension phase will continue study drug administration while awaiting their clinical 
remission status from the local reader. Subjects will be assigned to the treatment for 
the extension phase treatment upon receipt of their clinical remission status. 
• 
Subjects who achieved clinical remission in the induction phase will continue 
the same treatment. 
• 
Subjects who did not achieve clinical remission in the induction phase and: 
o who received placebo BID will receive 800 mg BBT-401-1S QD and 
placebo QD 
o who received 800 mg BBT-401-1S QD and placebo QD will receive 800 
mg BBT-401-1S BID 
o who received 800 mg BBT-401-1S BID will continue the same 
treatment. 
Subjects will attend the study site on Days 85,  112 (last dose of treatment), and 
126 (for Korean sites only). Additionally, subjects will be contacted by telephone on 
Day 71 for safety and compliance monitoring; however, at the discretion of the 
investigator, subjects may be requested to attend a study site visit on this day. 
The total planned study duration (screening to follow-up) is approximately 20 and 22 
weeks for subjects who are enrolled into the extension phase in the sites of Korea 
and other countries respectively, and approximately 14 weeks for subjects who are 
not enrolled into the extension phase. 
2.3 Sample Size and Power 
Approximately 36 subjects will be randomised. There has not been any formal 
statistical assessment of the sample size. However, the number of subjects is 
common in early clinical studies and is considered sufficient to achieve the objectives 
of the study. 
3. Efficacy and Safety Variables 
3.1 Primary Endpoint(s) 
The primary efficacy endpoint is the clinical response rate at Day 57, as measured 
by a reduction of ≥3 points and ≥30% improvement from baseline of total Mayo 
score, which includes a decrease in rectal bleeding subscore of ≥1 point or an 
absolute rectal bleeding subscore ≤1. 


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The primary safety endpoints are adverse events (AEs) and serious adverse events 
(SAEs). 
3.2 Secondary Endpoints 
The secondary efficacy endpoints are: 
• 
Clinical remission at Day 57, as measured by a total Mayo score of ≤2 points, 
with no individual subscore exceeding 1 point 
• 
Achievement of endoscopic remission at Day 57, as measured by a Mayo 
endoscopic subscore of 0 or 1. 
• 
Change from baseline to Day 57 in the total Mayo score 
3.3 Exploratory Endpoints 
The exploratory efficacy endpoints are: 
• 
Endoscopic response rate at Day 57, as defined by a ≥2-point reduction from 
baseline in Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score 
• 
Endoscopic response rate at Day 57, as defined by a reduction of ≥1 grade in 
the Mayo endoscopic subscore 
• 
Modified Mayo remission rate at Day 57, as defined by modified Mayo Clinical 
Score (mMCS) ≤2, Rectal Bleeding Score (RBS) =0, modified Mayo Endoscopic 
Score (mESS) ≤1, Stool Frequency Score (SFS) =0 or (1 if at least 1 point 
drop from baseline) 
• 
Symptomatic remission rate at Day 57, as defined by RBS =0, SFS = 0 
• 
Inflammatory Bowel Disease Questionnaire (IBDQ) total score, as measured 
by change from baseline 
• 
Histological improvement, as guided by change from baseline in Geboes score 
• 
Biomarkers, including C-reactive protein and faecal calprotectin, as measured 
by change from baseline 
• 
Clinical remission at Day 112, as measured by a total Mayo score of ≤2 points, 
with no individual subscore exceeding 1 point 
• 
Percentage of subjects with sustained remission at Day 112 
• 
Clinical response rate at Day 112. 
• 
Change from baseline to Day 57 in the partial Mayo score 
 
 
 
 
 
 
 


Statistical Analysis Plan 
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CONFIDENTIAL 
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Document Date: 26JAN2022 
 
 
 
4. Analysis populations 
4.1 Intent-to-treat Population 
The intent-to-treat (ITT) population will include all subjects who receive at least 1 
dose of study drug, and who have a partial Mayo score recorded on Day 1 and at 
least 1 post-baseline Mayo score recorded. Subjects are categorized in the treatment 
group to which they are randomized. 
4.2 Safety Population 
The safety population will include all subjects who receive at least 1 dose of study 
drug. Subjects are categorized in the treatment group of the treatment they actually 
receive. 
4.3 Pharmacokinetic Population 
The pharmacokinetic population will include all subjects who received at least 1 
dose of study drug and have at least 1 evaluable tissue concentration without a 
protocol deviation considered to significantly affect the pharmacokinetics. 
4.4 Per Protocol Population 
The per protocol population will include all subjects in the ITT who do not have pre-
defined major protocol deviations that may affect the primary efficacy endpoint and 
have completed the study until Visit 5 (Day 57). 
5. Data Handling 
Unless otherwise specified, the baseline value which is not related to the efficacy 
analysis is defined as the last value obtained before the date and time of the first 
dose of study drug. Post-baseline values are defined as value obtained after the first 
dose of study drug.  
The efficacy related baseline value (such as Total Mayo Score) is defined as the 
measurement taken at screening.  
Change from baseline is defined as a post-baseline value minus the baseline value. 
5.1 Time points and Visit Windows 
Day 1 is defined as the day of first dose of treatment.  Relative days after Day 1 are 
calculated as (assessment date – Day 1 date) + 1.  Relative days prior to Day 1 are 
calculated as (assessment date – Day 1 date).  The day prior to Day 1 is Day -1.  
All data will be analyzed using nominal study visits as defined in the Study Schedule 
and case report form (CRF).  No visit windows will be applied for summary and 
analysis. 


