Clinical trial NCT04556383
Conditions: Ulcerative Colitis
Keywords: Inflammatory Bowel Disease
Sponsor: GB004, Inc.
Start date: 2020-10-19; Completion date: 2022-06-01
Enrollment: 236 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A 2-part study, comprising of a 36-week placebo-controlled period (PCP) and a 24-week open-label extension (OLE) period, to assess the efficacy and safety of 2 dose regimens of GB004 when added to background UC therapy of 5-aminosalicylate (5-ASA) with or without systemic steroids.

Detailed description:

Arms: arm 1: PCP Placebo for oral administration for 36 weeks arm 2: PCP GB004 480 mg QD for oral administration for 36 weeks arm 3: PCP GB004 480 mg BID for oral administration for 36 weeks arm 4: OLE GB004 480 mg BID for oral administration for 24 weeks
Interventions: intervention 1: GB004 intervention 2: Placebo
Intervention descriptions: intervention 1: oral tablet intervention 2: oral tablet

Protocol documents:
Prot_000.pdf: 
GB004 (Oral) 
GB004, Inc.  
Protocol GB004-2101, Version 3.0, Amendment 2.0, 15 December 2021 
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CLINICAL STUDY PROTOCOL 
 
Protocol Title:  
A Phase 2, randomized, double-blind, placebo-controlled, multi-center 
study to evaluate GB004 in adult subjects with mild-to-moderate active 
ulcerative colitis 
Short Title: 
GB004 in adult subjects with active ulcerative colitis 
Protocol Number:  
GB004-2101 
Compound Number:  
GB004 
Study Phase:  
Phase 2 
 
Sponsor Name: 
GB004, Inc. 
Legal Registered 
Address: 
3013 Science Park Road 
San Diego, CA 92121, USA 
Regulatory Agency 
Identifier Number(s): 
IND Number: 133519 
EudraCT: 
2020-002306-12 
Version: 
3.0, Amendment 2.0 
Approval Date: 
15 December 2021 
 
Confidential 
This document contains proprietary and confidential information of GB004, Inc. Acceptance of 
this document constitutes agreement by the recipient that no previously unpublished information 
contained herein will be published or disclosed without the prior written approval of GB004, Inc. 
The following exceptions may occur under the condition that the party has agreed to keep this 
information confidential: 1) disclosure of information to the extent necessary to obtain informed 
consent, 2) disclosure of the document to study personnel under your supervision who need to 
know the contents for conducting the study, and 3) disclosure of the document to appropriate 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC). The foregoing shall not 
apply to disclosure required by governmental regulations or laws; however, GB004, Inc. shall be 
promptly notified of any such disclosure. 
 




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INVESTIGATOR AGREEMENT 
GB004-2101: A Phase 2, randomized, double-blind, placebo-controlled, multi-center study to 
evaluate GB004 in adult subjects with mild-to-moderate active ulcerative colitis. 
I, the undersigned, have read this protocol and agree to conduct this protocol in accordance with 
ethical principles as outlined in the International Council for Harmonisation (ICH) guidelines on 
Good Clinical Practice (GCP), any applicable laws and requirements and any additional 
conditions mandated by a regulatory authority and/or Institutional Review Board/Independent 
Ethics Committee (IRB/IEC). 
I acknowledge that I am responsible for the overall study conduct and I agree to personally 
conduct or supervise the described clinical study. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of GB004, Inc. 
 
 
 
 
Signature 
 
 
 
Name of Investigator 
 
Date 


GB004 (Oral) 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 2.0 (v3.0) 
15 December 2021 
Amendment 1.0 (v2.0) 
21 October 2020 
Original Protocol (v1.0) 
27 July 2020 
Amendment 2.0 (v3.0, 15 December 2021) 
Overall Rationale for the Amendment: 
The purpose of this amendment is primarily to make updates to Section 6.8 (Concomitant 
Medications) and Appendix 6 (Prohibited Medications). 
Table 1: 
Summary of Changes 
Section # and Name 
Description of Change 
Brief Rationale 
6.8 Concomitant Therapy 
 
Guidance has been added 
regarding the use of sensitive 
clinical substrates of OCT2 
and CYP2C8 with GB004. 
Results from in vitro studies indicate 
that a glucuronide metabolite of 
GB004, GBD242, may be an inhibitor 
of OCT2 and CYP2C8.  
Appendix 6 
Added dofetilide and 
sensitive substrates of 
CYP2C8 to Prohibited 
Medications.  
Concomitant use of dofetilide, which is 
contraindicated when used with OCT2 
inhibitors, is prohibited in this study. 
Concomitant use of sensitive substrates 
of CYP2C8 (eg, repaglinide, 
rosiglitazone, pioglitazone, and 
loperamide) is prohibited in this study. 
1.3.2 Open-Label Extension 
– Schedule of Activities   
Added Physician’s Global 
Assessment (PGA) at the 
OLE Follow-up visit. 
This assessment should occur at the 
OLE Follow-up visit. 
1.2 Study Schema 
Edited text in study schema 
for consistency with protocol 
text.  
For overall clarity and alignment with 
protocol text. 
4.1.2 OLE (24 Weeks) 
Added text “(if last dose of 
PCP IP has not been taken 
earlier in the day)” to the 
second sentence of the second 
paragraph. 
The change was made for clarity. 
5.2 Exclusion Criterion #22 
Estimated glomerular 
filtration rate (eGFR) was 
corrected to read 
< 60 mL/min/1.73 m2. 
Change was made to correct an earlier 
oversight.  


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9.4.1.1 Efficacy Analysis, 
Secondary Endpoints 
The second sentence was 
updated to read: Histologic 
remission at PCP Week 12 
and mucosal healing at PCP 
Week 12 will be evaluated 
among subjects with Baseline 
lamina propria neutrophils 
and neutrophils in epithelium 
RHI subscores > 0. 
Change was made to correct an earlier 
oversight.  
9.5 Interim Analysis 
1.1 Synopsis 
4.1.1 Placebo-Controlled 
Period (36 weeks) 
Text related to the optional, 
unblinded interim analysis 
was removed. 
The interim analysis is no longer 
planned.  
4.1.1 Placebo-Controlled 
Period (36 weeks) 
Removed the following 
sentence: “Subjects who 
permanently discontinue IP or 
withdraw from study during 
the PCP will not be eligible to 
enter the OLE.” 
The sentence was removed for clarity 
and because Section 4.1.2 clearly 
describes who is eligible for the OLE.  
4.1.1 Placebo-Controlled 
Period (36 weeks) 
Added text “without enrolling 
in the OLE” to the paragraphs 
discussing subjects who 
permanently discontinue IP 
and subjects who withdraw 
from the PCP. 
These changes were made for clarity. 
7.1 Discontinuation 
Added text “if the subject is 
not enrolling in the OLE” to 
the paragraph discussing 
Discontinuation of IP during 
the PCP. 
This change was made for clarity. 
Other minor corrections to grammatical or typographical errors were made that did not affect content. 


GB004 (Oral) 
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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................4 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES .........................................................................................................................10 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
1.1. 
Synopsis ......................................................................................................................11 
1.2. 
Study Schema .............................................................................................................15 
1.3. 
Schedule of Activities (SoA) ......................................................................................16 
1.3.1. 
Placebo-Controlled Period – Schedule of Activities ..................................................16 
1.3.2. 
Open-Label Extension - Schedule of Activities .........................................................21 
2. 
INTRODUCTION ......................................................................................................23 
2.1. 
Study Rationale ...........................................................................................................23 
2.2. 
Background .................................................................................................................23 
2.3. 
Benefit/Risk Assessment ............................................................................................25 
2.3.1. 
Benefit Assessments ...................................................................................................25 
2.3.2. 
Risk Assessments ........................................................................................................25 
2.3.3. 
Overall Benefit and Risk Conclusion .........................................................................26 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................27 
3.1. 
Placebo-Controlled Period Objectives and Endpoints ................................................27 
3.2. 
Open-Label Extension (OLE) Objectives and Endpoints ...........................................30 
3.3. 
Efficacy Endpoint Definitions ....................................................................................31 
4. 
STUDY DESIGN .......................................................................................................32 
4.1. 
Overall Study Design ..................................................................................................32 
4.1.1. 
Placebo-Controlled Period (36 weeks) .......................................................................32 
4.1.2. 
OLE (24 weeks) ..........................................................................................................33 
4.2. 
Scientific Rationale for Study Design ........................................................................33 
4.2.1. 
Study Population .........................................................................................................34 
4.2.2. 
Endpoint Selection ......................................................................................................34 
4.2.3. 
Placebo Rationale .......................................................................................................34 
4.3. 
Justification for Dose ..................................................................................................34 
4.4. 
Study Duration ............................................................................................................36 


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4.5. 
End of Study Definition ..............................................................................................36 
4.5.1. 
Placebo-Controlled Period ..........................................................................................36 
4.5.2. 
OLE .............................................................................................................................36 
5. 
ELIGIBILITY CRITERIA .........................................................................................36 
5.1. 
Inclusion Criteria ........................................................................................................36 
5.2. 
Exclusion Criteria .......................................................................................................37 
5.3. 
UC Disease Activity Criteria ......................................................................................39 
5.4. 
Screen Failures ............................................................................................................40 
6. 
INVESTIGATIONAL PRODUCT ............................................................................40 
6.1. 
Investigational Product(s) Administered ....................................................................40 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................42 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................42 
6.3.1. 
Assignment of a Subject Number ...............................................................................42 
6.3.2. 
Randomization and Stratification ...............................................................................42 
6.3.3. 
Investigational Product Numbers ...............................................................................42 
6.3.4. 
Blinding ......................................................................................................................42 
6.3.5. 
Unblinding of an Individual Subject ...........................................................................43 
6.4. 
Investigational Product Compliance ...........................................................................43 
6.5. 
Dose Modification ......................................................................................................44 
6.5.1. 
Investigational Product ...............................................................................................44 
6.5.2. 
Background UC Therapy ............................................................................................44 
6.6. 
Continued Access to Investigational Product After the End of the Study ..................45 
6.7. 
Treatment of Overdose ...............................................................................................45 
6.8. 
Concomitant Therapy .................................................................................................46 
6.8.1. 
Prohibited Medications Prior to the Screening Visit and Throughout the Study .......46 
7. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
SUBJECT WITHDRAWAL FROM STUDY ............................................................47 
7.1. 
Discontinuation of Investigational Product, Subject Withdrawal from the 
Study and Stopping Rules ...........................................................................................47 
7.1.1. 
Hemoglobin, Nausea, and Dizziness Stopping Criteria ..............................................48 
7.1.2. 
QTcF Stopping Criteria ..............................................................................................48 
7.1.3. 
Liver Function: Actions and Follow-up Assessments ................................................48 
7.1.4. 
Pregnancy ...................................................................................................................48 


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7.1.5. 
Introduction of New UC Therapy Stopping Criteria ..................................................49 
7.2. 
Lost to Follow-up .......................................................................................................49 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................49 
8.1. 
Efficacy Assessments .................................................................................................50 
8.1.1. 
Clinical, Endoscopic and Histologic Assessment .......................................................50 
8.1.2. 
Mayo Score and Modified Mayo Score ......................................................................50 
8.1.3. 
Robarts Histopathology Index (RHI) Score, Geboes Score and Ulcerative 
Colitis Index-100 ........................................................................................................52 
8.2. 
Safety Assessments .....................................................................................................52 
8.2.1. 
Physical Examinations ................................................................................................52 
8.2.2. 
Vital Signs ..................................................................................................................53 
8.2.3. 
Electrocardiograms .....................................................................................................53 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................53 
8.3. 
Adverse Events and Serious Adverse Events .............................................................54 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................54 
8.3.2. 
Method of Detecting Aes and SAEs ...........................................................................54 
8.3.3. 
Follow-up of Aes and SAEs .......................................................................................54 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................55 
8.3.5. 
Pregnancy ...................................................................................................................55 
8.3.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
Aes or SAEs ................................................................................................................55 
8.4. 
Pharmacokinetics ........................................................................................................55 
8.5. 
Pharmacodynamics and Biomarkers ...........................................................................56 
8.6. 
Pharmacogenetic .........................................................................................................56 
9. 
STATISTICAL CONSIDERATIONS .......................................................................56 
9.1. 
Statistical Hypotheses .................................................................................................56 
9.1.1. 
Placebo-Controlled Period ..........................................................................................56 
9.1.2. 
OLE .............................................................................................................................56 
9.2. 
Sample Size Determination ........................................................................................57 
9.2.1. 
Placebo-Controlled Period ..........................................................................................57 
9.2.2. 
OLE .............................................................................................................................57 
9.3. 
Populations for Analyses ............................................................................................57 
9.3.1. 
Placebo-Controlled Period ..........................................................................................57 


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9.3.2. 
OLE .............................................................................................................................57 
9.4. 
Statistical Analyses .....................................................................................................58 
9.4.1. 
PCP Week 12 Analysis ...............................................................................................58 
9.4.2. 
PCP Final Analysis .....................................................................................................59 
9.4.3. 
OLE Final Analysis ....................................................................................................59 
9.5. 
Interim Analyses .........................................................................................................60 
9.5.1. 
Data Review Committee .............................................................................................60 
10. 
APPENDICES ............................................................................................................61 
APPENDIX 1. REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS ..................................................................................................61 
APPENDIX 2. CLINICAL LABORATORY TESTS ................................................................65 
APPENDIX 3. ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................67 
APPENDIX 4. CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION ...............................................................................72 
APPENDIX 5. PHARMACOGENETICS ..................................................................................76 
APPENDIX 6. PROHIBITED MEDICATIONS ........................................................................77 
APPENDIX 7. LIVER SAFETY – ACTIONS AND FOLLOW-UP ASSESSMENTS ............78 
APPENDIX 8. INSTRUCTIONS FOR CALCULATING MAYO SCORE FOR UC 
DISEASE ACTIVITY CRITERIA ASSESSMENT ..................................................81 
APPENDIX 9. GUIDANCE TO ADDRESS A PANDEMIC OR OTHER GLOBAL 
HEALTH EMERGENCIES AND POTENTIAL IMPACT ON THE 
CLINICAL STUDY ...................................................................................................82 
APPENDIX 10. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................85 
APPENDIX 11. PROTOCOL AMENDMENT HISTORY ........................................................89 
11. 
REFERENCES ...........................................................................................................91 
 


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LIST OF TABLES 
Table 1: 
Summary of Changes ....................................................................................................4 
Table 2: 
Efficacy Endpoint Definitions ....................................................................................31 
Table 3: 
Investigational Product Formulation by Treatment Group .........................................41 
Table 4: 
Protocol-Required Safety Laboratory Assessments ...................................................65 
Table 5: 
Liver Safety Laboratory Assessments ........................................................................66 
Table 6: 
Liver Chemistry Criteria Requiring Additional Monitoring with Possible 
Dose Modification of Investigational Product ............................................................78 
Table 7: 
Liver Chemistry Criteria Requiring Investigational Product Interruption and 
Additional Monitoring ................................................................................................79 
Table 8: 
Instructions for Calculating Mayo Score For UC Disease Activity Criteria 
Assessments (at or after PCP Week 12 visit and prior to PCP Week 36 visit) ..........81 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 2, randomized, double-blind, placebo-controlled, multi-center study to 
evaluate GB004 in adult subjects with mild-to-moderate active ulcerative colitis 
Short Title: GB004 in adult subjects with active ulcerative colitis 
Rationale 
GB004 (formerly AKB-4924) is a novel small molecule in development for the treatment of 
inflammatory bowel disease (IBD). The novel approach of GB004 is based on evidence that 
hypoxia inducible factor 1 alpha (HIF-1α), a member of the hypoxia inducible factor (HIF) 
transcription factor family, has a crucial role in the maintenance of epithelial barrier integrity and 
in the modulation of the innate inflammatory response in mouse models of IBD. 
Small molecule prolyl hydroxylase inhibitors (PHDi’s) stabilize HIF-1α protein and have shown 
efficacy in multiple mouse models of IBD that include trinitrobenzene sulfonic acid (TNBS) and 
dextran sulfate sodium (DSS)-induced colitis models and the tumor necrosis factor alpha 
(TNFα)-driven terminal ileitis model (Ablin, 1999; Minaiyan, 2012). Prolyl hydroxylases (PHDs) 
are key regulators of the HIF pathway (Eltzschig, 2014). These findings support PHD inhibition 
as a target for treating ulcerative colitis (UC). 
GB004, a HIF-1α stabilizer, is being developed as an oral therapeutic, gut-targeted treatment for 
UC with higher intestinal than systemic exposure. The relatively low oral bioavailability (< 20%) 
and preferential distribution to the gastrointestinal (GI) tissues observed in nonclinical studies, 
combined with its mechanism of action in gut lumen and positive effects on gut healing and 
inflammation in animal models of colitis, provide rationale for further development in human 
subjects. 
GB004 has been shown in studies of both healthy volunteers (AKB-4924-CI-1001, 
AKB-4924-CI-1002, and GB004-1902) and patients with UC (GB004-1101) to be a gut-targeted 
treatment with higher intestinal than systemic exposure. In addition, the GB004-1101 study, 
although limited by only 4 weeks of dosing, showed trends in improvement in clinical and 
histologic outcomes in UC patients. GB004, Inc. has developed tablet formulations with 2 release 
profiles, tablets and delayed-release (DR) tablets, which have distinct systemic profiles with both 
delivering GB004 to the colonic tissue.  
This 2-part study, comprising of a 36-week placebo-controlled period and a 24-week open-label 
extension period, will assess the efficacy and safety of GB004 when added to background UC 
therapy of 5-aminosalicylate (5-ASA) with or without systemic steroids.  