Statistical Analysis Plan 
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Document Date: 26JAN2022 
 
 
 
5.2 Handling of Dropouts, Missing Data, and Outliers 
For the primary and secondary efficacy responder analysis based on the total Mayo 
score, subjects with missing data will be deemed as “unresponsive”. For subjects who 
received rescue therapy after the first dose of study drug and prior to Day 57, the 
response status will be deemed as “unresponsive” regardless of the Mayo score value 
at Day 57. 
In terms of the exploratory endpoints, for the endoscopic response rate by total Mayo 
score, if a subject has no Mayo endoscopic subscore on Day 57, then the last post-
baseline measurement prior to Day 57 will be used and the analysis will be based on 
the imputed value. If a subject does not have any post-baseline Mayo endoscopic 
subscore measurement, then the subject will be deemed as “unresponsive”. 
For modified Mayo remission rate at Day 57, if a subject has more than or equal to 2 
questions are not answered, then the subject will be considered as “unresponsive”. 
If a subject has only 1 question is not answered, then the last post-baseline question 
answered prior to Day 57 will be used to calculate the modified Mayo remission rate 
at Day 57. 
For systemic remission rate at Day 57 based by total Mayo score, if a subject has 2 
questions are not answered, then the subject will be considered as “unresponsive”. 
If a subject has only 1 question is not answered, then the last post-baseline question 
answered prior to Day 57 will be used to calculate the systemic remission rate at Day 
57. 
For the clinical remission at Day 112, the percentage of subjects with sustained 
remission on Day 112, and the clinical response rate at Day 112 which are all based 
on the total Mayo score, if a subject has more than or equal to 3 questions are not 
answered, then the subject will be considered as “unresponsive”. If a subject has less 
than 3 questions are not answered, then the last post-baseline question(s) answered 
prior to Day 112 will be used to calculate the total Mayo score and information 
relevant to derive hose Day 112 related exploratory endpoints.  
For the UCEIS exploratory endpoint, if a subject has 1 unanswered UCEIS descriptor 
for the Day 57 visit, the last post-baseline value for the UCEIS descriptor prior to Day 
57 will be used to calculate the final index score and to classify the achievement of 
endoscopic response by Day 57. If a subject has more than 1 unanswered UCEIS 
descriptor for the Day 57 visit, the last post-baseline value of the UCEIS index score 
prior to Day 57 will be used to classify the achievement of endoscopic response by 
Day 57. If a subject does not have any post-baseline measurement, then the subject 
will be deemed as “unresponsive”.  
In terms of handling missing/incomplete IBDQ, the following rule (as shown in the 
table below) will be followed before any imputation to be taken into a place: 
Number of Missing Values 
Comments /Actions 
 
Subscore 
1 
Subscore 
2 
Subscore 
3 
Subscore 
4 
 
Scenario A 
0 
0 
0 
0 
You can compute 4 subscores and the 
full IBDQ 


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Scenario B 
1 
0 
0 
0 
You can compute both the full IBDQ and 
the 4 subscores, by replacing the 
missing value with the average mean 
(computed on the data available for its 
own subscore) 
Scenario C 
1 
1 
1 
1 
You can compute both the full IBDQ and 
the 4 subscores, by replacing the 
missing values with the average means 
(each one computed on the data 
available for its own subscore) 
Scenario D 
2 
0 
0 
0 
You can compute the full IBDQ by 
replacing the 2 missing values with the 
average mean (computed on the data 
available for its own subscore). You can 
compute only 3 subscores 
Scenario E 
2 
1 
0 
1 
You can compute the full IBDQ by 
replacing the missing values with the 
average means (each one computed on 
the data available for its own subscore). 
You can compute only 3 subscores 
Scenario F 
2 
1 
1 
1 
You cannot compute the full IBDQ 
(more than 4 missing values). 
You can compute only 3 subscores 
Scenario G 
2 
2 
0 
0 
You cannot compute the full IBDQ 
because in more than one subscore 
there are 2 missing values (even though 
the total missing value is not exceeding 
4). You can compute only 2 subscores. 
Scenario H 
0 
0 
3 
0 
You cannot compute the full IBDQ 
because there is one subscore with 
more than 2 missing values. You can 
compute only 3 subscores. 
 
If the IBDQ missing value scenario is not covered via the process described above, 
the last post-baseline measurement will be used and analysis will be based on the 
imputed value. 
Missing histopathology data will be considered as non-remission when analysis is 
performed. 
Missing biomarkers data will not be imputed. 
Handling of missing/incomplete concomitant medication start/stop date will be 
documented in Section 6.4.2 Previous and Concomitant Medication. 
Handling of missing/incomplete AE start/stop date will be documented in 
Section 6.7.2 Adverse Events. 
6. Statistical Methods 
6.1 General Principles 
Continuous variables will be summarised by the standard descriptive statistics: 
number of subjects (n), mean, standard deviation, median, minimum, and maximum. 


Statistical Analysis Plan 
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Document Date: 26JAN2022 
 
 
 
Frequency of subjects or events and percentages will be summarised in categorical 
variables. 
All data processing, summarization and analyses will be performed using Labcorp’s 
SAS Environment / Version 9.4 (or later) of the SAS statistical software package. 
The following principles will be applied to all TFLs unless otherwise stated: 
Principle 
Value 
Suggested Alternative Values 
Significant tests 
The significance testing will be 
performed and the 95% confidence 
interval will be reported where 
applicable. 
 
Treatment group 
labels and order 
presented 
• 
800 mg BBT-401-1S QD and 
placebo QD 
• 
800 mg BBT-401-1S BID 
• 
Placebo BID 
• 
BBT-401-1S QD +Placebo QD 
• 
BBT-401-1S BID 
• 
Placebo BID 
Tables 
Data in summary tables presented 
by phase, assessment and visit 
(where applicable). 
 
Listings 
All data collected presented by 
phase, subject, assessment and 
visit (where applicable), unless 
otherwise specified 
 
Descriptive 
summary statistics 
for continuous 
variables 
Number of subjects (n), mean, 
standard deviation (SD), minimum, 
median, and maximum. 
 
Descriptive 
summary statistics 
for categorical 
variables 
Frequency counts and percentages 
[n (%)] 
 
Denominator for 
percentages 
Number of subjects in the analysis 
population, unless stated otherwise 
in table shell(s) 
 
Include “Missing” 
as category 
Demographics and Other Baseline 
Characteristics only  
 
Display for 0 
percentages 
0  
 
Display to one 
more decimal 
place than 
collected value 
Mean 
Mean Difference 
Median 
 
Display to two 
more decimal 
places than 
collected value 
Standard Deviation 
Standard Error 
Confidence Interval 
 
Limit of precision 
for displays 
3 decimal places for non-derived 
variables and 5 decimal places for 
derived variables 
 
Date Format 
DDMMMYYYY 
 


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For subjects who progress into the extension phase and have achieved clinical 
remission in the induction phase, subjects will continue with the same treatment in 
the extension phase. If subjects have not achieved clinical remission in the induction 
phase, then a treatment will be assigned follows the described in Section 2.2. Data 
display will be summarised/listed by study phase where it is applicable as subjects 
may switch treatments between induction phase and extension for the Safety 
Population.  
6.2 Subject Disposition and Data Sets Analyzed 
Subject disposition will be listed and summarised and will include the number and 
percentage of subjects: 
• 
screened 
• 
enrolled 
• 
treated 
• 
included in each study population (ITT, Safety, PK and Per Protocol Population). 
The number and percentage of subjects who complete the treatment/study at 
induction phase and who discontinue early from induction phase including primary 
reasons for discontinuation, will be presented by treatment group 
 
Additionally, a separate disposition for the extension will be summarised by treatment 
group 
 and will include the number and percentage of 
subjects: 
• 
enter the extension phase 
• 
treatment received during the extension phase 
• 
early discontinue from extension phase with primary reason 
• 
complete the extension phase 
Screen failures will be listed with the reasons for failing the screen. 
6.3 Protocol Deviations 
All protocol deviations will be listed. In addition, all important protocol deviations will 
be summarised separately for each phase and by treatment group for the ITT 
Population. 
6.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarised by treatment 
group for the ITT Population.  Standard descriptive statistics will be presented for the 
continuous variables of: 
• 
age (years) [as collected on the CRF] 


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• 
weight (kg) 
The total counts and percentages of subjects will be presented for the categorical 
variables of: 
• 
sex 
• 
race 
• 
ethnicity 
6.4.1 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) [Version 23.1 (or a later version if updated during the study)].  All medical 
history will be listed, and the number and percentage of subjects with any medical 
history will be summarised by system organ class (SOC) and preferred term (PT) by 
treatment group for ITT.   
6.4.2 Previous and Concomitant Medications 
Medications received prior to or concomitantly with treatment will be coded by 
Labcorp using the WHODrug Dictionary [Sep2020 B3 (or a later version if updated 
during the study)], Anatomical Therapeutic Chemical (ATC) Classification codes.  
Prior medications and concomitant medications are defined as follows: 
Prior medications are taken with a start and stop dates prior to the first dose date 
and time of treatment.  
Concomitant medications are those with a start date on or after the first dose date 
and time of treatment, or those with a start date before the first dose date of 
treatment and a stop date on or after the first dose date and time of treatment or 
ongoing end of study. 
If there are missing/partial medication start/end dates, the following rule will be used 
to determine whether the medication is a concomitant medication: 
• 
If month/year of the start date is after the month/year of Day 1, the medication 
will be considered as concomitant medication. 
• 
If month/year of the start date is equal or before the month/year of Day 1, and 
the end date is present, the end date will be used to determine whether the 
medication is prior or concomitant. If the end date is on or after Study Day 1, the 
medication will be considered as concomitant medication. Otherwise, if the 
medication stopped before Study Day 1, then the medication is a prior medication. 
• 
If month/year of the start date is equal to the month/year of Day 1, and the end 
date is a partial date, the medication will be considered as concomitant 
medication.  