GB004 (Oral) 
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Objectives and Endpoints 
Placebo-Controlled Period (PCP) (Primary, Secondary and Safety Objectives and 
Endpoints) 
Objectives 
Endpoints 
Primary 
• 
To evaluate the effect of GB004 
compared to placebo on clinical 
remission at PCP Week 12  
• 
Proportion of subjects with clinical remission at PCP 
Week 12, defined as a Modified Mayo score ≤ 2, with 
a Rectal bleeding subscore of 0, Stool frequency 
subscore of 0 or 1 (with a ≥ 1 point decrease from 
baseline), and Endoscopic subscore of 0 or 1 
Secondary 
• 
To evaluate the effect of GB004 
on clinical response, histologic 
remission, endoscopic 
improvement, mucosal healing at 
PCP Week 12 
 
• 
Proportion of subjects with clinical response at PCP 
Week 12, defined as reduction in the Modified Mayo 
score of ≥ 2 points and ≥ 35 percent reduction from 
baseline, including a decrease in Rectal bleeding 
subscore of ≥1 or absolute Rectal bleeding subscore 
of ≤ 1 
• 
Proportion of subjects with histologic remission at 
PCP Week 12, defined as Robarts Histopathology 
Index (RHI) ≤ 3 with lamina propria neutrophils 
subscore = 0 and neutrophils in epithelium subscore = 
0  
• 
Proportion of subjects with endoscopic improvement 
at PCP Week 12, defined as endoscopic subscore of 0 
or 1 
• 
Proportion of subjects with mucosal healing at PCP 
Week 12, defined as endoscopic improvement and 
histologic remission  
• 
To evaluate the effect of GB004 
on clinical remission, clinical 
response, histologic remission, 
endoscopic improvement, and 
mucosal healing at PCP Week 36 
• 
Proportion of subjects with clinical remission at PCP 
Week 36 
• 
Proportion of subjects with clinical response at PCP 
Week 36 
• 
Proportion of subjects with histologic remission at 
PCP Week 36 
• 
Proportion of subjects with endoscopic improvement 
at PCP Week 36 
• 
Proportion of subjects with mucosal healing at PCP 
Week 36 
Safety 
• 
To evaluate the safety and 
tolerability of GB004  
• 
Incidence of treatment-emergent adverse events 
(TEAEs) 


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Open-Label Extension (OLE) (Primary) 
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety and 
tolerability of GB004 
• 
Incidence of TEAEs 
Overall Design 
This is a 2-part study in adult subjects with mild-to-moderate active UC who have disease activity 
despite treatment with 5-ASA with or without systemic steroids: 
• The Placebo-Controlled period (PCP) is a randomized, placebo-controlled, multi-
center, 36-week study evaluating the efficacy, safety, tolerability and pharmacokinetics 
(PK) of 2 dose regimens of GB004; the initial 12 weeks of treatment will be double-
blind. 
• The OLE is an open-label, multi-center, 24-week study evaluating the safety and 
tolerability of GB004 twice per day (BID) dose regimen  
Subjects who complete the Week 36 visit on IP and subjects who meet the predefined UC Disease 
Activity criteria at or after PCP Week 12 visit and prior to PCP Week 36 visit on IP can enter the 
OLE (for details refer to Section 5.3). 
All subjects participating in the study will be required to maintain a stable dose of 5-ASA 
throughout the study. Subjects on systemic corticosteroids must remain on a stable dose during the 
initial 12 weeks of the PCP (for details refer to Section 6.5.2). After the PCP Week 12 visit, a 
standardized taper from systemic corticosteroids may be attempted at any time. 
All subjects will attend a Follow-up visit at the clinic 4 weeks after last dose of IP. 
A data review committee (DRC) will periodically convene to review unblinded overall safety and 
emerging efficacy results (Section 9.5.1). 
A schematic of the study design is presented in Section 1.2. 
Placebo-Controlled Period (36 weeks) 
After signing an informed consent form (ICF), subjects will be screened for study eligibility over 
a Screening period of up to 5 weeks. During the Screening period, subjects will capture stool 
frequency and rectal bleeding symptoms in a provided electronic diary (eDiary) on a daily basis. 
Flexible sigmoidoscopy or colonoscopy will be performed at screening. Subjects not meeting the 
eligibility criteria will be deemed screen failures and will not continue participation in the study.  
On Day 1/Week 0, eligible subjects will be randomized 1:1:1 to receive the following treatments 
for 36 weeks: 
• GB004 480 mg BID 
• GB004 480 mg once daily (QD) 
• Placebo 




















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2. 
INTRODUCTION 
2.1. 
Study Rationale 
GB004 (formerly AKB-4924) is a novel small molecule in development for the treatment of 
inflammatory bowel disease (IBD). The novel approach of GB004 is based on evidence that 
hypoxia inducible factor 1 alpha (HIF-1α), a member of the hypoxia inducible factor (HIF) 
transcription factor family, has a crucial role in the maintenance of epithelial barrier integrity and 
in the modulation of the innate inflammatory response in mouse models of IBD. 
Small molecule prolyl hydroxylase inhibitors (PHDi’s) stabilize HIF-1α protein and have shown 
efficacy in multiple mouse models of IBD that include trinitrobenzene sulfonic acid (TNBS) and 
dextran sulfate sodium (DSS)-induced colitis models and the tumor necrosis factor alpha (TNFα)-
driven terminal ileitis model (Ablin, 1999; Minaiyan, 2012). Prolyl hydroxylases (PHDs) are key 
regulators of the HIF pathway (Eltzschig, 2014). These findings support PHD inhibition as a 
target for treating ulcerative colitis (UC). 
GB004, a HIF-1α stabilizer, is being developed as an oral therapeutic, gut-targeted treatment for 
UC with higher intestinal than systemic exposure. The relatively low oral bioavailability (< 20%) 
and preferential distribution to the gastrointestinal (GI) tissues observed in nonclinical studies, 
combined with its mechanism of action in gut lumen and positive effects on gut healing and 
inflammation in animal models of colitis, provide rationale for further development in human 
subjects. 
GB004 has been shown in studies of both healthy volunteers (AKB-4924-CI-1001, 
AKB-4924-CI-1002, and GB004-1902) and patients with UC (GB004-1101) to be a gut-targeted 
treatment with higher intestinal than systemic exposure. In addition, the GB004-1101 study, 
although limited by only 4 weeks of dosing, showed trends in improvement in clinical and 
histologic outcomes in UC patients. GB004, Inc. has developed tablet formulations with 2 release 
profiles, tablets and delayed-release (DR) tablets, which have distinct systemic profiles with both 
delivering GB004 to the colonic tissue.  
This 2-part study, comprising of a 36-week placebo-controlled period and a 24-week open-label 
extension period, will assess the efficacy and safety of GB004 when added to background UC 
therapy of 5-aminosalicylate (5-ASA) with or without systemic steroids. 
2.2. 
Background 
UC is the result of an unrelenting, severe inflammatory response mounted against an 
environmental trigger in a genetically susceptible host. The inflammatory response, in turn, causes 
a breach in intestinal barrier integrity which allows influx of luminal antigens setting up a vicious 
cycle of inflammation and epithelial injury that perpetuates the disease process. 
UC symptoms include rectal bleeding and diarrhea (Schroeder, 1987). Consistently, UC is 
associated with a significantly reduced quality of life and recent data indicate increased mortality 
especially among patients diagnosed at early ages. Despite the improved efficacy of UC treatment 
with anti-tumor necrosis factor (anti-TNF) agents and anti-integrin agents (eg, vedolizumab), 
there remains a large subset of patients who either do not respond adequately to conventional 


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therapy or biologic therapy and do not achieve long-term remission. Perhaps the best indicator of 
the inadequacy of current therapy is that surgery is required for about 23-46% of patients with UC 
(Shen, 2008). Considering the worldwide increase in UC, novel approaches to managing UC are 
urgently needed. (Bernstein, 2012; Kaplan, 2012; Singh, 2015). 
The overall goal of treatment for patients with active UC is to induce and maintain remission and 
to induce and maintain mucosal healing (de Mattos, 2015; Heyman, 2005; Jain, 2019; 
Lamb, 2019; Ng, 2009; Singh, 2019). Treatment of UC consists of anti-inflammatory and 
immunosuppressive therapies that are chosen to maximize efficacy while avoiding toxicity. The 
therapy chosen is therefore dependent on the patient’s disease severity and their response to 
therapy (Jain, 2019; Kelsen, 2020; Ko, 2019; Kornbluth, 2010; Ng, 2009). While agents used to 
treat mild to moderate UC are generally well tolerated, as the severity of UC increases, so do the 
potential toxicities of the medications required to manage the disease. In mild to moderate UC 
patients unresponsive to local therapy or in patients with more severe or more extensive disease, 
systemic treatment with an oral 5-ASA, such as mesalamine, olsalazine, sulfasalazine, and 
balsalazide, is commonly required (Jain, 2019; Ng, 2009; Turner, 2011; Whaley, 2019). After 
patients fail 5-ASA therapy, the next recommended add-on therapy is oral systemic or locally 
acting steroids (Ko, 2019). While >90% of UC patients in population-based cohorts receive 
5-ASA therapy within 1 year of diagnosis, 50% will also be prescribed steroids during the course 
of their disease (Singh, 2019). Therapies indicated for moderate to severe UC after steroids are 
either oral immunomodulators or biologics. These therapies are associated with higher rates of 
clinical remission, but also with higher risk of adverse events such as infection or malignancy 
(Kirchgesner, 2018). Biologics are typically employed after the failure of 5-ASAs due to the 
associated risks of these therapies, lack of durable response due to immunogenicity, and 
requirement of parental administration. There is an ongoing unmet medical need for an oral UC 
treatment that is highly effective in achieving long-term remission and mucosal healing with 
limited side effects in these patients with 5-ASA failure and prior to biologics (Levesque, 2015). 
GB004, a HIF-1α stabilizer, is being developed as an oral therapeutic, gut-targeted treatment for 
UC. The GB004 mechanism of action in gut lumen, positive effects on gut healing and 
inflammation in animal models of colitis, trends in improvement in disease related outcomes such 
as histologic remission, mucosal healing, rectal bleeding, and safety and tolerability results over 4 
weeks of treatment in the Phase 1b GB004-1101 study, provide rationale for further development 
of GB004 in UC subjects. 


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2.3. 
Benefit/Risk Assessment 
More detailed safety findings from completed and ongoing studies may be found in the 
Investigator’s Brochure (IB). 
2.3.1. 
Benefit Assessments 
Development of GB004 for UC is supported by its mechanism of action, which stabilized HIF-1α 
in Phase 1, and the evidence that GB004 show enhanced healing and decreased inflammation in 
animal models of colitis. 
The potential benefits of GB004 treatment for subjects in this study were shown in the 
GB004-1101 Phase 1b Study and included trends in improvement with GB004 compared to 
placebo in histologic remission, rectal bleeding, and mucosal healing; however, the study was 
limited by the 28 days of dosing and small sample size. This longer Phase 2 clinical study is 
designed to evaluate the impact of GB004 on these efficacy endpoints and provide sufficient time 
for the initial improvement of the clinical signs and symptoms of ulcerative colitis, and then the 
longer-term impact on clinical remission and mucosal healing. This study will also allow for 
subjects in the PCP to transition to OLE at or after PCP Week 12 and before PCP Week 36 and 
receive GB004 480 mg BID if they meet the predefined UC disease activity criteria (Section 5.3). 
2.3.2. 
Risk Assessments 
As of May 27, 2020, a total of 117 subjects, comprising 94 healthy volunteers and 23 subjects 
with active UC, have received GB004. GB004 Powder for Oral Solution has been studied in 
healthy volunteers receiving single and multiple doses up to 240 mg daily for 8 days (AKB-4924-
CI-1001 and AKB-4924-CI-1002) and in subjects with active UC receiving 120 mg daily for 28 
days (GB004-1101). GB004 formulations (Powder for Oral Solution and tablets) have been 
studied in healthy volunteers receiving doses up to 240 mg daily for 7 days (GB004-1902). There 
are no identified risks of GB004. There are 2 potential risks of GB004. 
These potential risks are: 
• Nausea: The overall incidence of nausea was 18.8% (22/117) in GB004-treated 
subjects versus none in placebo-treated subjects. Nausea in GB004-treated subjects 
was generally characterized as: mild, occurring more frequently with GB004 doses of 
120 mg or greater, first occurring within the first hour after the first dose and lasting 1 
day, without concurrent vomiting, and of low clinical impact with infrequent 
discontinuations of GB004 (1 subject). 
• Dizziness: The overall incidence of dizziness was 11.1% (13/117) in GB004-treated 
subjects versus 4.9% (2/41) in placebo-treated subjects. Dizziness in GB004-treated 
subjects was generally characterized as: mild, occurred more frequently with GB004 
doses of 120 mg or greater, first occurring within 1 day after first dose and lasting 1 
day, without impairment of function, and with no discontinuation of GB004. 
Preliminary safety results from the study of GB004 tablet formulations (GB004-1902) show that 
nausea and dizziness were reported  less frequently than were previously reported with the 
solution formulation. GB004 formulations have been studied in a Phase 1 study (GB004-1902) in 
healthy volunteers receiving daily doses of 120 mg solution or placebo, or up to 240 mg tablet, 


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delayed-release tablet, or placebo for 7 days. Overall, TEAEs were reported by 9 of 32 (28%) 
subjects who received GB004 and 3 of 10 (30%) subjects who received placebo. All TEAEs were 
mild in severity. TEAEs reported in more than one subject in the GB004 group included nausea 
(9% GB004; none in placebo), headache (9% GB004; 10% placebo), diarrhea (6% GB004; 
20% placebo), and liver function test elevation (6% GB004; none in placebo). Preliminary safety 
results from this study suggest that GB004 formulations of 120 mg solution and up to 240 mg 
tablet, and 240 mg DR tablet are generally well tolerated in healthy subjects. 
GB004 Powder for Oral Solution has been studied in subjects with active UC receiving daily 
doses of 120 mg in a Phase 1b study (GB004-1101). The majority of adverse events (AEs) were 
reported as Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2 in severity 
and were considered not related. The most common (≥ 10%) TEAEs reported in GB004-treated 
subjects included nausea (21.7% GB004; 0% placebo) and dysgeusia (13% GB004; 0% placebo). 
Preliminary results suggest that GB004 Powder for Oral Solution 120 mg daily is generally well 
tolerated in subjects with active UC. 
2.3.3. 
Overall Benefit and Risk Conclusion 
Given the potential benefits for subjects and the potential benefit of identifying a new therapeutic 
for UC and the potential risks of GB004, the benefit versus risk ratio for GB004 is considered 
favorable. 


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3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Placebo-Controlled Period Objectives and Endpoints 
Objectives 
Endpoints 
(see definitions for efficacy endpoints in Section 3.3) 
Primary 
• To evaluate the effect of GB004 
compared to placebo on clinical 
remission at PCP Week 12 
• Proportion of subjects with clinical remission at 
PCP Week 12, defined as a Modified Mayo 
score ≤ 2, with a Rectal bleeding subscore of 0, 
Stool frequency subscore of 0 or 1 (with a ≥ 1 
point decrease from baseline), and Endoscopic 
subscore of 0 or 1 
Secondary 
• To evaluate the effect of GB004 
on clinical response, histologic 
remission, endoscopic 
improvement and mucosal 
healing at PCP Week 12   
• Proportion of subjects with clinical response at 
PCP Week 12, defined as reduction in the 
Modified Mayo score of ≥ 2 points and ≥ 35 
percent reduction from baseline, including a 
decrease in Rectal bleeding subscore of ≥1 or 
absolute Rectal bleeding subscore of ≤ 1 
• Proportion of subjects with histologic remission 
at PCP Week 12, defined as Robarts 
Histopathology Index (RHI) ≤ 3 with lamina 
propria neutrophils subscore = 0 and 
neutrophils in epithelium subscore = 0 
• Proportion of subjects with endoscopic 
improvement at PCP Week 12, defined as 
endoscopic subscore of 0 or 1 
• Proportion of subjects with mucosal healing at 
PCP Week 12, defined as endoscopic 
improvement and histologic remission  
• To evaluate the effect of GB004 
on clinical remission, clinical 
response, histologic remission, 
endoscopic improvement, and 
mucosal healing at PCP Week 36 
• Proportion of subjects with clinical remission at 
PCP Week 36 
• Proportion of subjects with clinical response at 
PCP Week 36 
• Proportion of subjects with histologic remission 
at PCP Week 36 
• Proportion of subjects with endoscopic 
improvement at PCP Week 36 


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Objectives 
Endpoints 
(see definitions for efficacy endpoints in Section 3.3) 
• Proportion of subjects with mucosal healing at 
PCP Week 36 
Safety 
• To evaluate the safety and 
tolerability of GB004 
• Incidence of treatment emergent adverse events 
(TEAEs) 
Exploratory 
• To evaluate other safety 
outcomes 
• Change from Baseline in laboratory, vital signs, 
and electrocardiogram (ECG) parameters 
• To explore other measures of the 
effect of GB004 on disease 
activity over time 
• Proportion of subjects with resolution of Rectal 
bleeding  
• Proportion of subjects with histologic response  
• Proportion of subjects with Geboes score ≤ 2  
• Proportion of subjects with steroid-free clinical 
remission at PCP Week 36 
• Proportion of subjects with clinical remission 
by Mayo score and resolution of rectal bleeding  
• Proportion of subjects with clinical remission 
by Mayo score  
• Proportion of subjects with clinical response by 
Mayo score  
• Proportion of subjects with Modified Mayo 
score of ≤ 2, with no individual subscore > 1  
• Proportion of subjects with disease clearance  
• Proportion of subjects with symptomatic 
remission  
• Proportion of subjects with modified 
symptomatic remission  
• Proportion of subjects with Partial Mayo 
remission 
• Proportion of subjects with reduction of ≥ 2 
points from baseline in partial Mayo score  


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Objectives 
Endpoints 
(see definitions for efficacy endpoints in Section 3.3) 
• Proportion of subjects with a 6-point Mayo 
score clinical remission  
• Change from Baseline in Modified Mayo score  
• Change from Baseline in Mayo score  
• Change from Baseline in Partial Mayo score 
over time 
• Change from Baseline in Mayo subscores over 
time 
• Change from Baseline in RHI score  
• Change from Baseline in the UC-100 Index  
• To explore the PK of GB004 
• Plasma and colon tissue concentrations of 
GB004 
• To explore target engagement 
(TE) and pharmacodynamic 
(PD) response 
• Change from baseline in tissue and blood 
markers of target engagement, eg, HIF-1α, 
EGLN1-2-3, etc. 
• Change from baseline in markers of 
pharmacodynamics, eg, fecal calprotectin, fecal 
lactoferrin, and neutrophil activity 
(myeloperoxidase) 
• Change from baseline in tissue, blood, and stool 
in downstream genes and proteins, eg, CAIX, 
MPO, c-reactive protein (CRP), TJP, CLDN1, 
etc. as a function of exposure (Cmax, Tmax, 
AUC), efficacy endpoints (eg, clinical 
remission, clinical response), and/or safety 
endpoints 
• To explore baseline markers with 
response to treatment with 
GB004 
• Relationship between tissue, blood, and stool 
baseline markers (eg, HIF-1α, EGLN1-2-3, 
calprotectin, etc.) and response to treatment, as 
measured by efficacy endpoints (eg, clinical 
remission, clinical response), and/or safety 
endpoints 
• To explore pharmacogenetics 
(PGx)  
• Effect of naturally occurring genetic variation 
on the efficacy (eg, clinical remission, clinical 
response), safety, and/or PK profile (Cmax, Tmax, 


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Objectives 
Endpoints 
(see definitions for efficacy endpoints in Section 3.3) 
AUC) and tissue concentrations associated with 
treatment with GB004 
3.2. 
Open-Label Extension (OLE) Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate the safety and 
tolerability of GB004 
• Incidence of TEAEs 
Exploratory 
• To evaluate other safety 
outcomes 
• Change from GB004 baseline in laboratory, vital 
signs, and ECG parameters 
• To explore measures of the 
effect of GB004 on disease 
activity over time 
• Proportion of subjects with resolution of Rectal 
bleeding at OLE Week 24 
• Proportion of subjects with partial Mayo score 
of ≤2 with no individual subscore >1 over time 
• Proportion of subjects with reduction of ≥2 
points from GB004 baseline in partial Mayo 
score over time 
• Change from GB004 baseline in partial Mayo 
score over time 
• Proportion of subjects with a 6-point Mayo 
score clinical remission at OLE Week 24 
• To explore PD response 
• Change from GB004 baseline in fecal 
calprotectin 
• Change from GB004 baseline in blood, and 
stool in downstream markers, included but not 
limited to CRP 
 


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3.3. 
Efficacy Endpoint Definitions 
Table 2: 
Efficacy Endpoint Definitions 
Note: For the purposes of the endpoint definitions, refer to Section 9.4 for baseline definitions. 
Endpoint 
Definitions 
Clinical remission 
Modified Mayo score ≤ 2, with a Rectal bleeding subscore of 0, Stool 
frequency subscore of 0 or 1 (with ≥1 point decrease from baseline), and 
Endoscopic subscore of 0 or 1 (refer to Section 8.1.2 for Modified Mayo 
score) 
Clinical response 
Reduction in the Modified Mayo score of ≥ 2 points and ≥ 35% from 
baseline, including a decrease in Rectal bleeding subscore of ≥1 or 
absolute Rectal bleeding subscore of ≤ 1  
Histologic remission 
RHI ≤ 3 with lamina propria neutrophils subscore = 0 and neutrophils in 
epithelium subscore = 0 (refer to Section 8.1.3) 
Endoscopic improvement 
Endoscopic subscore 0 or 1 
Mucosal healing 
Endoscopic improvement and histologic remission 
Resolution of Rectal 
bleeding 
Rectal bleeding subscore = 0 
Histologic response 
Decrease from baseline in RHI of ≥ 7 (refer to Section 8.1.3) 
Steroid-free remission 
Clinical remission with no systemic corticosteroid use among subjects 
who were using systemic corticosteroids at baseline 
Clinical remission by 
Mayo score 
Mayo score ≤ 2, with no Mayo individual subscores >1 (refer to 
Section 8.1.2 for Mayo score) 
Clinical response by 
Mayo score 
Reduction in the Mayo score of ≥ 3 points and ≥ 30% from baseline, 
including a decrease in Rectal bleeding subscore of ≥ 1 or absolute Rectal 
bleeding subscore of ≤1 
Disease clearance 
Clinical remission and histologic remission (Danese, 2020) 
Symptomatic remission 
Mayo score of ≤ 2, with no individual subscore > 1 and both Rectal 
bleeding and Stool frequency subscores of 0 
Modified symptomatic 
remission 
Endoscopic improvement, resolution of Rectal bleeding and Stool 
frequency subscore of 0 
Partial Mayo remission 
Partial Mayo score of ≤ 2 with no individual subscore >1 (refer to 
Section 8.1.2 for partial Mayo score) 
6-point Mayo score 
clinical remission 
6- point Mayo score < 2 with a Rectal bleeding subscore of 0 and Stool 
frequency subscore of 0 or 1 (with ≥ 1 point decrease from baseline) 
(Lewis, 2008) (refer to Section 8.1.2 for 6-point Mayo score) 
Abbreviations: RHI, Robarts Histopathology Index. 