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If a medication cannot be classified as “prior” or “concomitant” after applying 
imputation rules for missing/incomplete dates, it will be classified as concomitant. 
Prior medications and concomitant medications will be listed together and 
summarised by treatment group for the ITT Population. 
The number and percentage of subjects using each medication will be displayed 
together with the number and percentage of subjects using at least one medication 
within each therapeutic class (ATC-Level 2), chemical subgroup (ATC-Level 4), and 
generic term. 
Medication starting date which is within the induction phase will be summarised under 
the induction phase. Similarly, a medication starting date which is within the 
extension phase will be summarised under the extension phase. 
6.4.3 Concomitant Procedure 
Procedure received concomitantly with treatment will be coded 
 
 
  
Concomitant procedures will be documented on the CRF. The number and percentage 
of subjects using each procedure will be displayed together with the number and 
percentage of subjects using at least one medication 
 
 for each phase 
and by treatment group for the Safety Population. 
6.4.4 Rescue Therapy 
Rescue medications and rescue procedures are both considered as rescue therapy for 
this study. Both rescue medication and rescue procedure will be documented on the 
CRF. 
6.4.4.1 
Rescue Medication 
Rescue medication will be coded by Labcorp using the WHODrug Dictionary [Version 
Sep2020 B3 (or a later version if updated during the study)], ATC Classification 
codes.  
The number and percentage of subjects using each therapy will be displayed together 
with the number and percentage of subjects using at least 1 medication within each 
therapeutic class (ATC-Level 2), chemical subgroup (ATC-Level 4), and generic term 
for each phase and by treatment group for the Safety Population. 


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6.4.4.2 
Rescue Procedure 
Rescue procedure will be coded by Labcorp using the Medical Dictionary for 
Regulatory Activities (MedDRA) [Version 23.1 (or a later version if updated during 
the study)]. 
The number and percentage of subjects with any rescue procedue will be summarised 
by system organ class (SOC) and preferred term (PT) for each phase and by 
treatment group for the Safety Population. 
6.5 Measurements of Treatment Compliance 
Percentage compliance is calculated as: 
Overall Compliance: 
100 * actual dose (capsules) taken/expected dose (capsules) administered 
 
 
The expected dose administered is defined as number of days * 8  (capsules). Where 
number of days is calculated as the last treatment date – the first treatment date 
+1. 
Compliance under Induction Phase: 
100 * actual dose (capsules) taken/expected dose (capsules) administered 
 
 
 
The expected dose administered is defined as number of days * 8 (capsules). Where 
number of days is calculated as the last treatment date – the first treatment date +1 
during the induction phase. 
Compliance under Extension Phase: 
100 * actual dose (capsules) taken/expected dose (capsules) administered 
 
 
 
The expected dose administered is defined as number of days * 8  (capsules). Where 
number of days is calculated as the last treatment date – the first treatment date +1 
during the extension phase. 
Percentage compliance will be summarised descriptively for each study phase by 
treatment group for the Safety Population. A pooled overall percentage compliance 


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will also be summarised descriptively by induction assigned treatment for the Safety 
Population. 
The number and percentage of compliant subjects will be presented for each study 
phase by treatment group and pooled overall labelled by induction assigned 
treatment for the Safety Population, where compliant is defined as percentage 
compliance between 80.0% and 120.0% inclusive. The following percentage 
compliance categories will also be presented for overall and each study phase: 
• 
<80.0% 
• 
80.0% - 120.0% 
• 
>120.0% 
6.6 Efficacy 
6.6.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the clinical response rate at Day 57, as measured 
by a reduction of ≥3 points and ≥30% improvement from baseline of total Mayo 
score, which includes a decrease in rectal bleeding subscore of ≥1 point or an 
absolute rectal bleeding subscore ≤1. Centrally read Mayo endoscopic subscores will 
be used to evaluate the objectives of the study. 
The stool frequency and rectal bleeding subscores will use the average of the last 3 
non-missing assessments recorded in the subject diary. If an endoscopy is 
performed, the average of the last 3 non-missing assessments recorded in the subject 
diary prior to bowel preparation should be used. If the subscore is not an integer, the 
subscore should be rounded to the nearest integer. Subjects with missing values will 
be considered as unresponsive as described in Section 5.2. 
Total Mayo Score will be calculated based on the response achieved from all 4 
subscores ranged from 0-3 each out of a total sum of 12. 
For example: If stool frequency = 2, rectal bleeding = 1, physician’s global 
assessment = 2 and findings on endoscopy = 2 then total mayo score is 7 
(2+1+2+2=7). 
The percentage of improvement at day 57 is calculated as: 
((Baseline Sum of the Total Mayo Score – Day 57 Sum of the Total Mayo Score)/ 
Baseline Sum of the Total Mayo Score) x 100%. 
Subjects with a reduction of ≥3 points and ≥30% improvement from baseline of total 
Mayo score as well as a decrease in rectal bleeding subscore of ≥1 point or an 
absolute rectal bleeding subscore ≤1 will be considered as slowing a clinical response 
at Day 57. 


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The number and proportion of subjects with the 95% confidence interval (CI) of 
clinical response rate at Day 57 will be calculated using the exact binomial method 
for each treatment. The Fisher’s exact test will be used to evaluate any differences 
between treatments at Day 57 and will be summarised for the induction phase by 
treatment group for the ITT Population. No adjustments will be made for multiple 
comparisons.  
6.6.2 Secondary Efficacy Analysis 
Centrally read Mayo endoscopic subscores will be used to evaluate the secondary 
objectives of the study. 
The stool frequency and rectal bleeding subscores will use the average of the last 3 
non-missing assessments recorded in the subject diary. If an endoscopy is 
performed, the average of the last 3 non-missing assessments recorded in the subject 
diary prior to bowel preparation should be used. If the subscore is not an integer, the 
subscore should be rounded to the nearest integer. Missing values will be considered 
as unresponsive as described in Section 5.2. 
• Clinical remission at Day 57, as measured by a total Mayo score of ≤2 
points, with no individual subscore exceeding 1 point.  
Total Mayo Score will be calculated based on the response achieved from all 4 
subscores ranged from 0-3 each out of a total sum of 12.  
Subjects who have a sum of total Mayo score ≤2 points, with no individual subscore 
exceeding 1 point at Day 57, will be considered as achieving clinical remission. 
The number and proportion of subjects with the 95% confidence interval (CI) of 
clinical remission rate at Day 57 will be calculated using the exact binomial method 
for each treatment. The Fisher’s exact test will be used to evaluate any differences 
between treatments at Day 57 will be summarised for the induction phase by 
treatment group for then ITT Population. 
• Achievement of endoscopic remission at Day 57, as measured by a Mayo 
endoscopic subscore of 0 or 1. 
The number and proportion of subjects achieving endoscopic remission at Day 57 
with the 95% CI will be calculated using the exact binomial method for each 
treatment. The Fisher’s exact test will be used to evaluate any differences between 
treatments at Day 57 will be summarised for the induction phase by treatment 
group for the ITT Population. 
• Change from baseline to Day 57 in the Total Mayo score. 


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Analysis of covariance (ANCOVA) with change from baseline as the dependent 
variable and baseline value as the covariate variable will be used to compare the 
change from baseline to Day 57 in the total Mayo score between each treated 
group and the placebo group. The 95% CI for the treatment differences in the 
change from baseline will be calculated, and the p-value will be provided. 
The normality assumption will be checked through the Shapiro-Wilk test of the 
residuals from the ANCOVA. If the normality assumption is violated at the 0.01 
level of significance, an additional nonparametric analysis 
 
 will be used to compare each treated group to the placebo group.  
6.6.3 Sensitivity Analysis 
The following sensitivity analysis will be performed on the primary efficacy endpoint 
(the clinical response rate at Day 57) and the first secondary efficacy endpoint (the 
clinical remission rate at Day 57). 
For these analyses, the following rules will apply. 
 
 
 
 
 
 
 
In addition, the primary efficacy analysis will also be performed for the per-protocol 
population. 
6.6.4 Subgroup Analysis 
There is no pre-specified subgroup analysis for this study.  
6.6.5 Exploratory Analysis 
• 
Endoscopic response rate by Day 57, as defined by a ≥2-points reduction 
from baseline in UCEIS score via central reading.  
The UCEIS score will be calculated as the sum of the scores of all descriptors. 
The higher the score, the worse the UC. Baseline total UCEIS score minus Day 
57 UCEIS score will be used to calculate the number of subjects who have a ≥2 
points reduction. With a difference ≥2 points will be considered as endoscopic 
response. Missing value will be imputed based on the description from Section 
5.2. 


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The actual and change from baseline will be presented. The number and 
proportion of subjects with the 95% CI of endoscopic response rate at Day 57 
will be calculated using the exact binomial method for each treatment. The 
Fisher’s exact test will be used to evaluate any differences between treatments 
at Day 57 and will be summarised for the induction phase by treatment group for 
ITT Population. 
• 
Endoscopic response rate at Day 57, as defined by a reduction of ≥1 grade 
in the Mayo endoscopic subscore 
The Mayo endoscopic subscore will be based on Part 4 of the total Mayo score - 
“Investigator-reported Findings on endoscopy”. The change in endoscopic score is 
calculated as the difference between the baseline and Day 57 scores. A difference 
of ≥1 grade is considered as endoscopic response. Missing values will be imputed 
based on the description from Section 5.2. 
The number and proportion of subjects with the 95% CI of endoscopic response 
rate at Day 57 will be calculated using the exact binomial method for each 
treatment. The Fisher’s exact test will be used to evaluate any differences between 
treatments at Day 57 and will be summarised for the induction phase by treatment 
group for ITT Population. 
• 
Modified Mayo remission rate at Day 57, as defined by a mMCS≤2, RBS=0, 
mESS≤1, SFS=0 or (1 if at least 1 point drop from baseline) 
The modified Mayo remission will be based on the Total Mayo Score with all the 
following 4 conditions are satisfied: 1. mMCS≤2, and 2. Rectal Bleeding Score=0, 
and 3. mESS≤1, and 4. Stool Frequency Score=0 or (1 if at least 1 point drop from 
baseline), where mMCS will be collected in the Modified Mayo Score form as the 
sum of RBS, mESS and SFS. Missing values will be imputed based on the 
description from Section 5.2. 
The number and proportion of subjects with the 95% CI of modified Mayo 
remission rate at Day 57 will be calculated using the exact binomial method for 
each treatment. The Fisher’s exact test will be used to evaluate any differences 
between treatments at Day 57 and will be summarised for the induction phase by 
treatment group for ITT Population. 
• 
Symptomatic remission rate at Day 57, as defined by RBS=0, SFS=0 
The symptomatic remission rate at Day 57 will be based on the Rectal Bleeding 
Score =0 and Stool Frequency Score=0 from Total Mayo Scoare. Missing values 
will be imputed based on the description from Section 5.2. 


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The number and proportion of subjects with the 95% CI of symptomatic remission 
rate at Day 57 will be calculated using the exact binomial method for each 
treatment. The Fisher’s exact test will be used to evaluate any differences between 
treatments at Day 57 and will be summarised for the induction phase by treatment 
group for ITT Population. 
• 
Inflammatory Bowel Disease Questionnaire (IBDQ) total score, as 
measured by change from baseline 
The IBDQ is a health-related quality-of-life (HRQoL) tool measuring bowel, 
systemic, emotional, and social function. Scores for each question range between 
1 and 7, reflecting poor to good HRQoL, for a range of possible total scores from 
32 to 224. In terms of the 4 aspects of patients live and their corresponding 
questions, it is summarised in the following table. 
 