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4. 
STUDY DESIGN 
4.1. 
Overall Study Design 
This is a 2-part study in adult subjects with mild-to-moderate active UC who have disease activity 
despite treatment with 5-ASA with or without systemic steroids: 
• The Placebo-Controlled period (PCP) is a randomized, placebo-controlled, multi-
center, 36-week study evaluating the efficacy, safety, tolerability and pharmacokinetics 
(PK) of 2 dose regimens of GB004; the initial 12 weeks of treatment will be double-
blind  
• The OLE is an open-label, multi-center, 24-week study evaluating the safety and 
tolerability of GB004 twice per day (BID) dose regimen  
Subjects who complete the Week 36 visit on IP and subjects who meet the predefined UC Disease 
Activity criteria at or after PCP Week 12 visit and prior to PCP Week 36 visit on IP  can enter the 
OLE (for details refer to Section 5.3). 
All subjects participating in the study will be required to maintain a stable dose of 5-ASA 
throughout the study. Subjects on systemic corticosteroids must remain on a stable dose during the 
initial 12 weeks of the PCP (for details refer to Section 6.5.2). After the PCP Week 12 visit, a 
standardized taper from systemic corticosteroids may be attempted at any time. 
All subjects will attend a Follow-up visit at the clinic 4 weeks after last dose of IP. 
A data review committee (DRC) will periodically convene to review unblinded overall safety and 
emerging efficacy results (Section 9.5.1). 
A schematic of the study design is presented in Section 1.2. 
4.1.1. 
Placebo-Controlled Period (36 weeks) 
After signing an informed consent form (ICF), subjects will be screened for study eligibility over 
a Screening period of up to 5 weeks. During the Screening period, subjects will capture stool 
frequency and rectal bleeding symptoms in a provided electronic diary (eDiary) on a daily basis. 
Flexible sigmoidoscopy or colonoscopy will be performed at screening. Subjects not meeting the 
eligibility criteria will be deemed screen failures and will not continue participation in the study. 
On Day 1/Week 0, eligible subjects will be randomized 1:1:1 to receive the following treatments 
for 36 weeks: 
• GB004 480 mg BID 
• GB004 480 mg once daily (QD) 
• Placebo 
Randomization will be stratified by systemic corticosteroid use at baseline (yes/no). 
All subjects will dose investigational product (IP) BID to maintain the blind (for details refer to 
Section 6.1). The first dose of IP will be administered in the clinic on Day 1/Week 0 with food. 
All subsequent doses will be taken at home with food, with the exception of the morning doses at 


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the Week 2, 4, 8, 12, and 36 visits where IP will be administered in the clinic, with food, after 
predose blood collection as specified in the Schedule of Activities (SoA) in Section 1.3.1 – PCP. 
After initiation of IP on Day 1/Week 0, subjects will return to the clinic and will be evaluated as 
specified in the SoA, see Section 1.3.1. A flexible sigmoidoscopy with biopsies will be performed 
at the PCP Week 12 and Week 36 visits (and at the Unscheduled UC Disease Activity Criteria 
Assessment visit(s) and at the Early Withdrawal from Study visit, if applicable). 
Subjects who permanently discontinue IP without enrolling in the OLE will be encouraged to 
continue in the PCP and will complete the Early Discontinuation of IP visit at the time of IP 
discontinuation and then complete the remaining PCP study visits per the SoA. At subsequent 
visits, all study procedures will be completed per the SoA excluding dispensation/return and 
accountability of IP. 
Subjects who withdraw from the PCP without enrolling in the OLE, regardless of the reason, will 
be requested to return to the clinic to complete the Early Withdrawal from Study visit and will be 
asked to return for a Follow-up visit approximately 4 weeks after their last dose of IP to assess 
safety. 
For dose modifications refer to Section 6.5.1. 
4.1.2. 
OLE (24 weeks) 
Subjects may participate in the 24-week OLE if in the opinion of the Investigator they have been 
compliant with study procedures and: 
• Completed the Week 36 visit on IP; or 
• Met the predefined UC Disease Activity criteria any time after PCP Week 12 visit and 
prior to PCP Week 36 visit on IP (refer to Section 5.3) 
Beginning at the OLE Enrollment visit, all subjects will receive GB004 480 mg BID for 24 
weeks. All doses will be taken at home with food with the exception of the morning dose at the 
OLE Enrollment visit (if last dose of PCP IP has not been taken earlier in the day), OLE Week 2, 
12 and End of OLE visit/Early termination (ET) visit where IP will be administered in the clinic, 
with food, after predose blood collection as specified in the SoA (Section 1.3.2 – OLE). 
Subsequently, subjects will return to the clinic and be evaluated as specified in the SoA 
(Section 1.3.2 - OLE). 
Consideration should be given to discontinuing IP for subjects who do not show clinical 
improvement per Investigator’s judgement by OLE Week 12. Subjects who permanently 
discontinue IP during the OLE will be withdrawn from the study, complete the End of OLE/ET 
visit and will be asked to return for a Follow-up visit approximately 4 weeks after their last dose 
of IP to assess safety. 
4.2. 
Scientific Rationale for Study Design 
The PCP is designed as a randomized, placebo-controlled study to evaluate the efficacy and safety 
of 2 dose regimens of GB004 relative to placebo over a 36-week treatment period. The first 12 
weeks will be double-blind. 


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The OLE is designed to primarily evaluate the safety and tolerability of GB004 BID over a 
24-week treatment period and allows subjects who originally were assigned to placebo in the PCP 
to have an opportunity to be treated with GB004. 
4.2.1. 
Study Population 
The target population is adult subjects with mild-to-moderate active UC and have disease activity 
despite treatment with 5-ASA with or without prednisone (or equivalent), beclomethasone, 
budesonide, or budesonide-MMX. Mild-to-moderate active UC will be defined as a Mayo score of 
5-10, inclusive, with an Endoscopic subscore of ≥ 2, a Stool frequency subscore ≥ 1, and a Rectal 
bleeding subscore ≥ 1. 
4.2.2. 
Endpoint Selection 
Clinical remission has been chosen as the primary endpoint based on its clinical and regulatory 
importance in UC and the GB004 mechanism of action, which may lead to restoration of 
epithelial barrier function and resolution of inflammation and symptoms. This Phase 2 study is 
designed to evaluate the impact of GB004 on a set of efficacy endpoints while allowing sufficient 
time for the initial improvement of the clinical signs and symptoms of UC. Safety will be 
evaluated throughout with AE monitoring and other safety assessments. 
4.2.3. 
Placebo Rationale 
The study will compare the impact of adding GB004 versus placebo to background therapy for 
UC. Placebo will be used as a comparator to assess any differences in treatment effect or 
perception of response due to participation in the study. A placebo-controlled design is necessary 
because UC is a disease that waxes and wanes over time and is measured by endpoints with 
subjective components. It is important to be able to differentiate the biological activity of GB004 
compared to the “placebo effect,” which may be as high as 15 to 20% depending on the endpoint 
chosen. Comparisons between the GB004 and placebo treatment groups will facilitate 
differentiation of the GB004 safety profile from that of the background UC therapy. 
4.3. 
Justification for Dose 
Phase 1 studies have shown GB004 to be a gut-targeted treatment with higher intestinal than 
systemic exposure with trends in improvement in histologic remission, rectal bleeding, and 
mucosal healing in subjects with UC. The previous Phase 1b study in subjects with UC 
(GB004-1101) was limited by 4 weeks of dosing with a low dose (GB004 Powder for Oral 
Solution 120 mg QD) and by the number of subjects evaluated. Colonic concentrations were 
variable but frequently below target concentrations based on efficacy predictions from nonclinical 
animal models of colitis. Therefore, higher doses (480 mg QD and 480 mg BID) are planned in 
this Phase 2 study (refer to study schema in Section 1.2). This Phase 2 study is designed to 
evaluate the impact of GB004 on a set of efficacy endpoints while allowing sufficient time for the 
initial improvement of the clinical signs and symptoms of ulcerative colitis, and then to assess (at 
36 weeks) the longer term impact on clinical remission and mucosal healing. 
The PCP will evaluate 2 dose regimens of GB004, 480 mg (240 mg GB004 tablets and 240 mg 
GB004 DR tablets) administered BID or QD, compared to placebo. Subjects will be dosed under 


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fed conditions. These doses and the longer treatment duration are supported by completed 
nonclinical toxicology and clinical studies based on the following considerations: 
• Tolerability and safety profile of GB004 from the SAD and MAD studies, and 
evidence of target engagement from colon tissue biopsies from the MAD study. 
• Preliminary tolerability, safety, PK profile with minimal observed accumulation of 
GB004 following QD dosing for 28 days, and trends in improvement in disease-related 
outcomes such as histologic remission and mucosal healing in the Phase 1b GB004-
1101 study in subjects with active UC. 
• Preliminary tolerability, safety, and PK profile of GB004 tablets and GB004 DR 
tablets in the Phase 1a GB004-1902 study in healthy male and female volunteers, 
which demonstrated tablet plasma exposures that enable dosing at the proposed 
Phase 2 dose levels with a combination of GB004 tablets and GB004 DR tablets. The 
maximum observed concentration at steady-state (Cmax) and AUClast of GB004 tablets 
were similar to those with GB004 Powder for Oral Solution. When subjects were given 
GB004 tablets when fed, steady-state Cmax and AUC0-24 of GB004 appeared to be 
generally similar to subjects given GB004 tablets when fasted after normalization to 
dose. Given the rapid elimination of GB004 from systemic circulation, the steady-state 
Cmax of GB004 following BID dosing is expected to be similar to that following QD 
dosing, while daily AUC are expected to double following BID dosing compared to 
QD dosing. GB004 DR tablets when given fasted had a lower Cmax and AUClast than 
GB004 tablets fasted or GB004 solution. 
Based on the current safety and PK results with GB004 tablets at doses up to 240 mg, adequate 
safety margins of the projected human 480 mg GB004 (240 mg GB004 tablets and 240 mg 
GB004 DR tablets) BID treatment arm exposure values, and the selected doses taken with food, 
the proposed Phase 2 doses are expected to be tolerated. 
The OLE will evaluate GB004 480 BID because this dose is expected to inform long-term safety 
of GB004 at doses at or below this maximum dose in the study. 
The 9-month nonclinical toxicology results, and clinical safety, tolerability, PK and target 
engagement data, along with the preliminary evidence of clinical activity of GB004 in subjects 
with UC, support evaluating GB004 480 mg administered BID or QD under fed conditions for up 
to 60 weeks. 




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5. Colonoscopy within the past 2 years (or during the Screening period) to screen for 
dysplasia (unless otherwise recommended by local and national guidelines) if the subject 
has had UC for 8 or more years duration. 
Allowed UC Therapy 
6. Currently receiving treatment for UC, on a stable dose for at least 2 weeks prior to flexible 
sigmoidoscopy or colonoscopy, with oral 5-ASA (eg, mesalamine, sulfasalazine) alone or 
with one of the following oral treatments: 
a. prednisone ≤ 20 mg/day or equivalent or 
b. beclomethasone ≤ 5 mg/day or 
c. budesonide or budesonide multi-matrix (MMX) of ≤ 9 mg/day 
Body Mass Index (BMI) 
7. BMI 18 to 35 kg/m2. 
Pregnancy and Contraception 
Contraception use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
8. Women meeting the definition of non-childbearing potential or women of childbearing 
potential must agree to the contraceptive guidance (see Appendix 4). 
9. Men must agree to the contraceptive guidance (see Appendix 4). 
Informed Consent 
10. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
5.2. 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Excluded Prior Therapy 
1. Prior approved biologic therapy used for the treatment of UC. 
2. Enemas or suppository formulations of steroids or 5-aminosalicylates within 2 weeks of 
screening flexible sigmoidoscopy/colonoscopy. 
3. Tofacitinib, oral cyclosporine, sirolimus or mycophenolate mofetil within 8 weeks of 
Day 1. 
4. Azathioprine, or 6-mercaptopurine within 1 day of Day 1. 
5. Anti-diarrheal medications (e.g., loperamide, diphenoxylate/atropine) during screening. 
6. Epoetin alfa within 8 weeks of Day 1. 
7. Cholestyramine or other drugs interfering with enterohepatic circulation within 14 days of 
Day 1. 


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8. Chronic non-steroidal anti-inflammatory agents (NSAID) use (occasional use of NSAID, 
acetaminophen, or aspirin up to 325 mg/day is allowed). 
9. Treatment with strong cytochrome P450 (CYP) 3A inhibitors and/or CYP3A inducers, and 
inhibitors of uridine-diphosphoglucuronosyl transferase (UGT) within 21 days or within 5 
half-lives, whichever is longer, of the respective medication prior to Day 1 (see 
Appendix 6 for examples). 
Medical Conditions 
10. Diagnosis of Crohn’s disease or indeterminate colitis, pouchitis. 
11. Fulminant colitis, toxic megacolon, or in Investigator’s judgement likely to require 
colectomy or ileostomy within 16 weeks of Day 1. 
12. Stool sample positive for Clostridium difficile (C difficile) toxin, stool pathogens, or ova 
and parasites infection on screening laboratory tests. If positive, subjects may be treated 
and retested. 
13. A current malignancy, current colonic dysplasia or previous history of cancer in remission 
for less than 5 years prior to screening. Subjects will not be excluded if they had localized 
carcinoma of the skin that was resected for cure, cervical dysplasia that has been 
adequately treated, or colonic dysplasia that has been completely removed. 
14. Known pre-existing, unstable liver disease (as defined by the presence of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices or 
persistent jaundice), cirrhosis, known biliary abnormalities, known pre-existing non-
alcoholic steatohepatitis (NASH), or active infection with Hepatitis B or Hepatitis C. 
15. Immunodeficiency, including that due to human immunodeficiency virus (HIV), other 
than that explained by systemic corticosteroid use. 
16. Other concurrent medical conditions: known, pre-existing clinically significant endocrine, 
autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, cardiovascular, 
respiratory (eg, including active tuberculosis), hematological, or any other system 
abnormalities that are uncontrolled with standard treatment. 
17. Any other medical condition or laboratory abnormality that, in the opinion of the 
Investigator, would prohibit the subject from participating in the study. 
Diagnostic assessments 
18. QTcF ≥ 450 msec for males or QTcF ≥ 470 msec for females at screening by central 
overread. If QTcF is above specified limit and there are no other clinically significant 
abnormalities, repeat assessment is allowed with permission by the Sponsor’s Medical 
Monitor (or designee). 
19. Hemoglobin <7.5 g/dL, platelet count <100,000/µL, absolute neutrophils count < 1200/µL 
at screening. 
20. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper 
limit of normal (ULN) at screening. 


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21. Total bilirubin > ULN at screening, unless likely related to diagnosis of Gilbert’s 
syndrome, in the opinion of the Investigator. 
22.  Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 calculated by chronic 
kidney disease epidemiology collaboration (CKD-EPI). 
Prior Clinical Study Experience 
23. Treatment with an investigational medication or treatments (eg, hyperbaric oxygen 
treatment) within the past 30 days or within 5 half-lives of the medication, whichever is 
longer, prior to screening. (This also includes investigational formulations of marketed 
products.) 
24. Have previously received treatment with GB004/AKB-4924. 
Other Exclusions 
25. A history or suspected history of alcohol misuse or substance abuse, per the discretion of 
the principal investigator, within 12 months prior to screening. 
26. Female subject who is pregnant or breastfeeding. Female subjects should not be enrolled if 
they are planning to become pregnant during the time of study participation. A urine 
pregnancy test is required of all women of child-bearing potential. 
5.3. 
UC Disease Activity Criteria 
Subjects meeting the following predefined UC Disease Activity criteria at or after the PCP 
Week 12 visit and prior to PCP Week 36 visit on IP may enter the OLE and receive GB004 BID 
treatment. Refer to Table 8 for Mayo score calculation instructions in Appendix 8. 
• A Mayo score: 
− with Endoscopic subscore ≥2 using the centrally read endoscopy score from the 
flexible sigmoidoscopy, 
AND 
− greater than or equal to the Mayo score at the PCP Day 1/Week 0 visit 
AND 
• Exclusion of other causes of disease activity unrelated to underlying UC (eg, 
infections), at the discretion of the Investigator 


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5.4. 
Screen Failures 
Subjects will be assigned a subject number at the time of signing the ICF. Subjects who are not 
randomized will be labeled as screen failures. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure subjects to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information includes 
informed consent date, demography, screen failure details (including eligibility criteria), and any 
SAE. 
Subjects who are labelled as screen failures may be eligible to rescreen once upon approval by the 
Sponsor’s Medical Monitor (or designee). A new subject number will be assigned if approved to 
rescreen. 
6. 
INVESTIGATIONAL PRODUCT 
6.1. 
Investigational Product(s) Administered 
Each dose of IP will consist of a combination of GB004 tablets and GB004 delayed-release 
(equivalent term to gastro-resistant) tablets or of matching placebo tablets and will be taken orally 
BID on a fed stomach at approximately the same time each day, 8 to 12 hours apart. 
The GB004 tablets, GB004 delayed-release tablets, and placebo tablets are similar and 
indistinguishable in terms of appearance, odor, and taste, such that the blind is maintained. 


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Table 3: 
Investigational Product Formulation by Treatment Group 
Investigational 
Product Name 
GB004 (Active) 
PCP and OLE 
Placebo (Control) 
PCP only 
Dose Formulation 
GB004 round film-coated tablets 
Matching placebo 
round film-coated 
tablets 
Unit Dose 
Strength 
60 mg per tablet 
Placebo tablet 
Dose regimen 
 
GB004 480 mg BID (PCP and OLE): 
4 tablets + 4 delayed-release tablets, BID 
Placebo: 
8 placebo tablets BID 
GB004 480 mg QD (PCP only): 
• 
4 tablets + 4 delayed-release tablets, QD 
morning 
• 
8 placebo tablets, QD evening 
Route of 
Administration 
Oral, with food 
IP to be taken BID (approximately 8 to 12 hours apart) at approximately the 
same time each day. 
Sourcing 
IP will be provided to the site centrally by the Sponsor or designated 
representative. For exceptions, refer to Appendix 9. 
Packaging 
PCP: GB004 tablets, GB004 delayed-release tablets, and GB004 placebo 
tablets will be packaged in 68 count, 60 cc high-density polyethylene 
(HDPE) bottles, with child-resistant induction-sealed closures. 
OLE: GB004 tablets and GB004 delayed-release tablets will be packaged in 
68 count, 60 cc high-density polyethylene (HDPE) bottles, with child-
resistant induction-sealed closures. 
Bottles will be dispensed in 4-bottle sets supplying 2 weeks of dosing 
(sufficient for 17 days of treatment) consisting of 2 bottles used for morning 
dosing and 2 bottles for evening dosing. Subjects to dose 4 tablets per bottle 
per day.  
Refer to the Pharmacy Manual for additional details. 
Labeling 
Label text will at a minimum include the protocol number, lot number, 
storage conditions, and Sponsor name and address. Labels will comply with 
local regulatory requirements for IPs. 
Storage 
Requirements 
Store at 2°C to 8°C; for more details refer to the Pharmacy Manual. 


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6.2. 
Preparation/Handling/Storage/Accountability 
• Bottles containing GB004 tablets or placebo will be shipped to clinical sites using 
temperature monitoring devices and stored at 2°C to 8°C. The Investigator or designee 
must confirm appropriate temperature conditions have been maintained during transit 
for all IP received and any discrepancies are reported and resolved before use of the IP. 
• Only randomized subjects may receive IP and only authorized site staff may supply IP. 
At the study site, all IP must be stored in a secure, refrigerated (2°C to 8°C), 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and 
authorized site staff. 
• Subjects will be provided with coolers for transport of IP from the study site to their 
home location. Once at home, IP is to be stored in a refrigerator. 
• The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for IP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Assignment of a Subject Number 
At the Screening visit, a unique subject number will be assigned to a subject upon signing of the 
ICF. 
6.3.2. 
Randomization and Stratification 
At PCP Day 1/Week 0 visit, all subjects who meet eligibility criteria will be centrally randomized 
1:1:1 to GB004 480 mg BID, GB004 480 mg QD, or placebo using an interactive response 
technology (IRT) system. 
Before the study is initiated, directions for use of the IRT system will be provided to the sites. 
Randomization will be stratified by systemic corticosteroid use at baseline (yes/no). 
6.3.3. 
Investigational Product Numbers 
IP will be dispensed at the study visits as summarized in the SoA (Section 1.3.1 – PCP and 
Section 1.3.2 – OLE). On PCP Day 1/Week 0 visit, the IRT system will assign IP bottle number(s) 
based on the subject’s randomized treatment group. 
For subsequent visits when IP is dispensed, the IRT system will assign new IP bottle number(s) 
based on the subject’s randomized/assigned treatment group. 
6.3.4. 
Blinding 
Subjects, investigators and site personnel, and the Sponsor (with exceptions described below) will 
be blinded to individual subject treatment assignments in the PCP. All subjects will dose IP BID 
to maintain the blind. 


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The study will be unblinded to the Sponsor at the time of the PCP Week 12 Analysis (see 
Section 9.4). Therefore, the PCP will be double-blind through PCP Week 12 and will remain 
blinded to subjects, investigators, and site staff throughout the PCP. 
Sponsor (or designee) personnel will have access to unblinded individual subject treatment 
assignments for the purposes of study-required activities, including management of IP inventory, 
production of summaries of data for DRC review, and performance of bioanalytical analysis of 
PK and gene/protein concentrations. These personnel will not be directly involved in the conduct 
of the study. 
A DRC will periodically convene to review unblinded overall safety and emerging efficacy results 
(refer to Section 9.5.1). 
6.3.5. 
Unblinding of an Individual Subject 
The IRT system will be programmed with blind-breaking instructions. In case of a medical 
emergency, the Investigator has the sole responsibility for determining if unblinding of a subject’s 
treatment assignment is warranted. Subject safety must always be the first consideration in 
making such a determination. If the Investigator decides that unblinding is warranted, the 
Investigator, when possible, should make every effort to contact the Sponsor to discuss unblinding 
a subject’s treatment assignment unless this could delay medical emergency treatment of the 
subject. If a subject’s treatment assignment is unblinded, the Sponsor must be notified within 24 
hours after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation. 
Appropriate personnel at the Sponsor will unblind suspected unexpected serious adverse reactions 
(SUSARs) for the purpose of regulatory reporting. The Sponsor will submit SUSARs to Regulatory 
Agencies in blinded or unblinded fashion according to local law. The Sponsor will submit SUSARs to 
Investigators in a blinded fashion. 
6.4. 
Investigational Product Compliance 
The first dose of IP will be administered in the clinic on PCP Day 1/Week 0 with food. All 
subsequent doses will be taken at home with food with the exception of the morning doses at the 
PCP Week 2, 4, 8, 12, and 36 visits and OLE Enrollment, Week 2, 12 and EOT visits where IP 
will be administered in the clinic, with food, after pre-dose blood collection as specified in the 
SoA (Section 1.3.1 – PCP and Section 1.3.2 – OLE). 
After initiation of IP on PCP Day 1/Week 0 visit, subjects will visit the clinic for assessments of 
IP use as specified in the SoA (Section 1.3.1 – PCP and Section 1.3.2 – OLE). IP accountability 
will be assessed by counting returned tablets. Subjects who demonstrate poor IP compliance 
should be re-educated on the importance of taking their medications as prescribed. 
Subjects will be asked to record dosing information on a daily basis in an eDiary. 
For additional details refer to Study Reference Manuals. 


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Guidance for Missed Dose(s) 
If a dose is missed, subjects should be instructed to skip the missed dose if there are less than 6 hours 
before the time of the next dose, resume dosing at their next scheduled dosing time, and document the 
missed dose. 
6.5. 
Dose Modification 
6.5.1. 
Investigational Product 
Dose modification, as described below, may be considered for treatment-related AEs and liver 
chemistry laboratory abnormalities. 
Dose reduction will be prescribed in two steps (as detailed in the Study Reference Manuals): 
• First reduction step: IP dose will be reduced by 2 tablets BID 
• Second reduction step (only if either treatment-related AE or liver function 
abnormality persist for 7 days following initiation of first step of dose reduction): IP 
dose will be reduced further by 1 tablet BID 
Treatment-related AEs (other than liver chemistry laboratory abnormalities described below): 
Dose modification of IP may be undertaken only after consultation and approval from the 
Sponsor’s Medical Monitor (or designee) for AEs assessed by the Investigator as treatment-
related, such as tolerability related AEs. Subjects may be requested to attend an unscheduled visit 
after dose reduction (before potential re-administration of IP at a higher dose as described below), 
to collect blood samples for safety and PK, if possible. 
Liver chemistry laboratory abnormality:  
• Dose modification of IP may be undertaken only after consultation and approval from 
the Sponsor’s Medical Monitor (or designee) for confirmed ALT or AST ≥ 3 × ULN 
and < 5 × ULN meeting the criterion described in Table 6 in Appendix 7.  
• For confirmed ALT or AST ≥3 × ULN meeting criteria in Table 7 in Appendix 7, IP 
should be discontinued. 
In both study periods, following dose reduction, IP may be re-administered at a higher dose in 
consultation with the Sponsor's Medical Monitor (or designee). 
After consultation and approval from the Sponsor’s Medical Monitor (or designee), subjects with 
a dose reduction during the PCP may enter the OLE at the reduced dose (reduced number of 
tablets as specified above) or at full dose (480 mg BID). 
6.5.2. 
Background UC Therapy 
New UC therapies may not be started between 2 weeks prior to the screening flexible 
sigmoidoscopy/colonoscopy and the PCP Week 36 visit. Subjects requiring introduction of new 
therapies to treat UC will be discontinued from IP as described in Section 7.1.5. 


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5-ASA 
Subjects should remain on their stable UC background oral 5-ASA therapy from 2 weeks prior to 
screening flexible sigmoidoscopy/colonoscopy used to assess the baseline Mayo score through the 
duration of their time on study. Any changes in existing UC background therapies should be 
discussed with the Sponsor’s Medical Monitor (or designee), if possible. 
Systemic steroid tapering 
Subjects receiving oral prednisone ≤ 20 mg/day (or equivalent) or beclomethasone ≤ 5 mg/day or 
budesonide or budesonide MMX of ≤ 9 mg/day should remain on their stable dose from 2 weeks 
prior to screening flexible sigmoidoscopy/colonoscopy used to assess the baseline Mayo score 
through the PCP Week 12 visit. At the discretion of the Investigator, systemic steroids may be 
tapered after the PCP Week 12 visit as described below. For subjects who cannot tolerate systemic 
steroid taper without recurrence of clinical symptoms of either UC or steroid withdrawal, the 
systemic steroid dose may be increased (up to the baseline dose if required). 
Prednisone (or equivalent) tapering 
• Subjects receiving prednisone at a dose of > 10 mg/day (or equivalent) should have 
their dose reduced at a rate of 5 mg per week until a 10 mg/day dose is achieved.  
• Subjects receiving prednisone at a dose of 10 mg/day (or equivalent) either or when 
this dose is achieved by tapering during the OLE, are to have their dose reduced at a 
rate of 2.5 mg per week until discontinuation.  
Beclomethasone or Budesonide tapering 
• Subjects receiving beclomethasone should taper their dose of 5 mg every day to 5 mg 
every other day for 2 weeks then discontinue beclomethasone. 
• Subjects receiving budesonide or budesonide MMX should taper their dose of 9 mg 
every day to 9 mg every other day for 2 weeks then discontinue budesonide or 
budesonide MMX. 
6.6. 
Continued Access to Investigational Product After the End of the 
Study 
No additional intervention is planned beyond the OLE EOT visit. 
6.7. 
Treatment of Overdose 
Any dose of IP greater than the prescribed daily dose within the same calendar day will be 
considered an overdose. 
There is no specific treatment recommended to treat an overdose of IP and the subject should 
receive treatment directed towards any symptoms manifested. 
In the event of an overdose, the Investigator should: 
• Contact the Sponsor’s Medical Monitor (or designee) as soon as possible. 


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• Closely monitor the subject for any AE/SAE and laboratory abnormalities. 
• Document the quantity of the excess dose as well as the duration of the overdose in the 
electronic case report form (eCRF). 
Decisions regarding dose interruptions will be made by the Investigator in consultation with the 
Sponsor's Medical Monitor (or designee) based on the clinical evaluation of the subject. 
6.8. 
Concomitant Therapy 
At least a 4-hour interval is required between taking IP tablets and mineral supplements, and 
antacids that contain polyvalent cations (eg, iron, aluminum, and zinc). 
Results from in vitro studies indicate that a glucuronide metabolite of GB004, GBD242, may be 
an inhibitor of OCT2 and CYP2C8.  
If sensitive clinical substrates of OCT2 (such as metformin or dalfampridine) are used 
concomitantly with GB004, refer to the prescribing information of the clinical substrate for 
assessing the benefit and risk of concomitant use. Initiation of sensitive clinical substrates of 
OCT2 is permitted only after discussion with the Sponsor’s Medical Monitor (or designee) and 
consideration of alternatives.  
Concomitant use of sensitive substrates of CYP2C8 (eg, repaglinide, rosiglitazone, pioglitazone, 
and loperamide) is prohibited in this study pending further evaluation of the potential for GBD242 
to inhibit CYP2C8 activity clinically. 
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
vitamins, and/or herbal supplements) that the subject is receiving at the time of enrollment or 
receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Sponsor's Medical Monitor (or designee) should be contacted if there are any questions 
regarding concomitant or prior therapy.  
6.8.1. 
Prohibited Medications Prior to the Screening Visit and Throughout the Study 
Please refer to Appendix 6 for further details regarding prohibited medications. 


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7. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
SUBJECT WITHDRAWAL FROM STUDY 
7.1. 
Discontinuation of Investigational Product, Subject Withdrawal from 
the Study and Stopping Rules 
Discontinuation of IP 
In some instances, it may be necessary for a subject to permanently discontinue IP. 
PCP: Permanent discontinuation of IP does not mean withdrawal from the study, and the subject 
will be encouraged to remain in the study and continue to complete any remaining PCP study 
visits as per the SoA (Section 1.3.1 – PCP) if the subject is not enrolling in the OLE. A follow-up 
visit will be conducted approximately 4 weeks after last dose of IP. The reason for discontinuation 
of IP will be recorded in the eCRF.  
OLE: Subjects who permanently discontinue IP during the OLE will be withdrawn from the study, 
complete the End of OLE/ET visit, and will be asked to return for a Follow-up visit approximately 
4 weeks after their last dose of IP to assess safety. 
Withdrawal from the Study 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the Investigator or at the institution. The reason for 
subject withdrawal from the study will be recorded in the eCRF. At the time of withdrawal from 
the PCP, an Early Withdrawal from Study visit should be conducted, as shown in the SoA 
(Section 1.3.1 – PCP) and from the OLE, the EOT visit should be conducted as shown in the SoA 
(Section 1.3.2 – OLE). See the SoA for data to be collected at the time of study withdrawal and 
follow-up and for any further evaluations that need to be completed. If a subject withdraws from 
the study, he/she may request destruction of any samples taken and not tested, and the Investigator 
must document this in the site study records. 
A subject may discontinue IP or withdraw from the study for the following reasons: 
• Adverse event 
• Death 
• Lack of efficacy 
• Lost to follow-up 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Site terminated by Sponsor 
• Study terminated by Sponsor 


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• Withdrawal by subject 
For stopping criteria related to hemoglobin, nausea, and dizziness, refer to Section 7.1.1. 
For stopping criteria relating to QTcF prolongation, refer to Section 7.1.2. 
For liver chemistry abnormality actions and follow-up assessments, refer to Section 7.1.3 and 
Appendix 7 and for dose modification, refer to Section 6.5.1. 
Pregnancy is a criterion for mandatory permanent discontinuation of IP (see Section 7.1.4). 
For stopping criteria related to introduction of new therapy to treat UC between 2 weeks prior to 
the screening flexible sigmoidoscopy/colonoscopy and the PCP Week 36 visit, refer to 
Section 7.1.5. 
7.1.1. 
Hemoglobin, Nausea, and Dizziness Stopping Criteria 
Individual subjects will be permanently discontinued from IP for any of the following: 
• Hemoglobin increase of > 4 g/dL from baseline and above ULN, and is assessed by the 
Investigator as a related AE.  
• Nausea that prevents daily activity, requires outpatient IV hydration, and is assessed by 
the Investigator as a related AE. 
• Dizziness that prevents daily activity, requires medical intervention, and is assessed by 
the Investigator as a related AE. 
7.1.2. 
QTcF Stopping Criteria 
Subjects must permanently discontinue IP for QTcF >500 msec. 
7.1.3. 
Liver Function: Actions and Follow-up Assessments 
Liver chemistry will be evaluated as specified in the SoA (Section 1.3.1 – PCP and Section 1.3.2 – 
OLE). 
For ALT or AST ≥3 × ULN, refer to Appendix 7 for guidelines on monitoring and criteria for 
possible dose modifications (Section 6.5.1) and temporary interruption of IP with possible 
restarting criteria and actions. 
Any occurrence of a confirmed ALT or AST value ≥3 × ULN will be monitored and evaluated for 
an etiology (for example viral hepatitis, drug and herbal supplements, environmental exposure, 
alcohol use, and other) in consultation with the Sponsor (Appendix 2,  Table 5). 
7.1.4. 
Pregnancy 
A subject must permanently discontinue IP if she becomes pregnant. See Appendix 4 and 
Section 8.3.5 for additional details. 
See the SoA (Section 1.3.1 – PCP and Section 1.3.2 – OLE) for data to be collected at the time of 
IP discontinuation (Early Withdrawal from Study visit in PCP and EOT visit for OLE) and 
follow-up and for any further evaluations that need to be completed. 


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7.1.5. 
Introduction of New UC Therapy Stopping Criteria 
A subject requiring introduction of a new therapy to treat UC between 2 weeks prior to the 
screening flexible sigmoidoscopy/colonoscopy and the PCP Week 36 visit must permanently 
discontinue IP. 
7.2. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to engage for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit (for exceptions refer to Appendix 9): 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 1.3.1 – PCP and 
Section 1.3.2 – OLE). Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor’s Medical Monitor 
(or designee) immediately upon occurrence or awareness to determine if the subject 
should continue or discontinue IP. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• In case of natural disasters or pandemics, some visits/study procedures may be done 
via virtual visits or at home visits. Refer to Appendix 9 and Study Reference Manuals 
for more details. 