Aspects 
Questions 
Range of Score 
Bowel 
1, 5, 9, 13, 17, 20, 22, 24, 
26, 29 
10 to 70 
Systemic 
2, 6, 10, 14, 18 
5 to 35 
Emotional 
3, 7, 11, 15, 19, 21, 23, 
25, 27, 30, 31, 32 
12 to 84 
Social Function 
4, 8, 12, 16, 28 
5 to 35 
Total Score 
1~32 
32 to 224 
 
Descriptive statistics on total score and its four aspects: bowel, systemic, 
emotional, and social function at each scheduled visit as well as change from 
baseline will be calculated for each phase and by treatment group for the ITT 
Population.  
The following categories with number and percentage of subjects will also be 
presented for total score at each post-baseline visit: 
• 
change >= 16 points from baseline 
• 
total score >= 170 
Mixed Model Repeated Measures (MMRM), with repeated change from baseline 
values as the dependent variable and baseline values as the covariate variable, 
will be used to compare the change from baseline to Day 29 and 57 in the IBDQ 
score between treatment and placebo group. The sample SAS code is provided in 
Apendix 2. The 95% CI for the difference in the change from baseline will be 
calculated for each treatment, and the p-value will be provided. 


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The normality assumption will be checked through the Shapiro-Wilk test. If the 
normality assumption is violated at the 0.01 level of significance, an additional 
nonparametric analysis 
 will be used to 
compare each treated group to the placebo group.  
• 
Histologic remission using histologic category 
Subjects will be dichotomized as “histological remission” versus “histological non-
remission” based on the option recorded on the CRF. Subjects with histologic 
category recorded as “histologic near remission” and “Other” will be categorised 
as “histologic non-remission”. On the other hand, those recorded with “histologic 
healing”, 
“histologic 
remission”, 
“histologic 
remission 
without 
basal 
plasmacytosis”, and “histologic remission without basal plasmacytosis or 
increased mucosal eosinophils” will be grouped to “histologic remission”. 
A shift table (i.e., cross-tabulations “histologic remission” and “histologic non-
remission” at screening versus Day 57) in a form of 2 x 2 table will be presented 
for each treatment. 
The number and proportion of subjects within each combined category will be 
summarised by treatment group for the ITT Population.  
• 
Biomarkers, including C-reactive protein and faecal calprotectin, as 
measured by change from baseline 
Descriptive statistics on biomarkers at each scheduled visit as well as change from 
baseline will be calculated for each phase by treatment group for the ITT Population. 
• Clinical remission at Day 112, as measured by a total Mayo score of ≤2 
points, with no individual subscore exceeding 1 point.  
Total Mayo Score will be evaluated. Subjects who have a total Mayo score ≤2 
points, with no individual subscore exceeding 1 point at Day 112, will be considered 
as achieving clinical remission. 
The number and proportion of subjects with the 95% CI of clinical remission rate 
at Day 112 will be calculated using the exact binomial method for each treatment. 
The Fisher’s exact test will be used to evaluate any differences between treatments 
at Day 112 for the extension phase by treatment group for the ITT Population. 
• Sustained remission at Day 112.  
Total Mayo Score will be evaluated. Subjects who have a total Mayo score ≤2 
points, with no individual subscore exceeding 1 point at day 57 and day 112 will 
be considered as achieving sustained remission at day 112. 
The number and proportion of subjects with the 95% CI of sustained remission at 
Day 112 will be calculated using the exact binomial method for each treatment. 


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The Fisher’s exact test will be used to evaluate any differences between treatments 
at Day 112 for the extension phase by treatment group for the ITT Population. 
• Clinical response rate at Day 112.  
The number and proportion of subjects with the 95% CI of clinical response rate 
at Day 112 will be calculated using the exact binomial method for each treatment. 
The Fisher’s exact test will be used to evaluate any differences between treatments 
at Day 112 for the extension phase by treatment group for the ITT Population.  
• Change from baseline to Day 57 in the Partial  Mayo score. 
Mixed Model Repeated Measures (MMRM), with repeated change from baseline 
values as the dependent variable and baseline values as the covariate variable, will 
be used to compare the change from baseline to Day 29 and 57 in the partial Mayo 
score between treatment and placebo group. The sample SAS code is provided in 
Apendix 2. The 95% CI for the difference in the change from baseline will be 
calculated for each treatment, and the p-value will be provided. 
The normality assumpltion will be checked through Shapiro-Wilk test of the 
residuals during the use of MMRM. If the normality assumption is violated at the 
0.01 level of significance, an additional nonparametric analysis 
 
 will be used to compare each treated group to the 
placebo group.  
    
6.7 Safety 
6.7.1 Extent of Exposure 
Duration of exposure will be defined in days as: 
Overall Exposure: 
 (date of the last dose – date of the first dose) + 1-off-drug days  
If date of the first dose date is missing, then the date of the first dose dispensed will 
be used. If the last dose date is missing then, then the last available dose date will 
be used.  
Induction Phase Exposure: 
 (date of the last dose from the induction phase – date of the first dose from the 
induction phase) + 1-off-drug days  
If date of the first dose date is missing, then the date of the first dose dispensed in 
the induction phase will be used. If the last dose date is missing then, then the last 
available dose date in the induction phase will be used. 