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8.1. 
Efficacy Assessments 
8.1.1. 
Clinical, Endoscopic and Histologic Assessment 
Throughout the study, subjects will capture Stool frequency and Rectal bleeding symptoms on a 
daily basis in an eDiary. For evaluation of eligibility, the Rectal bleeding and Stool frequency 
subscores of the Mayo score will each be calculated based on the average of the most recent 3 
days with non-missing data within 14 days prior to the PCP Day 1/Week 0, excluding the day of 
and the day after flexible sigmoidoscopy/colonoscopy and the day(s) of bowel preparation, if 
performed. Subjects bowel preparation for flexible sigmoidoscopy/colonoscopy should follow 
standard clinical practice. Subjects will be instructed that a stool is defined as a trip to the toilet 
when the subject has either a bowel movement, or passes blood alone, blood and mucus, or mucus 
only. 
Screening, PCP Week 12, and PCP Week 36 (and at an Unscheduled UC Disease Activity Criteria 
Assessment visit(s) and the Early Withdrawal from Study visit, if applicable) endoscopic 
subscores will be assessed by both a central reader (who is blinded to treatment assignment, visit, 
and subject symptoms) and local endoscopist (who is blinded to treatment assignment). The same 
local endoscopist assesses the endoscopic subscore for a particular subject throughout the study, if 
possible. Differences between the local endoscopist and the central reader will be adjudicated by a 
second blinded central reader as described in the Imaging Charter. Centrally read endoscopic 
subscores will be used for both eligibility determination and efficacy analyses. Histologic scores 
(eg, RHI) will be evaluated by a blinded central reader.  
Flexible sigmoidoscopy/colonoscopy and histology assessments will consist of assessing the 
Endoscopic subscore of the sigmoid colon at approximately 15 to 25 cm from the anal verge. Six 
biopsies will be obtained during the endoscopic procedures from the area that appears to be most 
affected by UC in this sigmoid colon segment.  
Biopsies may also be evaluated for PK, gene expression, and immunohistochemistry signals of 
biological activity. 
8.1.2. 
Mayo Score and Modified Mayo Score 
Mayo score is used for inclusion into the study rather than a Modified Mayo score (used to 
evaluate efficacy) given the limited information available at the study inception regarding 
Modified Mayo score cut points that define a mild-to-moderate patient population. 
The Mayo score is a conventional assessment of UC disease activity and is commonly used in 
clinical studies of UC. The score is composed of four subscores, each ranging from 0 to 3, that are 
summed to give a total score ranging from 0 to 12 points, with higher scores indicating greater 
severity (Adapted from Schroeder, 1987): 
1. Stool frequency: 
0 = Normal number of stools for this subject 
1 = 1 to 2 stools more than normal 
2 = 3 to 4 stools more than normal 
3 = 5 or more stools than normal 


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Each subject serves as his or her own control to establish the degree of abnormality of the 
stool frequency. The control value is the number of stools in a 24-hour period when the 
subject was in remission from UC, or, if the subject does not report having previously 
achieved remission from UC, the number of stools the subject reports per day before 
initial onset of signs and symptoms of UC. 
2. Rectal bleeding: 
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passes 
The daily bleeding score represents the most severe bleeding of the day. 
3. Findings on endoscopy: 
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern) 
2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions) 
3 = Severe disease (spontaneous bleeding, ulceration) 
4. Physician’s Global Assessment 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 
The PGA acknowledges the three other criteria, the subject’s recollection of abdominal 
discomfort and general sense of wellbeing, and other observations, such as physical 
findings and the subject’s performance status. It is recommended that the same physician 
performs the PGA for a particular subject throughout the study. 
The Modified Mayo score is an endpoint measure composed of: Stool frequency, Rectal bleeding, 
and Endoscopic subscores (where the Endoscopic subscore value of 1 does not include friability), 
each ranging from 0 to 3, that are summed to give a total score ranging from 0 to 9 points, with 
higher scores indicating greater severity. 
The Partial Mayo score is an endpoint measure composed of: Stool frequency, Rectal bleeding, 
and PGA subscores, each ranging from 0 to 3, that are summed to give a total score ranging from 
0 to 9 points, with higher scores indicating greater severity. 
The 6-point Mayo score is an endpoint measure composed of: Stool frequency and Rectal 
bleeding subscores, each ranging from 0 to 3, that are summed to give a total score ranging from 0 
to 6 points, with higher scores indicating greater severity. 


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8.1.3. 
Robarts Histopathology Index (RHI) Score, Geboes Score and Ulcerative Colitis 
Index-100 
The RHI is a validated instrument that measures histological disease activity in UC. The RHI 
consists of 4 items: chronic inflammatory infiltrate, lamina propria neutrophils, neutrophils in 
epithelium, and erosion or ulceration. The RHI score ranges from 0-33 and is derived from 
Geboes score (Mosli, 2017). 
RHI =  1 x chronic inflammatory infiltrate level (4 levels) 
+ 2 x lamina propria neutrophils (4 levels)  
+ 3 x neutrophils in epithelium (4 levels) 
+ 5 x erosion or ulceration (4 levels after combining Geboes 5.1 and 5.2)  
The Geboes score is divided into 6 grades: architectural changes [grade 0], chronic inflammatory 
infiltrate [grade 1], lamina propria eosinophils and neutrophils [grade 2A and 2B], neutrophils in 
epithelium [grade 3], crypt destruction [grade 4] and erosions or ulcerations [grade 5]. The Geboes 
score is calculated as the highest grade with a corresponding subgrade score > 0, excluding Geboes 
Grade 2A, and ranges from 0 to 5. 
The Ulcerative Colitis Index-100 (UC-100) score is the composite index (1 + 16 x Stool frequency 
subscore [0 to 3] + 6 x Endoscopic subscore [0 to 3] + 1 x RHI score [0 to 33]) (Jairath, 2019). 
8.2. 
Safety Assessments 
8.2.1. 
Physical Examinations 
A complete physical examination will be performed at timepoints designated in the SoA 
(Section 1.3.1 – PCP and Section 1.3.2 – OLE) and will include: 
• General appearance/inspection 
• Skin 
• Neck 
• Lymphatic 
• Respiratory 
• Cardiovascular 
• Abdominal system 
• HEENT (head, eyes, ears, nose, throat) 
• Other- for those body systems, not listed above considered necessary per PI’s 
discretion 
A symptom-directed physical examination will be conducted if clinically indicated throughout the 
study. Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 


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8.2.2. 
Vital Signs 
• Heart rate, respiratory rate, temperature and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed with the subject in a sitting 
position with a completely automated device. Manual techniques will be used only if 
an automated device is not available or if the automated cuff sizes available are not 
large enough for the subject’s arm circumference. 
• Vital signs will be measured after 5 minutes rest and prior to ECG measurements on 
days where the 12-lead ECG will be obtained. 
• Height and weight will also be measured and recorded. Height will only be recorded at 
Screening. 
8.2.3. 
Electrocardiograms 
• 12-lead ECGs will be obtained at timepoints specified in the SoA (Section 1.3.1 – PCP 
and Section 1.3.2 – OLE) using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals. 
• Subjects with evidence of a significant abnormality in the 12-lead ECGs obtained at 
screening, including prolongation of the QTc interval, will not be eligible to randomize 
into the study. 
• ECG will be centrally read by the Sponsor’s designee via the electronic portal. 
• Original paper tracings and tracing copies of the ECGs should be stored in the  source 
documents. 
8.2.4. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 for the list of clinical laboratory tests to be performed and the 
SoA (Section 1.3.1 – PCP and Section 1.3.2 – OLE) for the timing and frequency. 
Details for collection, processing, and shipping of samples to the central laboratory are 
provided in a separate Central Laboratory Manual. 
• The Investigator must review and document review of the laboratory report. The 
Investigator must record any clinically relevant changes occurring during the study in 
the AE section of the eCRF. The laboratory reports must be filed with the source 
documents. 
• All laboratory tests with values considered clinically significant during participation in 
the study should be repeated as medically indicated until the values return to normal or 
baseline or are no longer considered clinically significant by the Investigator or 
Sponsor’s Medical Monitor (or designee). 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 


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− All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the Central Laboratory Manual and the SoA 
(Section 1.3.1 – PCP and Section 1.3.2 – OLE). 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE and SAE can be found in Appendix 3. 
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. The Investigator and qualified 
designees remain responsible for following AEs that are serious, considered related to the IP or 
study procedures, or that caused the subject to discontinue from IP or from the study (see 
Section 7.1). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
AEs and SAEs will be collected beginning at the time of consent through the end of the follow-up 
period (including PCP and OLE). All medical occurrences, with the exception of SAEs, that begin 
after obtaining ICF and before first dose of IP will be recorded on the Medical History section of 
the eCRF and not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee immediately upon the site 
learning of an event and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
it being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event to be reasonably 
related to the IP or study participation, the Investigator must promptly notify the Sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.2). Further 
information on follow-up procedures is given in Appendix 3. 


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8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of an IP under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of an IP under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and investigators. 
• Investigator Safety Reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy, and 
then the reports will be forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator Safety Report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female subjects and female partners of male subjects will 
be collected after the start of study IP and until birth. 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Worsening of UC will be evaluated by efficacy assessments (Section 8.1) and is a disease-related 
outcome not qualifying as an AE unless the Investigator considers the worsening UC to have met 
the definition of an SAE (Appendix 3). Worsening UC meeting the definition of an SAE will be 
reported in the appropriate eCRF. Worsening UC not meeting the definition of an SAE should not 
be reported as an AE. Worsening UC will be evaluated by efficacy endpoints and by the 
occurrence of SAEs, and will be monitored by the Sponsor on a routine basis. 
8.4. 
Pharmacokinetics 
Blood will be collected and used for the measurement of plasma concentrations of GB004, and 
metabolites of GB004 (glucuronide [GBD242] and glucoside [GBD243]) as specified in the SoA 
(Section 1.3.1 – PCP and Section 1.3.2 – OLE). On the visit day, the subject should be instructed 
to take the dose at the site following the predose blood sample draw. If a subject withdraws early 
from the study, a blood sample may also be taken, if possible. 
Colon tissue samples will be collected during flexible sigmoidoscopy/colonoscopy and may be 
used for measuring concentration of GB004. 


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Additionally, stool samples may be analyzed for levels of GB004. 
Samples may also be used for assay development and characterization of potential metabolites of 
GB004. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel. 
8.5. 
Pharmacodynamics and Biomarkers 
Blood, stool, and colonic biopsy samples should be collected as designated in the SoA 
(Section 1.3.1 – PCP and Section 1.3.2 – OLE) and may be used for exploratory assessment of 
TE/PD biomarkers, eg, histology, c-reactive protein (CRP), fecal calprotectin, fecal lactoferrin, 
gene expression, and immunohistochemistry, e.g. HIF-1α, EGLN1-2-3, etc. 
Samples may be stored at a facility selected by the Sponsor, to enable further analysis of 
biomarker responses to GB004, for a maximum of 8 years (or according to local regulations) 
following the last subject’s last visit for the study. 
Residual blood, and urine samples may be stored for potential future identification of factors or 
profiles that correlate with measures of response to GB004. 
Please refer to the study specific Central Laboratory Manual for PD biomarker details. 
8.6. 
Pharmacogenetic 
Pharmacogenetic (PGx) analyses may be performed on any bio-sample from subjects who have 
consented for PGx sampling. Subject confidentiality will be maintained. 
Suitable bio-samples should be collected from all subjects, where permitted by law and local 
authorities. Those subjects who are prohibited from participating in the PGx research by law 
and/or local authorities, and those subjects providing a written (documented) opt-out, may still 
participate in the study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
9.1.1. 
Placebo-Controlled Period 
The PCP is designed to demonstrate the superiority of each GB004 treatment group to placebo on 
the primary endpoint of the proportion of subjects with clinical remission at PCP Week 12. The 
PCP is also designed to demonstrate the superiority of each GB004 treatment group to placebo on 
the primary endpoint of the proportion of subjects with clinical remission at PCP Week 36. 
9.1.2. 
OLE 
The purpose of the OLE period is to evaluate the long-term safety and tolerability of GB004. No 
formal statistical hypotheses are being tested. 


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9.2. 
Sample Size Determination 
9.2.1. 
Placebo-Controlled Period 
A total sample size of approximately 195 subjects (approximately 65 per treatment group, 
randomized 1:1:1, with stratification by systemic corticosteroid use at baseline [yes/no]) is 
estimated to provide approximately 80% power to detect a difference of 20.4% between each 
GB004 treatment group and placebo for the primary endpoint of proportion of subjects with 
clinical remission at PCP Week 12 based on a chi-squared test at an 0.050 two-sided level of 
significance. This assumes the proportion of subjects with clinical remission at PCP Week 12 is 
10% in the placebo group and 30.4% in each GB004 treatment group and a dropout rate by PCP 
Week 12 of approximately 8%. Subjects with missing clinical remission status at PCP Week 12 
will be considered as having not met the primary endpoint. 
Using the same sample size assumptions as above for the primary endpoint of proportion of 
subjects with clinical remission at PCP Week 12 (ie, a difference of 20.4% between each GB004 
treatment group and placebo, with a 10% proportion in the placebo group), there will be 
approximately 80% power for the secondary endpoint of the proportion of subjects with clinical 
remission at PCP Week 36 based on a chi-squared test at an 0.050 two-sided level of significance. 
Subjects with missing clinical remission status at PCP Week 36 will be considered as having not 
met the endpoint. 
9.2.2. 
OLE 
There is no formal sample size calculation for this period of the study. This is an extension of the 
PCP. Subjects must complete at least 12 weeks of treatment in the PCP prior to dosing in the 
OLE. Therefore, the maximum number of subjects potentially eligible to participate in the OLE 
will not be greater than the total number of subjects randomized in the PCP (approximately 195 
subjects). 
9.3. 
Populations for Analyses 
9.3.1. 
Placebo-Controlled Period 
The following major analysis populations are defined for the PCP: 
• Intent-to-treat (ITT) Population: All subjects who are randomized and receive at least 1 
dose of IP, with subjects grouped according to randomized treatment. 
• Safety Population: All subjects who receive at least 1 dose of IP, with subjects grouped 
according to their actual treatment. 
9.3.2. 
OLE 
The following major analysis populations are defined for the OLE: 
• OLE Safety Population: All subjects who receive at least one dose of IP in the OLE. 
• GB004-treated Safety Population: All subjects who receive at least one dose of GB004 
in PCP and/or OLE. 


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9.4. 
Statistical Analyses 
Three separate formal statistical analyses will be performed:   
• The PCP Week 12 Analysis will be conducted after all subjects either complete the 
PCP Week 12 visit or withdraw from the study prior to completion of the PCP Week 
12 visit. This analysis will evaluate endpoints at or up through PCP Week 12. 
• The PCP Final Analysis will be conducted after all subjects either complete the PCP  
or withdraw from the study prior to completion of the PCP;  This analysis will evaluate 
all PCP endpoints. 
• The OLE Final Analysis will be conducted after all subjects either complete the OLE 
period or withdraw from the study prior to completion of the OLE period. 
The study will be unblinded to the Sponsor at the time of the PCP Week 12 Analysis. Therefore, 
the PCP will be double-blind through PCP Week 12 and will remain blinded to subjects, 
investigators, and site staff throughout the PCP. 
In general, continuous variables will be summarized using the number of subjects with non-
missing data, mean, standard deviation, standard error (where appropriate), median, minimum, 
and maximum. Categorical variables will be summarized using counts and percentages.  
For the PCP Week 12 Analysis and the PCP Week 36 Analysis, baseline will be defined as the last 
non-missing value prior to first dose of IP in the PCP. For the OLE Analysis, GB004 baseline will be 
defined as the last non-missing value prior to the first dose of GB004 in the study. 
This section is a summary of the planned statistical analyses of the primary, secondary, and safety 
endpoints. 
9.4.1. 
PCP Week 12 Analysis 
9.4.1.1. 
Efficacy Analyses 
The ITT population will be utilized for efficacy analyses. 
Primary Endpoint  
The primary endpoint of the proportion of subjects with clinical remission at PCP Week 12 will 
be compared between each GB004 treatment group and placebo by a Cochran-Mantel Haenszel 
(CMH) chi-squared test (Mantel, 1959) stratified by systemic corticosteroid use at baseline 
(yes/no) with a two-sided 0.050 level of significance. If stratum cell sizes are too small based on 
the Mantel-Fleiss criterion (Mantel, 1980), Pearson’s chi-squared test will be used instead. 
For the comparison of each GB004 treatment group versus placebo, the p-value from the CMH 
chi-squared test will be reported, along with the estimated Mantel-Haenszel common odds ratio 
across strata and corresponding 95% CI. The number and proportion of subjects meeting the 
primary endpoint and corresponding 95% Wilson (Score) CIs (Wilson, 1927) will be summarized 
by treatment group. The absolute difference in proportion between each GB004 treatment group 
and placebo will also be summarized, with the 95% CI for the absolute difference based on the 
Newcombe continuity-corrected method (Newcombe, 1998). 


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In the primary analysis of the primary endpoint, subjects with missing clinical remission status at 
PCP Week 12 will be considered as having not met the primary endpoint. The primary endpoint 
will also be analyzed using various other methodological approaches for handling subjects with 
missing data as sensitivity analyses. 
Secondary Endpoints 
The secondary endpoints of the proportion of subjects with clinical response at PCP Week 12, the 
proportion of subjects with histologic remission at PCP Week 12, the proportion of subjects with 
endoscopic improvement at PCP Week 12, and the proportion of subjects with mucosal healing at 
PCP Week 12 will be analyzed using the same approach as the primary endpoint. Histologic 
remission at PCP Week 12 and mucosal healing at PCP Week 12 will be evaluated among 
subjects with Baseline lamina propria neutrophils and neutrophils in epithelium 
RHI subscores > 0. 
These secondary endpoints will be assessed at a two-sided level of significance of 0.050 for the 
comparison of each GB004 treatment group and placebo. 
9.4.1.2. 
Safety Analyses 
All safety analyses will be performed using the Safety Population. Safety data will be listed by 
subject. 
Safety analyses will be focused on treatment-emergent AEs, defined as an AE with onset on or 
after the start of study treatment. The incidence of AEs will be summarized by treatment group, 
including the incidence by system organ class and preferred term, severity, and relationship to 
study drug, the incidence of SAEs, the incidence of AEs that lead to discontinuation of study drug, 
and the incidence of AEs that lead to withdrawal from study. 
9.4.2. 
PCP Final Analysis 
The PCP Final Analysis will be performed using the same methodological approaches as the PCP 
Week 12 Analysis. 
9.4.3. 
OLE Final Analysis 
The OLE Safety population will be used as the primary analysis population for safety analyses, 
which will be based on data from the OLE period. 
Select safety analyses will summarize the safety experience of all subjects treated with GB004 in 
the PCP or the OLE period, using the GB004-Treated Safety population, with data combined 
across the PCP and OLE. 
Additionally, in order to inform assessment of whether there appear to be any new or worsening 
safety signals in the OLE period, select safety analyses will summarize the placebo-controlled 
safety experience in the PCP side-by-side with the continuing GB004 safety experience in the 
OLE period (using subjects in the OLE Safety population who were previously treated with 
GB004). 
Safety analyses will be focused on TEAEs, defined as an AE with onset on or after the start of 
study treatment in the respective analysis. The incidence of AEs will be summarized by treatment 


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group, including the incidence by system organ class and preferred term, severity, and relationship 
to study drug, the incidence of SAEs, the incidence of AEs that lead to discontinuation of study 
drug, and the incidence of AEs that lead to withdrawal from study. The incidence of AEs and 
SAEs by system organ class and preferred term may also be presented by time intervals. Incidence 
rates of AEs adjusted for time on study (eg, number of subjects per 1000 subject-years) may also 
be presented. 
9.5. 
Interim Analyses 
During the OLE, interim analyses will be performed as needed for regulatory reporting, safety 
updates, publications, or as otherwise required by the Sponsor. 
9.5.1. 
Data Review Committee 
A DRC, comprised of Sponsor representatives not directly involved in the conduct of the study, 
and external expert physician(s), will regularly monitor overall safety and emerging efficacy 
results on an unblinded basis, as well as general aspects of study conduct, to ensure that the 
benefits and risks of study participation remain acceptable. 
Based on these regular reviews of emerging results, the DRC will recommend continuation, 
modification, or termination of the study. 
Composition of the DRC, meeting structure, schedule, and procedures, the content and format of 
DRC reports, and other relevant details will be determined in consultation with DRC members 
and detailed in a separate DRC charter. 


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10. 
APPENDICES 
APPENDIX 1. 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 (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects. 
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulation (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding 
the study. 
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center. 


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• The medical record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign the 
ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. 
• Subjects who are rescreened are required to sign a new ICF. 
• The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The Investigator or authorized designee will 
explain to each subject the objectives of the exploratory research. Participants will be 
told that they are free to refuse to participate and may withdraw their consent at any 
time and for any reason during the storage period. A separate signature will be required 
to document a subject's agreement to allow any remaining specimens to be used for 
exploratory research. Participants who decline to participate in this optional research 
will not provide this separate signature. 
Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be 
transferred. 
• The subject must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the subject. 
• The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
Dissemination of Clinical Study Data 
A clinical study report will be developed by the Sponsor at completion of data analysis. This 
report will be a clinical and statistical integrated report, according to the ICH E3 guidelines. 
Data Quality Assurance 
• All subject data relating to the study will be recorded on eCRF unless 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. 