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Extension Phase Exposure: 
 (date of the last dose from the extension phase – date of the first dose from the 
extension phase) + 1-off-drug days  
If date of the first dose date is missing, then the date of the first dose dispensed in 
the extension phase will be used. If the last dose date is missing then, then the last 
available dose date in the extension phase will be used. 
Duration of exposure will be listed and summarised using descriptive statistics for 
each phase and overall by treatment group for the Safety Population.    
The number and percentage of subjects with an overall duration of exposure in the 
following categories will be summarised for each phase and by treatment group for 
the Safety Population:  
• 
<22 days 
• 
≥22 and <57 days 
• 
≥57 days 
Overall duration will be summarised by treatment received during the induction 
phase. Exposure during each study phase will be summarised by the actual treatment 
received respectively during each study phase. 
6.7.2 Adverse Events 
All AEs recorded on the CRF will be coded using the MedDRA dictionary [Version 23.1 
(or a later version if updated during the study)] and treatment – emergent AEs 
(TEAEs) are defined as follows: 
• 
TEAEs are events with start date on or after the date and time of the first dose of 
treatment or events with start date prior to the date and time of the first dose of 
treatment whose severity worsens on or after the date and time of the first dose 
of treatment.  
If an event where AE start/stop date is missing/partial, the following imputation rule 
will be applied: 
Imputation rules for start date of AEs: 
• 
If start date is completely missing, start date will be imputed to be the first dose 
date of study treatment; 
• 
For a partial start date (day is missing, or day and month are both missing): 
- none missing part of the partial date < the first dose date: the last day of the 
month/year 
- none missing part of the partial date = the first dose date: the first dose date 
- none missing part of the partial date > the first dose date: the first day of the 
month/year 
Imputation rules for end date of AEs: 


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• 
If end date is completely missing, then end date remains missing (assuming 
ongoing event); 
• 
For a partial end date, the last day/month will be imputed. If only day is missing, 
the last day of the month will be imputed; if both day and month are missing, 
then the last day of the year will be imputed. If the imputed end date is after the 
end of study date, then imputed end date will be set as the end of study date. 
If imputed AE start date is after the imputed AE stop date, then start date will be set 
to the imputed AE stop date. 
Imputed dates will be used to determine whether an AE is treatment-emergent and 
will not be displayed in data listings. 
All AE data will be listed.  Treatment-emergence status will be flagged in the listing. 
In addition, corresponding listings of SAEs, AEs leading to discontinuation of 
treatment and AEs resulting in death will be produced. 
Summary tables of TEAEs will be produced for each phase by treatment group for the 
Safety Population. AE starting date which is within the induction phase will be 
summarised under the induction phase. Similarly, an AE starting date which is within 
the extension phase will be summarised under the extension phase.  
The severity of all AEs is recorded as mild, moderate, or severe.  If severity is missing 
for a TEAE, it will be considered severe only in the overall category in the summary 
tables.  
The relationship between an AE and treatment is assessed as not related, unlikely 
related, possible related, or related.  A treatment-related AE is an AE considered by 
the investigator as possibly related, or related to treatment or with unknown/missing 
relationship to treatment.   
An overview table will summarize the number and percentage of subjects with at 
least one of the following TEAEs, where subjects with more than one TEAE in a 
particular category are counted only once in that category: 
• 
Any TEAE; 
• 
Treatment-Related TEAE; 
• 
TEAE Leading to Treatment Discontinuation;  
• 
Serious Treatment Emergent Adverse Event (Serious TEAE);  
• 
Treatment-Related Serious TEAE;  
• 
Serious TEAE Leading to Death; 
• 
Treatment-Related Serious TEAE Leading to Death;  
• 
Serious TEAE Leading to Treatment Discontinuation;  


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• 
Treatment-Related Serious TEAE Leading to Treatment Discontinuation 
The number and percentage of subjects reporting each AE will be summarised by 
System Organ Class (SOC) and Preferred Term (PT) for each phase and by treatment 
group for the Safety Population.  Tables will be sorted alphabetically by SOC. PTs will 
be sorted by descending overall total.  The following summaries will be produced: 
• 
TEAEs, by SOC and PT; 
• 
Treatment-Related TEAEs, by SOC and PT; 
• 
TEAEs by Relationship to Treatment, by SOC and PT; 
• 
TEAEs by Maximum Severity, by SOC and PT; 
• 
TEAEs Related to Treatment by Maximum Severity, by SOC and PT; 
• 
TEAEs Causing Discontinuation from Treatment, by SOC and PT; 
• 
Treatment-Related TEAEs Causing Discontinuation from Treatment, by SOC and 
PT; 
• 
Serious TEAEs, by SOC and PT; 
• 
Treatment-Related Serious TEAEs, by SOC and PT; 
• 
TEAEs Leading to Death, by SOC and PT; 
In the above summaries, subjects with more than one AE within a particular SOC are 
counted only once for that SOC.  Similarly, subjects with more than one AE within a 
particular PT are counted only once for that PT.  For summaries by maximum severity, 
subjects with multiple AEs within a particular SOC or PT will be counted under the 
category of their most severe AE within that SOC or PT. AEs with missing severity 
will be included (as severe) in the overall count of subjects with AEs, but will not be 
included in the counts of subjects with AEs within a SOC or PT.  
6.7.3 Laboratory Evaluations 
Data for the following hematology, blood chemistry, and urinalysis analytes received 
recorded in the CRF will be summarised and listed and by visit for each study phase 
and by treatment group for the Safety Population.   