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• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized 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 per ICH-GCP and local regulations or institutional 
policies. 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. 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
• Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained. These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 


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Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the Investigator 
• Discontinuation of further IP development 
Publication Policy 
The publication policy for this study is located within the Clinical Study Agreement with the 
Investigator and/or Institution. 




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• 
Urine Pregnancy Test 
The additional tests listed in Table 5 will be collected only as part of liver safety actions and 
follow-up (see Section 7.1.3). 
Table 5: 
Liver Safety Laboratory Assessments 
• 
Hepatitis A immunoglobulin M (IgM) antibody 
• 
HBsAg 
• 
Hepatitis C virus antibody 
• 
Hepatitis E IgM antibody 
• 
Cytomegalovirus IgM antibody 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or 
monospot testing) 
• 
Anti-nuclear antibody 
• 
Anti-smooth muscle antibody 
• 
Type 1 anti-liver kidney microsomal antibodies 
• 
Quantitative total immunoglobulin G (IgG) or gamma globulins 
• 
Serum acetaminophen assay 
• 
Serum creatine phosphokinase (CPK) 
• 
Lactate dehydrogenase (LDH) 
• 
Complete Blood Count with differential 
• 
Obtain blood sample for pharmacokinetic (PK) analysis 
The above assessments will be conducted only if required. 
 












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APPENDIX 4. CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION 
1. Definitions 
Women of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of IP, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied 
to determining study entry. 
Note: Documentation can come from review of the subject’s medical records, medical 
examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is 
required. 
• Female subjects on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before baseline into the study. 


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2. Contraception Guidance 
Male Participants: 
Male subjects are eligible to participate if they agree to the following from consent through at 
least 90 days after the last dose of IP: 
• Refrain from donating sperm 
PLUS either: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
OR 
• Must agree to use contraception/barrier (condom) 
Female Participants: 
A female subject is eligible to participate if she is not pregnant or breastfeeding, and at least one 
of the following conditions applies: 
• Is not a woman of childbearing potential (WOCBP) 
OR 
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described in the 
table below, from 30 days prior to screening, during the study period, and for 30 days 
after the last dose of IP and agrees not to donate eggs (ova, oocytes) for the purpose of 
reproduction during this period. The Investigator should evaluate the effectiveness 
of the contraceptive method in relationship to the first dose of IP. 
• A WOCBP must have a negative highly sensitive pregnancy test 
within 24 hours before the first dose of IP. If the urine test is positive or cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In 
such cases, the subject must be excluded from participation if the serum pregnancy 
result is positive. 


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Highly Effective Methodsa That Have Low User Dependency 
• Implantable progestogen-only hormone contraception associated with inhibition 
of ovulationb  
• Intrauterine device (IUD)  
• Intrauterine hormone-releasing system (IUS)b  
• Bilateral tubal occlusion  
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.)  
Highly Effective Methodsa That Are User Dependent 
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation 
− oral 
− intravaginal 
− transdermal 
− injectable  
• Progestogen-only hormone contraception associated with inhibition of ovulationb 
− oral 
− injectable  
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the IP. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the subject.)  
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
a. Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly. 
b. Acceptable contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction). 


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3. Collection of Pregnancy Information 
Male subjects with partners who become pregnant 
The Investigator will attempt to collect pregnancy information on any male subject’s female 
partner who becomes pregnant while the male subject is in this study. 
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the Investigator will record pregnancy information on the appropriate form and submit it to 
the Sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will also 
be followed to determine the outcome of the pregnancy. Information on the status of the mother 
and child will be forwarded to the Sponsor. Follow-up must be conducted at least until birth 
or termination of the pregnancy. 
Female subjects who become pregnant 
The Investigator will collect pregnancy information on any female subject who becomes pregnant 
while participating in this study. Information will be recorded on the appropriate form and 
submitted to the Sponsor within 24 hours of learning of a subject's pregnancy. 
The subject will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on the subject and the neonate and the information will be 
forwarded to the Sponsor. Follow-up must be conducted at least until birth or termination of the 
pregnancy. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion 
is always considered to be an SAE and will be reported as such. Any post-study pregnancy related 
SAE considered reasonably related to the IP by the Investigator will be reported to the Sponsor as 
described in Appendix 3. While the Investigator is not obligated to actively seek this information 
in former study subjects, he or she may learn of an SAE through spontaneous reporting. 
Any female subject who becomes pregnant while participating in the study will 
discontinue IP or be withdrawn from the study. 


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APPENDIX 5. PHARMACOGENETICS 
Use and Analysis of DNA 
• Germ line variation may impact a subject’s response to IP, susceptibility to, and severity 
and progression of disease. Variable response to IP may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action 
of the drug; disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a biosample may be collected for 
analysis from subjects. 
• Samples may be analyzed for genetic variations in genes which dramatically affect the 
pharmacokinetics of GB004, the safety, and/or efficacy profile. Often times, a large 
variability in the plasma concentration–time profiles of any medicine can be linked to loss 
of function mutations in the drug metabolizing enzymes and/or transporters. For example, 
substantial efforts have been made in reducing the risk of drug–drug interactions related to 
cytochrome P450 enzymes and variability caused by polymorphic expression of 
metabolizing enzymes (eg, UGT1A1, UGT1A6, UGT2B7). The effects of single 
nucleotide polymorphisms (SNPs) on the PK of GB004 uncovered in the course of this 
study may help guide future clinical studies and regulatory review of GB004. Additional 
pharmacogenetic analyses may be conducted if it is hypothesized that doing so may help 
resolve issues with the clinical data (eg, safety and/or pharmacodynamic observations) 
during the study. 
• The results of these analyses may be reported in a separate study summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 
• The samples will be retained while research on GB004 continues but no longer than 
8 years or other period as per local requirements. 
• The Sponsor may elect to measure the naturally occurring variation across a range of 
relevant pharmacogenetic markers using modern laboratory assays, eg, the ThermoFisher 
DMET™ Plus Solution. This assay, for example, would cover 1,936 genetic variants 
across 231 relevant genes, using a single array, and would include many genetic variants 
that cannot easily be detected using other assays, eg, SNPs and indels with secondary 
polymorphisms in close proximity, triallelic markers, and variants from multi-gene 
families. Particular emphasis would, in this case, be placed on covering the PharmaADME 
“Core ADME Genes” (32 genes) and PharmaADME “Core Markers” (185 variants). If the 
Sponsor finds it necessary, it may move beyond the PharmaADME core content to cover 
common and functional variants associated with the mechanism of action of GB004, 
hepatic detoxification pathways, and/or other markers associated with adverse drug events 
eg, CYP3A4 (392A>G), structural variants in transporter genes – an important 
pharmaceutical target eg, ABCG2 (421C>A), enrichment for mutations in absorption, 
distribution, metabolism, elimination (ADME) regulatory genes eg, PPARD, inclusion of 
many population specific markers eg, VKORC1. 


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APPENDIX 6. PROHIBITED MEDICATIONS 
The following medications are prohibited throughout the study: 
• Azathioprine 
• 6-mercaptopurine 
• Any per rectum therapy (eg, enemas or suppository formulations of steroids or 
5-aminosalicylates) except those required for flexible sigmoidoscopy preparation 
• Marketed biologic therapies for any condition such as adalimumab, infliximab, 
vedolizumab, rituximab, golimumab, ustekinumab 
• Tofacitinib, oral cyclosporine, sirolimus, mycophenolate mofetil 
• Epoetin alfa 
• Cholestyramine or other drugs interfering with enterohepatic circulation 
• Any investigational agent other than GB004 
• Chronic NSAID use (occasional use of NSAID, acetaminophen, or aspirin up to 
325 mg/day is allowed) 
• Anti-diarrheal medications (eg, loperamide, diphenoxylate/atropine) 
• 
Strong CYP3A inhibitors and/or CYP3A inducers (eg, boceprevir, cobicistat, conivaptan, 
danoprevir, ritonavir, elvitegravir, grapefruit juice, indinavir, itraconazole, ketoconazole, 
lopinavir, paritaprevir, ombitasvir, dasabuvir, posaconazole, saquinavir, telaprevir, 
tipranavir, troleandomycin, voriconazole, clarithromycin, diltiazem, idelalisib, nefazodone, 
nelfinavir, (carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort) 
• 
Inhibitors of UGT (eg, atazanavir; oral cannabidiol [≥5 mg/kg/day]; elbasvir and 
grazoprevir; encorafenib; epirubicin; oral fluconazole; fostamatinib; glecaprevir and 
pibrentasvir; isavuconazole; nelfinavir; ombitasvir and paritaprevir and ritonavir and 
dasabuvir; pazopanib; regorafenib; valproic acid).  
• 
Dofetilide 
• Sensitive CYP2C8 substrates (eg, repaglinide, rosiglitazone, pioglitazone, loperamide). 
 
 
 
 


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APPENDIX 7. LIVER SAFETY – ACTIONS AND FOLLOW-UP 
ASSESSMENTS 
Liver assessments performed as part of the standard clinical chemistry evaluations will be 
evaluated as specified in the SoA (Section 1.3.1 – PCP and Section 1.3.2 – OLE) and Appendix 2 
(Table 5). Parameters will include ALT, AST, GGT, ALP, total bilirubin, and direct bilirubin. 
For subjects with ALT or AST ≥ 2 × ULN and < 3 × ULN, confirm the value within 72 hours. 
Contact the Sponsor's Medical Monitor (or designee) to determine if additional liver monitoring is 
indicated. Blood sample for pharmacokinetic (PK) analysis should also be obtained. 
For liver chemistry abnormalities actions and follow-up assessments refer to Section 7.1.3, and for 
dose modification refer to Section 6.5.1. The criteria requiring additional liver monitoring with 
possible IP interruption is provided in Table 6. 
Table 6: 
Liver Chemistry Criteria Requiring Additional Monitoring with Possible Dose 
Modification of Investigational Product  
Criteria 
Actions 
ALT or AST ≥ 3 ULN and 
< 5 ULN 
AND bilirubin ≤ 2 ULN 
AND without symptoms 
believed to be related to liver 
injury or hypersensitivitya 
AND who can be monitored 
weekly for 4 weeks 
• 
Notify the Sponsor's Medical Monitor (or designee) within 24 
hours of learning of the abnormality to discuss subject safety. 
“Liver Safety Laboratory Assessment” in Table 5 may be 
requested by the Sponsor's Medical Monitor (or designee). 
• 
Confirm values within 24-48 hours via repeat laboratories 
(include ALT, AST, GGT, ALP, total bilirubin, direct bilirubin, 
and INR). 
• 
If unable to obtain repeat laboratories within 24-48 hours, 
decision to continue or interrupt IP will be determined by the 
Investigator in consultation with the Sponsor's Medical Monitor 
(or designee). 
• 
If repeat laboratories confirm that criteria are met, the dose of 
IP may be reduced, with approval from the Sponsor's Medical 
Monitor (or designee), to doses mentioned in Section 6.5.1. 
• 
Subject must return weekly or more frequently for repeat liver 
chemistry tests (ALT, AST, GGT, ALP, total bilirubin, direct 
bilirubin, and INR) until the abnormalities resolve, stabilize or 
return to baseline. 
• 
If at any time the subject meets liver chemistry interruption 
criteria (as specified in Table 7), then follow the instructions in 
“Liver Chemistry – Investigational Product Interruption 
Criteria” in Table 7 and in consultation with the Sponsor's 
Medical Monitor (or designee) initiate relevant assessment 
procedures. 
a New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia). 


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Table 7: 
Liver Chemistry Criteria Requiring Investigational Product Interruption and 
Additional Monitoring 
Liver Chemistry – IP Interruption Criteria 
ALT/AST (single occurrence) 
ALT or AST ≥ 5 ULN 
ALT/AST 
ALT or AST ≥ 3 ULN persists for ≥ 4 weeks 
+ Bilirubin a,b 
ALT or AST ≥ 3 ULN and 
bilirubin > 2 ULN (> 35% direct bilirubin) 
+ INR b 
ALT or AST ≥ 3 ULN and 
international normalized ratio (INR) > 1.5, if INR measured 
+ Cannot Monitor 
ALT or AST ≥ 3 ULN and cannot be monitored weekly for 4 weeks 
+ Symptomatic c 
ALT or AST ≥ 3ULN associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity 
ACTIONS 
• 
Immediately interrupt IP. 
• 
Report the event to the Sponsor's Medical Monitor (or designee) within 24 hours. 
• 
Repeat liver chemistry tests (include ALT, AST, GGT, ALP, total bilirubin, direct bilirubin, 
and INR) and perform the Liver Safety Laboratory Assessments (Table 5) within 24 hours. 
• 
If the repeat liver chemistry test confirms the criteria are met, monitor the subject until liver 
chemistry test abnormalities resolve, stabilize, or return to baseline after discussion with the 
Sponsor's Medical Monitor (or designee) (see MONITORING). 
• 
Do not restart IP unless Sponsor's Medical Monitor (or designee) approval is granted. If 
restart is granted, IP may be restarted at modified dose (Section 6.5.1). 
• 
If restart not granted, permanently discontinue IP and continue subject in the study for any 
protocol specified follow up assessments. 
• 
Complete an SAE data collection tool if the event also met the criteria for an SAE.b 
• 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography), liver biopsy, 
and/or specialist consultation to evaluate liver disease may be requested by the Sponsor. 
MONITORING 
If ALT or AST ≥ 3 ULN AND bilirubin > 
2 ULN or INR > 1.5: 
• 
Monitor subject twice weekly until liver 
chemistry test abnormalities resolve, 
stabilize, or return to baseline. 
If ALT or AST ≥ 3 ULN AND bilirubin ≤ 2 
ULN and INR ≤ 1.5: 
• 
Monitor subjects weekly until liver chemistry 
abnormalities resolve, stabilize, or return to 
baseline. 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue IP if ALT or AST ≥ 3 × ULN and bilirubin > 2 × ULN. Additionally, if serum 
bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin on 
dipstick which is indicative of direct bilirubin elevations suggesting liver injury. 
b All events of ALT or AST ≥ 3 × ULN and bilirubin > 2 × ULN (> 35% direct bilirubin) or ALT or AST ≥ 3 × ULN 
and INR > 1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). The INR stated threshold value will not apply to subjects 
receiving anticoagulants. INR is not part of routine laboratory assessments in this study. 


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c New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia) 


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APPENDIX 8. INSTRUCTIONS FOR CALCULATING MAYO SCORE 
FOR UC DISEASE ACTIVITY CRITERIA ASSESSMENT  
Table 8 provides instructions for calculating the Mayo score for assessing the predefined UC 
disease activity criteria at or after the PCP Week 12 visit and prior to the PCP Week 36 visit 
(Section 5.3) while the subject is receiving IP. 
Table 8: 
Instructions for Calculating Mayo Score For UC Disease Activity Criteria 
Assessments (at or after PCP Week 12 visit and prior to PCP Week 36 visit) 
Timepoint 
Instructions 
At PCP Week 12 visit (post 
endoscopy) 
• Use PCP Week 12 visit Mayo score and centrally 
read Endoscopic subscore  
At PCP post-Week 12 visit and 
prior to PCP Week 36 visit 
• Use 
− Updated centrally read Endoscopic subscore 
(unscheduled) if previous flexible sigmoidoscopy 
was conducted > 4 weeks prior, otherwise use PCP 
Week 12 centrally read Endoscopic subscore 
− Updated Stool frequency subscore, Rectal 
bleeding subscore, and PGA 
Notes:  
• 
If, after the PCP Week 12 visit and prior to the PCP Week 36 visit, the investigator becomes aware of an 
increase in UC disease activity outside the normal visit schedule in a subject on IP, then a subject may also be 
evaluated at an Unscheduled UC Disease Activity Criteria Assessment visit as specified in the SoA 
(Section 1.3.1).  
• 
Endoscopic subscores will be assessed by both a central reader (who is blinded to treatment assignment, visit, 
and subject symptoms) and local endoscopist (who is blinded to treatment assignment). Differences between the 
local endoscopist and the central reader will be adjudicated by a second blinded central reader as described in 
the Imaging Charter. 


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APPENDIX 9. 
GUIDANCE TO ADDRESS A PANDEMIC OR OTHER GLOBAL 
HEALTH EMERGENCIES AND POTENTIAL IMPACT ON THE 
CLINICAL STUDY 
In the occurrence of a global health emergency affecting the conduct of the ongoing study, such as the 
COVID-19 pandemic, study conduct may be adjusted due to subjects being in self-
isolation/quarantine, limited access to public places (including hospitals) due to the risk of spreading 
infections, and health care professionals being committed to critical tasks. 
Adjustments to the GB004-2101 protocol may be made as described below, in line with global 
regulatory authorities guidance in order to ensure the safety of study participants, maintain compliance 
with GCP, and minimize the risks to study integrity during the COVID-19 pandemic (EMA, April 
2020; FDA, March 2020; Health Canada, 03 April 2020; MHRH, 22 April 2020). Member states 
within the National Competent Authorities may issue their own guidance requiring country specific 
recommendations to be followed. 
Informed Consent 
• If written consent by the study subject is not possible (for example because of physical 
isolation due to COVID-19 or other global health emergencies), consent could be given 
orally by the study subject. 
• Study subjects and the person obtaining consent could sign and date separate ICFs. 
• In case a written informed consent cannot be obtained at the clinical site, electronic 
informed consent can be obtained remotely. Alternatively, the consent form may be 
sent to the subject or the subject’s legally authorized representative by facsimile or 
e-mail, and the consent interview may then be conducted by telephone/teleconference 
when the subject or subject’s legally authorized representative can read the consent 
form during the discussion; the subject or subject’s legally authorized representative 
will be requested to sign and date a blank piece of paper with a written statement 
affirming that they agree to participate in the study. 
• If re-consent is necessary for the implementation of new urgent changes in study 
conduct (mainly expected for reasons related to global health emergencies or important 
safety issues for other studies), alternative ways of obtaining may include contacting 
the study subject via phone or video-calls and obtaining oral consents, to be 
documented in the study subjects’ medical records, supplemented with e-mail 
confirmation. 
• The informed consent procedure is to remain compliant with the study protocol as well 
as local regulatory requirements. All relevant records should be archived in the 
investigator's site master file. A correctly signed and dated informed consent form 
should be obtained from the study subjects later, as soon as possible. 
Study Visits and Procedures 
• COVID-19 screening procedures that may be mandated by the health care system in 
which a clinical study is being conducted do not need to be reported as an amendment 
to the protocol even if done during clinical study visits. The Investigator in 


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consultation with the Sponsor will decide if it is in the best interest of COVID-positive 
subjects to remain in the study. 
• In the case of missed visits due to global health emergencies (or other health pandemic) 
related reasons: 
− The site should make every effort to contact the study subject to confirm and 
document the reason for the missed visit, and at minimum evaluate AEs/SAEs, and 
concomitant medications in order to assess subject safety. 
− The study subject should continue to collect the daily diary responses on the 
eDiary. 
• In order to maintain the integrity of the study, alternative methods of collecting study 
procedures may be considered where possible: 
− In cases where global health emergencies-related circumstances preclude a visit to 
the investigative site, remote visits (eg, by telemedicine or phone contact) will be 
allowed for relevant study procedures. 
− In certain situations, with Sponsor approval, and according to site business 
continuity plans, home visits may be used to collect laboratory samples and 
assessments as required by the protocol.  
− In certain situations, with Sponsor approval, a local laboratory may be used to 
collect laboratory samples as required by the protocol. Local analysis can be used 
for safety decisions. In addition, local laboratory can be used for study endpoints if 
samples drawn at the local laboratory cannot be shipped to the central laboratory. 
− Study assessments will only be conducted in a remote manner if they can be done 
without affecting the wellbeing of the subject during the study and with the same 
level of scientific integrity as assessments conducted in a physical study center.  
− Remote study assessments can be completed via online technology. The subject 
may interact with study personnel using online communication tools which 
incorporate telemedicine.  
− Serum pregnancy tests can be performed if urine pregnancy cannot be performed. 
− For flexible sigmoidoscopy assessments in the PCP at the PCP Week 12 visit, PCP 
Week 36 visit, Unscheduled UC Disease Activity Criteria Assessment visit(s) and 
Early Withdrawal from Study visit, other options such as mobile endoscopy may 
be considered with Sponsor’s approval. 
− If a subject is unable to complete the PCP Week 12 and/or Week 36 flexible 
sigmoidoscopy within the required timeframe (per SoA), there is flexibility to 
conduct the endoscopy up to 14 days beyond the visit window for the planned 
Week 12 and/or Week 36 timepoint while continuing on IP (if the subjects has not 
previously permanently discontinued IP); in this case, an unscheduled visit will be 
conducted at the planned Week 12 and/or Week 36 timepoint remotely (eg, by 
telemedicine) to collect AEs and concomitant medication (additional IP will be 


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dispensed as needed); the Week 12 and/or Week 36 visit assessments will be 
required at the clinic within 3 days post-endoscopy. 
Supply of Investigational Product 
• Alternative methods of supplying IP to enrolled study subjects (eg, direct-to-patient 
shipment from site) may be considered where possible. 
• Additional IP will not be released to the subject without an evaluation of subject 
safety, including protocol-required laboratory results (at a minimum hematology, 
clinical chemistries and pregnancy for WOCBP), and clearance communicated to 
the subject. Subjects must also consent for IP shipment. 
Monitoring and Audits 
• Certain Sponsor oversight responsibilities, such as monitoring and quality assurance 
activities need to be re-assessed and temporarily, alternative proportionate mechanisms of 
oversight may be required. On-site audits will be avoided or postponed, and if permitted 
under local regulations, social distancing restrictions should apply. 
• Cancelling or postponing of on-site monitoring visits and extending of the period between 
monitoring visits will be allowed. 
• To the extent on-site monitoring remains feasible, it should take into account national, 
local and/or organizational social distancing restrictions. 
• Centralized monitoring can be considered for data acquired by electronic data capture 
systems (eg, eCRFs, central laboratory or ECG / imaging data, electronic patient reported 
outcomes, etc.) that are in place or could be put in place provides additional monitoring 
capabilities that can supplement and temporarily replace on-site monitoring through a 
remote evaluation of ongoing and/or cumulative data collected from trial sites, in a timely 
manner. 
• Off-site monitoring can be conducted and will include phone calls, video visits, e-mails or 
other online tools in order to discuss the study with the investigator and site staff. Remote 
monitoring should be focused on review of critical study site documentation and 
source data. These activities could be used to get information on the clinical study 
progress, to exchange information on the resolution of problems, review of procedures, 
study subject status as well as to facilitate remote site selection and investigator training 
for critical study procedures. 
Risk Mitigation 
• The Sponsor will continually assess whether the limitations imposed by the COVID-19 
public health emergency on protocol implementation pose new safety risks to study 
subjects, and whether it is feasible to mitigate these risks by amending study processes 
and/or procedures. 


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APPENDIX 10. LIST OF ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
The terms IP and study drug are used interchangeably throughout this document.  
LIST OF ABBREVIATIONS  
DEFINITIONS OF TERMS 
5-ASA 
5-aminosalicylate 
ADME  
absorption, distribution, metabolism, elimination 
AE 
adverse event 
ALT 
alanine aminotransferase 
anti-TNF 
anti-tumor necrosis factor 
AST 
aspartate aminotransferase 
AUC 
area under the drug concentration versus time curve 
AUC(0-τ) 
area under the curve during a dose interval 
BID 
twice per day 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CI 
confidence interval 
CL/F 
total body clearance corrected for bioavailability 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD-EPI 
chronic kidney disease epidemiology collaboration 
CMC 
carboxy methyl cellulose 
CMH 
Cochran-Mantel-Haenszel 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
creatine phosphokinase  
CRP 
c-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
DR 
delayed-release or gastro-resistant 
DRC 
Data Review Committee 
DSS 
dextran sulfate sodium 
ECG 
electrocardiogram 


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LIST OF ABBREVIATIONS  
DEFINITIONS OF TERMS 
eCRF 
electronic case report form 
eDiary 
electronic diary 
eGFR 
estimated glomerular filtration rate 
EPO 
erythropoietin 
ET 
early termination 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase  
GI 
gastrointestinal 
HBsAg 
hepatitis B surface antigen 
HDPE 
high-density polyethylene 
HIF 
hypoxia inducible factor 
HIF-1α  
hypoxia inducible factor 1 alpha 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HPβCD 
2-hydroxypropyl-beta-cyclodextrin 
HRT 
hormone replacement therapy 
IB 
Investigator’s brochure 
IBD 
inflammatory bowel disease 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee  
IgG 
immunoglobulin G  
IgM 
Immunoglobulin M 
INR 
international normalized ratio  
IP 
investigational product 
IRB 
Institutional Review Board  
IRT 
interactive response technology 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
MAD 
multiple ascending dose 


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GB004, Inc.  
Protocol GB004-2101, Version 3.0, Amendment 2.0, 15 December 2021 
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LIST OF ABBREVIATIONS  
DEFINITIONS OF TERMS 
MMX 
multi-matrix 
NASH 
non-alcoholic steatohepatitis  
NOAEL 
no observed adverse effect level 
NSAID 
non-steroidal anti-inflammatory agents 
OLE 
open-label extension 
OTC 
over-the-counter 
PCP 
placebo-controlled period 
PD 
pharmacodynamics 
PGA 
Physician’s Global Assessment 
PGx 
pharmacogenetics 
PHD 
prolyl hydroxylase 
PHDi 
prolyl hydroxylase inhibitor 
PK 
pharmacokinetic 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RHI 
Robarts Histopathology Index 
RNA 
ribonucleic acid 
SAD 
single ascending dose 
SAE 
serious adverse event 
SNP 
single nucleotide polymorphism 
SoA 
Schedule of Activities  
SNP 
single nucleotide polymorphism 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2 
apparent terminal half-life 
Tmax 
time of occurrence of maximum observed concentration 
TE 
target engagement 
TEAE 
treatment-emergent adverse events 
TNBS 
trinitrobenzene sulfonic acid  
TNF-α 
tumor necrosis factor alpha  
UC 
ulcerative colitis 
UC-100 Index 
Ulcerative colitis 100 index 


GB004 (Oral) 
GB004, Inc.  
Protocol GB004-2101, Version 3.0, Amendment 2.0, 15 December 2021 
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Confidential 
LIST OF ABBREVIATIONS  
DEFINITIONS OF TERMS 
UGT 
uridine-diphosphoglucuronosyl transferase 
ULN 
upper limit of normal 
Vd/F 
oral apparent volume of distribution corrected for 
bioavailability 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cells 
WOCBP 
women of childbearing potential  


GB004 (Oral) 
GB004, Inc.  
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Confidential 
APPENDIX 11. PROTOCOL AMENDMENT HISTORY 
Amendment 1.0 (v2.0, 21 October 2020) 
Overall Rationale for the Amendment: 
The rationale for changes in this amendment includes primarily updates that extend the duration 
of the placebo-control period of the study and incorporate an open-label extension.  
Table 1: Summary of Changes 
Section # and Name 
Description of Change 
Brief Rationale 
Global change affecting all 
protocol sections, including, 
but not limited to: 
1 Protocol summary 
3 Objectives/endpoints 
4 Study design 
5 Eligibility criteria 
6 Investigational product 
7 Discontinuation of IP 
8. Study procedures 
9 Statistical consideration 
Extend the duration of 
placebo-controlled period 
(PCP) to 36 weeks and add a 
24-week open-label extension 
To evaluate the benefit-risk profile of 
GB004 compared to placebo with 
longer term dosing up to 36 weeks in 
terms of efficacy, safety, and 
tolerability, and to obtain further safety 
experience with the higher dose of 
GB004 (BID) in an open-label 
extension study 
1.1 Protocol synopsis 
1.3.1 SoA 
4.1 Overall study design 
Extend duration of screening 
period to 5 weeks 
To provide adequate time to complete 
all screening assessments 
2.3.2 Risk assessment 
Update risks 
To reflect emerging data and to align 
with the investigator’s brochure 
5.1 Inclusion criteria 
• 
Clarify age for inclusion 
• 
Add beclomethasone as 
allowed UC background 
therapy 
• 
To comply with different country 
regulations 
• 
To expand list of permitted 
background steroid therapy 
5.2 Exclusion criteria 
Exclude pregnant/lactating 
women 
To reflect that pregnant/lactating 
women should be excluded 
5.3 UC disease activity 
criteria 
Appendix 8 Instructions for 
calculating Mayo score for 
UC disease activity criteria 
assessment 
Add sections 
Part of modifying the study design 
(mentioned above) 
6.5.2 Background UC 
therapy 
Add tapering instructions for 
systemic steroids after PCP 
Week 12 
Part of modifying the study design 
(mentioned above) 


GB004 (Oral) 
GB004, Inc.  
Protocol GB004-2101, Version 3.0, Amendment 2.0, 15 December 2021 
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Section # and Name 
Description of Change 
Brief Rationale 
6.8 Concomitant therapy 
Delete section on CYP3A4 
Per emerging in vitro data suggesting 
that GB004 and its glucuronide 
metabolite have a low potential to 
inhibit CYP3A4 substrates 
8.1.3 RHI Score, Geboes 
Score and UC Index-100 
Add RHI calculation 
For clarity 
8.2.1 Physical examination 
Clarify and differentiate 
between complete and 
symptom-directed physical 
examination 
For clarity 
Appendix 9 Guidance to 
address a pandemic or other 
global health emergencies 
Update 
To reflect updated guidance by 
regulatory agencies 
General 
Minor clarifications 
throughout protocol 
Update list of abbreviations, 
formatting, hyperlinks 
For consistency and accuracy 
throughout protocol 


GB004 (Oral) 
GB004, Inc.  
Protocol GB004-2101, Version 3.0, Amendment 2.0, 15 December 2021 
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11. 
REFERENCES 
Ablin J, Shalev O, Okon E, Karmeli F, Rachmilewitz D. Deferiprone, an oral iron chelator, 
ameliorates experimental colitis and gastric ulceration in rats. Inflamm Bowel Dis. 
1999;5(4):253-261. 
 
Bernstein CN, Longobardi T, Finlayson G, Blanchard JF. Direct medical cost of managing IBD 
patients: a Canadian population-based study. Inflamm Bowel Dis. 2012;18(8):1498-1508. 
 
Danese S, Roda G, Peyrin-Biroulet L. Evolving therapeutic goals in ulcerative colitis: towards 
disease clearance. Nat Rev Gastroenterol Hepatol. 2020;17(1):1-2. 
 
de Mattos BR, Garcia MP, Nogueira JB, et al. Inflammatory bowel disease: an overview of 
immune mechanisms and biological treatments. Mediators Inflamm. 2015;2015:493012. 
 
Eltzschig HK, Bratton DL, Colgan SP. Targeting hypoxia signalling for the treatment of 
ischaemic and inflammatory diseases. Nat Rev Drug Discov. 2014;13(11):852-869. 
 
EMA. Guidance on the management of clinical trials during the COVID-19 (Coronavirus) 
pandemic, version 3, released 28 April 2020. Agency EM. April 2020. 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials covid19 en.pdf. 
 
FDA. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency – Guidance for Industry, Investigators and Institutional Review 
Boards. Updated April 16, 2020. U.S. Department of Health and Human Services Food and Drug 
Administration Center for Drug Evaluation and Research (CDER). March 2020. 
https://www.fda.gov/media/136238/download. 
 
Health Canada. Management of clinical trials during the COVID-19 pandemic: Notice to clinical 
trial sponsors. 03 April 2020. https://www.canada.ca/en/health-canada/services/drugs-health-
products/drug-products/announcements/management-clinical-trials-during-covid-19-
pandemic.html. 
 
Heyman MB, Kirschner BS, Gold BD, et al. Children with early-onset inflammatory bowel 
disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr. 2005;146(1):35-40. 
 
Jain S, Ahuja V, Limdi JK. Optimal management of acute severe ulcerative colitis. Postgrad 
Med J. 2019;95(1119):32-40. 
 
Jairath V, Jeyarajah J, Zou G, et al. A composite disease activity index for early drug 
development in ulcerative colitis: development and validation of the UC-100 score. Lancet 
Gastroenterol Hepatol. 2019;4(1):63-70. 
 
Kaplan GG, Seow CH, Ghosh S, et al. Decreasing colectomy rates for ulcerative colitis: a 
population-based time trend study. Am J Gastroenterol. 2012;107(12):1879-1887. 


GB004 (Oral) 
GB004, Inc.  
Protocol GB004-2101, Version 3.0, Amendment 2.0, 15 December 2021 
92 
Confidential 
 
Kelsen JR, Sullivan KE, Rabizadeh S, et al. North American Society for Pediatric 
Gastroenterology, Hepatology, and Nutrition Position Paper on the evaluation and management 
for patients with very early-onset inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 
2020;70(3):389-403. 
 
Kirchgesner J, Lemaitre M, Carrat F, Zureik M, Carbonnel F, Dray-Spira R. Risk of serious and 
opportunistic infections associated with treatment of inflammatory bowel diseases. 
Gastroenterology. 2018;155(2):337-346.e310. 
 
Ko CW, Singh S, Feuerstein JD, et al. AGA Clinical Practice Guidelines on the management of 
mild-to-moderate ulcerative colitis. Gastroenterology. 2019;156(3):748-764. 
 
Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College Of 
Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105(3):501-523. 
 
Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus 
guidelines on the management of inflammatory bowel disease in adults. Gut. 2019;68(Suppl 
3):s1-s106. 
 
Levesque BG, Ghosh S. Targeting integrins and safety in an emerging class of targeted oral 
therapies: are we prepared for rational and precision choices? Gastroenterology. 
2015;149(7):1669-1672. 
 
Lewis JD, Chuai S, Nessel L, Lichtenstein GR, Aberra FN, Ellenberg JH. Use of the noninvasive 
components of the Mayo score to assess clinical response in ulcerative colitis. Inflammatory 
bowel diseases. 2008;14(12):1660-1666. 
 
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of 
disease. J Natl Cancer Inst. 1959;22(4):719-748. 
 
Mantel N, Fleiss JL. Minimum expected cell size requirements for the Mantel-Haenszel one-
degree-of-freedom chi-square test and a related rapid procedure. Am J Epidemiol. 
1980;112(1):129-134. 
 
MHRH. Guidance: Managing clinical trials during Coronavirus (COVID-19). 22 April 2020. 
https://www.gov.uk/guidance/managing-clinical-trials-during-coronavirus-covid-19. 
 
Minaiyan M, Mostaghel E, Mahzouni P. Preventive therapy of experimental colitis with selected 
iron chelators and anti-oxidants. Int J Prev Med. 2012;3(Suppl 1):S162-S169. 
 
Mosli MH, Feagan BG, Zou G, et al. Development and validation of a histological index for UC. 
Gut. 2017;66(1):50-58. 
 
Newcombe RG. Interval estimation for the difference between independent proportions: 
comparison of eleven methods. Stat Med. 1998;17(8):873-890. 
 


GB004 (Oral) 
GB004, Inc.  
Protocol GB004-2101, Version 3.0, Amendment 2.0, 15 December 2021 
93 
Confidential 
Ng SC, Kamm MA. Therapeutic strategies for the management of ulcerative colitis. Inflamm 
Bowel Dis. 2009;15(6):935-950. 
 
Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly 
to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987;317(26):1625-
1629. 
 
Shen B, Lashner BA. Diagnosis and treatment of pouchitis. Gastroenterology & hepatology. 
2008;4(5):355-361. 
 
Singh S, Al-Darmaki A, Frolkis AD, et al. Postoperative mortality among patients with 
inflammatory bowel diseases: a systematic review and meta-analysis of population-based 
studies. Gastroenterology. 2015;149(4):928-937. 
 
Singh S, Feuerstein JD, Binion DG, Tremaine WJ. AGA technical review on the management of 
mild-to-moderate ulcerative colitis. Gastroenterology. 2019;156(3):769-808.e729. 
 
Turner D, Griffiths AM. Acute severe ulcerative colitis in children: a systematic review. Inflamm 
Bowel Dis. 2011;17(1):440-449. 
 
Whaley KG, Rosen MJ. Contemporary medical ,anagement of acute severe ulcerative colitis. 
Inflamm Bowel Dis. 2019;25(1):56-66. 
 
Wilson EB. Probable Inference, the Law of Succession, and Statistical Inference. J Amer Statis 
Assoc. 1927;22(158):209-212. 
 
 

SAP_001.pdf: 
Version: GB004-2101 PCP SAP_FINAL_V1.0_11APR2022.docx 
Page 1 of 61 
STATISTICAL ANALYSIS PLAN  
FOR 
PLACEBO-CONTROLLED PERIOD WEEK 12 ANALYSIS  
AND  
PLACEBO-CONTROLLED PERIOD FINAL ANALYSIS 
 
FINAL 
(Version 1.0) 
11 April 2022 
 
Protocol Number:  GB004-2101 
(Version 3.0, 15 December 2021) 
 
 
A Phase 2, randomized, double-blind, placebo-controlled, multi-center study 
to evaluate GB004 in adult subjects with mild-to-moderate active ulcerative 
colitis 
 
 
 
SPONSORED BY 
 
GB004, Inc., a wholly owned subsidiary of Gossamer Bio, Inc. 
 
 
 
PREPARED BY 
 
Gossamer Bio Services, Inc. 
 
 
 
 
 
 
 
 
 
This document is confidential and proprietary to GB004, Inc.  Acceptance of this document constitutes agreement by 
the recipient that no unpublished information contained herein will be reproduced, published, or otherwise disclosed 
without the prior written approval of GB004, Inc. 
 


GB004, Inc. 
 
PCP Statistical Analysis Plan 
Protocol No. GB004-2101 
 
 
 
 
 
      11 April 2022 
Version: GB004-2101 PCP SAP_FINAL_V1.0_11APR2022.docx 
 
Page 2 of 61 
VERSION CONTROL 
 
 
Version Number 
Date 
Comments/Changes 
1.0 
11 April 2022 
Final 
 




GB004, Inc. 
 