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Hematology 
Clinical Chemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
concentration 
Mean cell volume 
Platelet count 
Red blood cell count 
White blood cell (WBC) count 
WBC differential: 
 Basophils 
 Eosinophils 
 Lymphocytes  
 Monocytes 
 Neutrophils 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatine kinase 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Lipase 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Triglycerides 
Uric acid 
Bilirubin 
Blood 
Colour and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination 
 
Coagulation 
Prothrombin time 
Activated partial 
thromboplastin 
time 
International normalised 
ratio 
 
All laboratory data will be reported in International System of Units (SI)/Conventional 
units.  Out-of-reference-range values will be flagged as high (H) or low (L) in the 
listings.  
6.7.4 Vital Signs 
The following vital signs will be summarised and listed by visit for each study phase 
and by treatment group for the Safety Population. 
• 
systolic and diastolic blood pressure (mmHg); 
• 
pulse rate (beats/min); 
• 
tympanic temperature (°C). 
6.7.5 12-Lead Electrocardiograms 
The following quantitative ECG measurements will be taken during the study: 
• 
heart rate (beats/min); 
• 
PR interval (ms); 
• 
QRS duration (ms); 
• 
QT interval (ms); 
• 
QTcF interval (ms); 
• 
RR interval (ms); 


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An overall Investigator assessment of ECG will be provided (categories “normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant”). 
The ECG measurements and investigator assessment will be summarised and be 
listed by visit for each study phase and by treatment group for the Safety Population.  
6.7.6 Physical Examination 
Physical examination results (normal/ abnormal, not clinically significant/ abnormal, 
clinically significant) will be summarised and listed for each subject for each study 
phase and by treatment group for the Safety Population. 
6.8 PK Analysis 
Tissue concentrations data for the biopsy samples collected on Day 57 will be 
summarized and listed by treatment group for the PK population. 
6.9 Interim Analysis 
No formal interim analyses are planned for this study. However, an assessment of 
clinical remission will be performed at Day 57 to determine whether a subject will 
progress into the extension phase and the dose to be administered. 
7. Changes in Planned Analysis 
• histopathology healing using the Geboes score, as measured by change 
from baseline 
During the study design stage, it was determined that this study should be as similar 
as the BBT401-UC-004. Therefore, the same endpoint was kept as it is. During the 
BBT401-UC-004 CRF design, it was determined that it is difficult to record and 
compare Geboes Score directly and hence the study team decided to use histologic 
category as the tool for histopathology.  
To be consistent with the BBT401-UC-004, it is decided the way of analysis and the 
endpoint should be modified accordingly. Therefore, a change in histopathology 
analysis is amended to be consistent with the BBT401-UC-004. 
• 
Change from baseline to Day 57 in the Total Mayo score 
The study team decided to present the absolute change from baseline to Day 57 in 
the Total Mayo score. 
• 
Modified Mayo remission rate at Day 57, as defined by a mMCS <=2, 
RBS=0, mESS<=1, SFS=0 or (1 if at least 1 point drop from baseline)  
The study team decided to summarize the modified Mayo remission rate to better 
evaluate the effects of BBT-401-1S.  
• 
Symptomatic remission rate at Day 57, as defined by RBS=0, SFS=0 
The study team decided to add an additional analysis to summarize the symptomatic 
remission rate to investigate how symptoms improve over the study duration. 


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• 
Change from baseline to Day 57 in the partial Mayo score 
The study team decided to also present the change from baseline to Day 57 in the 
partial Mayo score to better evaluate the effects of BBT-401-1S. 
 
8. Data Issues 
No known data issues at the time of preparing this SAP. 
9. References 
1 
CPMP. Points to Consider on Missing Data. EMEA: London, 2001. Available at 
https://www.ema.europa.eu/en/documents/scientific-guideline/points-
consider-missing-data_en.pdf 
2 
ICH. ICH E3 Guideline: Structure and Content of Clinical Study Reports 
Questions & Answers, 2012. Available at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Eff
icacy/E3/E3_QAs_R1_Step4.pdf 
3 
R K. Pai, V Jairath, N Casteele, F Rieder, C E. Parker, G Y. Lauwers. The 
Emerging Role of Histologic Disease Activity Assessment in Ulcerative Colitis. 
Gastrointest Endosc 2018;88: 887-98. 
4 
G Guyatt, A Mitchell, E. J. Irvine, J Singer, N Williams, R Goodacre, C 
Tompkins. A New Measure of Health Status for Clinical Trials in Inflammatory 
Bowel Disease. Gastroenterology 1989;96:804-10 
 
10. Appendices 
Appendix 1: 
Document History 
Document Version, Status, Date 
Summary/Reason for Changes 
Version XXX, DDMMMYYYY 
Not applicable; the first version 
 
Appendix 2: 
Sample SAS Code for MMRM 
 
 
 
 
 
 


Statistical Analysis Plan 
Sponsor Name: Bridge Biotherapeutics, Inc. 
Sponsor Protocol ID: BBT401-UC-005 
 
 
 
 
CONFIDENTIAL 
Page 30 of 30 
Document Date: 26JAN2022