PCP Statistical Analysis Plan 
Protocol No. GB004-2101 
 
 
 
 
 
      11 April 2022 
Version: GB004-2101 PCP SAP_FINAL_V1.0_11APR2022.docx 
 
Page 4 of 61 
TABLE OF CONTENTS 
VERSION CONTROL ....................................................................................................................2 
APPROVALS ..................................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
INTRODUCTION ......................................................................................................11 
2. 
PROTOCOL SUMMARY ..........................................................................................11 
2.1. 
Placebo-Controlled Period Objectives and Endpoints ................................................11 
2.2. 
Efficacy Endpoint Definitions ....................................................................................14 
2.3. 
Overall Study Design and Plan ...................................................................................17 
2.3.1. 
Placebo-Controlled Period Study Design and Plan ....................................................17 
2.4. 
Study Population .........................................................................................................18 
2.5. 
Randomization, Stratification, and Blinding ..............................................................19 
2.5.1. 
Randomization and Stratification ...............................................................................19 
2.5.2. 
Blinding ......................................................................................................................19 
2.6. 
Sample Size Determination ........................................................................................19 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..............................20 
3.1. 
Determination of Data for Inclusion in Placebo-Controlled Period Analyses ...........22 
3.1.1. 
Placebo-Controlled Period Week 12 Analysis ...........................................................22 
3.1.2. 
Placebo-Controlled Period Final Analysis..................................................................22 
3.2. 
Analysis Visit Windowing ..........................................................................................22 
3.3. 
Standard Calculations .................................................................................................24 
3.4. 
Considerations Related to the COVID-19 Pandemic .................................................24 
4. 
ANALYSIS POPULATIONS ....................................................................................26 
4.1. 
All Enrolled Population ..............................................................................................26 
4.2. 
PCP Intent-to-Treat Population ..................................................................................26 
4.3. 
PCP Safety Population ................................................................................................26 
5. 
STUDY SUBJECTS ...................................................................................................27 
5.1. 
Disposition of Subjects ...............................................................................................27 
5.1.1. 
Placebo-Controlled Period Week 12 Analysis ...........................................................27 
5.1.2. 
Placebo-Controlled Period Final Analysis..................................................................28 


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5.2. 
Major Protocol Deviations ..........................................................................................28 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .....................28 
6.1. 
Demographic and Baseline Characteristics ................................................................28 
6.2. 
Baseline Disease Characteristics ................................................................................29 
6.3. 
Baseline Mayo Score and Subscores ..........................................................................29 
6.4. 
Baseline Histologic Activity .......................................................................................31 
6.5. 
UC Treatment History ................................................................................................32 
6.6. 
Medical History ..........................................................................................................33 
6.7. 
Prior and Concomitant Medications ...........................................................................33 
6.7.1. 
Concomitant Background UC Medications ................................................................34 
7. 
EXTENT OF EXPOSURE, COMPLIANCE, AND TIME ON STUDY ..................34 
7.1. 
Duration of Study Treatment ......................................................................................34 
7.2. 
Compliance .................................................................................................................36 
7.3. 
Prescribed Dose Modifications ...................................................................................36 
7.4. 
Time on Study .............................................................................................................37 
8. 
EFFICACY EVALUATION ......................................................................................38 
8.1. 
Overview of Efficacy Analysis Issues ........................................................................38 
8.1.1. 
Handling of Dropouts or Missing Data ......................................................................38 
8.1.1.1. 
Proportion-Based (Binary) Efficacy Endpoints ..........................................................38 
8.1.1.2. 
Change from Baseline (Continuous) Efficacy Endpoints ...........................................38 
8.1.2. 
Multicenter Studies .....................................................................................................38 
8.1.3. 
Multiple Comparisons/Multiplicity ............................................................................38 
8.1.4. 
Handling of Intercurrent Events (Treatment Failure Rules) .......................................39 
8.2. 
Efficacy Endpoints ......................................................................................................40 
8.3. 
Analysis Methods .......................................................................................................41 
8.3.1. 
Primary Endpoint ........................................................................................................41 
8.3.1.1. 
Primary Analysis ........................................................................................................41 
8.3.1.2. 
Sensitivity Analyses ....................................................................................................42 
8.3.1.2.1. 
Sensitivity Analysis #1: NRI Applied without ICE Handling Applied ......................43 
8.3.1.2.2. 
Sensitivity Analysis #2: ICE Handling without NRI Applied ....................................43 
8.3.1.2.3. 
Sensitivity Analysis #3: As-Observed Analysis without ICE Handling or 
NRI Applied ................................................................................................................44 


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8.3.1.2.4. 
Sensitivity Analysis #4: Logistic Regression with ICE Handling and NRI 
Applied .......................................................................................................................44 
8.3.2. 
Secondary Endpoints ..................................................................................................44 
8.3.2.1. 
Primary Analysis ........................................................................................................44 
8.3.2.2. 
Sensitivity Analyses ....................................................................................................44 
8.3.3. 
Potential Additional Sensitivity Analysis of Primary and Secondary 
Endpoints ....................................................................................................................45 
8.3.4. 
Exploratory Endpoints ................................................................................................46 
8.3.4.1. 
Exploratory Efficacy Endpoints .................................................................................46 
8.3.4.1.1. 
Proportion-Based (Binary) Exploratory Efficacy Endpoints ......................................46 
8.3.4.1.2. 
Change from Baseline (Continuous) Exploratory Efficacy Endpoints .......................46 
8.3.4.2. 
Pharmacokinetic Concentrations ................................................................................47 
8.4. 
Examination of Subgroups .........................................................................................47 
8.5. 
Efficacy Assessments .................................................................................................50 
8.5.1. 
Mayo Score .................................................................................................................50 
8.5.1.1. 
Mayo Subscores ..........................................................................................................51 
8.5.1.1.1. 
Physician’s Global Assessment ..................................................................................51 
8.5.1.1.2. 
Stool Frequency and Rectal Bleeding Score ..............................................................52 
8.5.1.1.3. 
Endoscopic Subscore ..................................................................................................52 
8.5.2. 
Histologic Assessments ..............................................................................................52 
8.5.2.1. 
Robarts Histopathology Index ....................................................................................52 
8.5.2.2. 
Geboes Score ..............................................................................................................54 
8.5.3. 
UC-100 Index .............................................................................................................55 
9. 
SAFETY EVALUATION ..........................................................................................55 
9.1. 
Adverse Events ...........................................................................................................55 
9.2. 
Clinical Laboratory Evaluation ...................................................................................57 
9.3. 
Vital Signs ..................................................................................................................58 
9.4. 
12-Lead ECGs ............................................................................................................59 
10. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .....................59 
11. 
REFERENCES ...........................................................................................................60 
 


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LIST OF TABLES 
Table 1: 
Placebo-Controlled Period Objectives and Endpoints ................................................12 
Table 2: 
Placebo-Controlled Period Efficacy Endpoint Definitions .........................................15 
Table 3: 
Efficacy Endpoints and Analysis Methods .................................................................40 
Table 4: 
Summary of Primary and Sensitivity Analyses of the Primary Endpoint ..................43 
Table 5: 
Subgroup Analyses .....................................................................................................48 
Table 6: 
Calculation of Mayo Scores........................................................................................50 
Table 7: 
RHI Scoring in Relation to Geboes Score ..................................................................53 
Table 8: 
Geboes Score ..............................................................................................................54 
Table 9: 
Vital Sign Parameter Abnormality Criteria ................................................................59 
 
  
 
 


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      11 April 2022 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
5-ASA 
5-aminosalicylate 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
AUC 
area under the drug concentration versus time curve 
BID 
twice per day 
BMI 
body mass index 
bpm 
beats per minute 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
maximum observed concentration 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus Disease 2019 
CRP 
C-reactive protein 
CSR 
clinical study report 
DRC 
data review committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
eDISH 
evaluation of drug-induced serious hepatotoxicity 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EPO 
erythropoietin  
FDA 
Food and Drug Administration 
GGT 
gamma-glutamyl transferase 
Hg 
mercury 
HIF-1α 
Hypoxia-inducible factor 1 alpha 
ICE 
intercurrent event 
ICH 
International Conference on Harmonisation 


GB004, Inc. 
 
PCP Statistical Analysis Plan 
Protocol No. GB004-2101 
 
 
 
 
 
      11 April 2022 
Version: GB004-2101 PCP SAP_FINAL_V1.0_11APR2022.docx 
 
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Abbreviation 
Definition 
IP 
investigational product 
IRT 
interactive response technology 
ITT 
intent-to-treat 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MAR 
missing at random 
MI 
multiple imputation 
MNAR 
missing not at random 
MPO 
myeloperoxidase 
NRI 
non-responder imputation 
OLE 
Open-Label Extension 
OR 
odds ratio 
PCP 
Placebo-Controlled Period 
PGA 
Physician’s Global Assessment 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBS 
rectal bleeding subscore 
RHI 
Robarts Histopathology Index 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCr 
serum creatinine 
SD 
standard deviation 
SE 
standard error 
SFS 
stool frequency subscore 
SoA 
schedule of activities 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
Tmax 
time of occurrence of maximum observed concentration 
UC 
ulcerative colitis  
UC-100 
Ulcerative Colitis 100 index 


GB004, Inc. 
 
PCP Statistical Analysis Plan 
Protocol No. GB004-2101 
 
 
 
 
 
      11 April 2022 
Version: GB004-2101 PCP SAP_FINAL_V1.0_11APR2022.docx 
 
Page 10 of 61 
Abbreviation 
Definition 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 
WHO 
World Health Organization 
 


GB004, Inc. 
 
PCP Statistical Analysis Plan 
Protocol No. GB004-2101 
 
 
 
 
 
      11 April 2022 
Version: GB004-2101 PCP SAP_FINAL_V1.0_11APR2022.docx 
 
Page 11 of 61 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of the 
statistical methodology to be used for analysis and reporting of study results for the Placebo-
Controlled Period (PCP) Week 12 Analysis and PCP Final Analysis of Study GB004-2101 and is 
based on protocol version 3.0 dated 15 December 2021. 
This SAP has been finalized and approved prior to unblinding of the Sponsor for the PCP 
Week 12 Analysis. A separate SAP describes the statistical methodology to be used for analysis 
and reporting of study results for the Open-Label Extension (OLE) Final Analysis. The 
3 separate formal statistical analyses to be performed for the study (PCP Week 12 Analysis, PCP 
Final Analysis, and OLE Final Analysis) are described in Protocol Section 9.4. 
Results to be reported will include summaries of subject disposition, demographic and baseline 
characteristics, major protocol deviations, prior and concomitant medications, medical history, 
duration of study treatment exposure and compliance, and primary, secondary, safety, and select 
exploratory endpoints.   
If additional analyses are required to supplement the planned analyses described in this SAP, 
they will be completed and identified in the clinical study report (CSR) as post hoc. 
This SAP was written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline (ICH E9, 1998) entitled 
Guidance for Industry E9 Statistical Principles for Clinical Trials, the most recent ICH E9(R1) 
Guideline (ICH E9(R1), 2019) entitled Addendum on Estimands and Sensitivity Analyses in 
Clinical Trials to the Guideline on Statistical Principles for Clinical Trials, and the most recent 
ICH E3 Guideline (ICH E3, 1995) entitled Guidance for Industry Structure and Content of 
Clinical Study Reports.  
In this document, investigational product (IP) and study treatment have the same meaning and 
refer to placebo, GB004 480 mg once daily (QD), and GB004 480 mg twice per day (BID). 
2. 
PROTOCOL SUMMARY 
This is a Phase 2, randomized, double-blind, placebo-controlled, multi-center study to evaluate 
GB004 in adult subjects with mild-to-moderate active ulcerative colitis (UC). The study consists 
of two parts, a 36-week placebo-controlled period and a 24-week open-label extension period, 
and will assess the efficacy and safety of GB004 when added to background UC therapy of 
5-aminosalicylate (5-ASA) with or without systemic corticosteroids. 
2.1. 
Placebo-Controlled Period Objectives and Endpoints 
Table 1 below, from Protocol Section 3.1, lists the PCP objectives and endpoints. 


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Table 1: 
Placebo-Controlled Period Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the effect of GB004 
compared to placebo on clinical 
remission at PCP Week 12 
• 
Proportion of subjects with clinical remission at PCP 
Week 12, defined as a Modified Mayo score ≤ 2, 
with a Rectal bleeding subscore of 0, Stool 
frequency subscore of 0 or 1 (with a ≥ 1 point 
decrease from baseline), and Endoscopic subscore 
of 0 or 1 
Secondary 
• 
To evaluate the effect of GB004 on 
clinical response, histologic 
remission, endoscopic improvement 
and mucosal healing at PCP 
Week 12   
• 
Proportion of subjects with clinical response at PCP 
Week 12, defined as reduction in the Modified Mayo 
score of ≥ 2 points and ≥ 35 percent reduction from 
baseline, including a decrease in Rectal bleeding 
subscore of ≥1 or absolute Rectal bleeding subscore 
of ≤ 1 
• 
Proportion of subjects with histologic remission at 
PCP Week 12, defined as Robarts Histopathology 
Index (RHI) ≤ 3 with lamina propria neutrophils 
subscore = 0 and neutrophils in epithelium 
subscore = 0 
• 
Proportion of subjects with endoscopic improvement 
at PCP Week 12, defined as endoscopic subscore 
of 0 or 1 
• 
Proportion of subjects with mucosal healing at PCP 
Week 12, defined as endoscopic improvement and 
histologic remission  
• 
To evaluate the effect of GB004 on 
clinical remission, clinical response, 
histologic remission, endoscopic 
improvement, and mucosal healing 
at PCP Week 36 
• 
Proportion of subjects with clinical remission at PCP 
Week 36 
• 
Proportion of subjects with clinical response at PCP 
Week 36 
• 
Proportion of subjects with histologic remission at 
PCP Week 36 
• 
Proportion of subjects with endoscopic improvement 
at PCP Week 36 
• 
Proportion of subjects with mucosal healing at PCP 
Week 36 
Safety 
• 
To evaluate the safety and 
tolerability of GB004 
• 
Incidence of treatment emergent adverse events 
(TEAEs) 


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Objectives 
Endpoints 
Exploratory 
• 
To evaluate other safety outcomes 
• 
Change from Baseline in laboratory, vital signs, and 
electrocardiogram (ECG) parameters 
• 
To explore other measures of the 
effect of GB004 on disease activity 
over time 
• 
Proportion of subjects with resolution of Rectal 
bleeding  
• 
Proportion of subjects with histologic response  
• 
Proportion of subjects with Geboes score ≤ 2  
• 
Proportion of subjects with steroid-free clinical 
remission at PCP Week 36 
• 
Proportion of subjects with clinical remission by 
Mayo score and resolution of rectal bleeding  
• 
Proportion of subjects with clinical remission by 
Mayo score  
• 
Proportion of subjects with clinical response by 
Mayo score  
• 
Proportion of subjects with Modified Mayo score of 
≤ 2, with no individual subscore > 1  
• 
Proportion of subjects with disease clearance  
• 
Proportion of subjects with symptomatic remission  
• 
Proportion of subjects with modified symptomatic 
remission  
• 
Proportion of subjects with Partial Mayo remission 
• 
Proportion of subjects with reduction of ≥ 2 points 
from baseline in partial Mayo score  
• 
Proportion of subjects with a 6-point Mayo score 
clinical remission  
• 
Change from Baseline in Modified Mayo score  
• 
Change from Baseline in Mayo score  
• 
Change from Baseline in Partial Mayo score over 
time 
• 
Change from Baseline in Mayo subscores over time 
• 
Change from Baseline in RHI score  
• 
Change from Baseline in the UC-100 Index  
• 
To explore the pharmacokinetics 
(PK) of GB004 
• 
Plasma and colon tissue concentrations of GB004 


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Objectives 
Endpoints 
• 
To explore target engagement and 
pharmacodynamic response 
• 
Change from baseline in tissue and blood markers of 
target engagement, eg, HIF-1α, EGLN1-2-3, etc. 
• 
Change from baseline in markers of 
pharmacodynamics, eg, fecal calprotectin, fecal 
lactoferrin, and neutrophil activity 
(myeloperoxidase) 
• 
Change from baseline in tissue, blood, and stool in 
downstream genes and proteins, eg, CAIX, MPO, c-
reactive protein (CRP), TJP, CLDN1, etc. as a 
function of exposure (Cmax, Tmax, AUC), efficacy 
endpoints (eg, clinical remission, clinical response), 
and/or safety endpoints 
• 
To explore baseline markers with 
response to treatment with GB004 
• 
Relationship between tissue, blood, and stool 
baseline markers (eg, HIF-1α, EGLN1-2-3, 
calprotectin, etc.) and response to treatment, as 
measured by efficacy endpoints (eg, clinical 
remission, clinical response), and/or safety endpoints 
• 
To explore pharmacogenetics 
• 
Effect of naturally occurring genetic variation on the 
efficacy (eg, clinical remission, clinical response), 
safety, and/or PK profile (Cmax, Tmax, AUC) and 
tissue concentrations associated with treatment with 
GB004 
The last three Exploratory objectives listed in Table 1 above and their corresponding endpoints 
will not be addressed in this SAP, with the exception of the endpoints for change from baseline 
in fecal calprotectin, fecal lactoferrin, and CRP. 
2.2. 
Efficacy Endpoint Definitions 
Table 2 below, from Protocol Section 3.3, defines the PCP efficacy endpoints.  








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• Placebo 
Randomization will be stratified by systemic corticosteroid use at baseline (yes/no). 
All subjects will dose IP BID to maintain the blind.  
The first dose of IP will be administered in the clinic on Day 1/Week 0 with food. All subsequent 
doses will be taken at home with food, with the exception of the morning doses at the Week 2, 4, 
8, 12, and 36 visits where IP will be administered in the clinic, with food, after predose blood 
collection. 
After initiation of IP on Day 1/Week 0, subjects will return to the clinic and will be evaluated as 
specified in the Schedule of Activities (SoA) of the protocol. A flexible sigmoidoscopy with 
biopsies will be performed at the PCP Week 12 and Week 36 visits (and at the Unscheduled UC 
Disease Activity Criteria Assessment visit(s) and at the Early Withdrawal from Study visit, if 
applicable). 
Subjects who permanently discontinue PCP IP without enrolling in the OLE will be encouraged 
to continue in the PCP and will complete the Early Discontinuation of IP visit at the time of IP 
discontinuation and then complete the remaining PCP study visits per the SoA. At subsequent 
visits, all study procedures will be completed per the SoA excluding dispensation/return and 
accountability of IP. 
Subjects who withdraw from the PCP without enrolling in the OLE, regardless of the reason, will 
be requested to return to the clinic to complete the Early Withdrawal from Study visit and will be 
asked to return for a Follow-up visit approximately 4 weeks after their last dose of IP to assess 
safety. 
Total duration for PCP participation per subject is up to 45 weeks, including a Screening period 
of up to 5 weeks, a treatment period of up to 36 weeks, and a 4-week safety Follow-up period.   
Subjects may participate in the 24-week OLE if in the opinion of the Investigator they have been 
compliant with study procedures and: 
• Completed the Week 36 visit on IP; or 
• Met the predefined UC Disease Activity criteria any time after PCP Week 12 visit 
and prior to PCP Week 36 visit on IP. 
2.4. 
Study Population  
The study population consists of adult subjects with mild-to-moderate active UC who have 
disease activity despite treatment with 5-ASA with or without prednisone (or equivalent), 
beclomethasone, budesonide, or budesonide multi-matrix. Mild-to-moderate UC is defined as a 
Mayo score of 5-10, inclusive, with an Endoscopic subscore of ≥ 2, a stool frequency 
subscore ≥ 1, and a Rectal bleeding subscore ≥ 1. 


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2.5. 
Randomization, Stratification, and Blinding 
2.5.1. 
Randomization and Stratification 
The study will randomize approximately 195 subjects, with approximately 65 subjects per 
treatment group, in a 1:1:1 ratio to GB004 480 mg BID, GB004 480 mg QD, and Placebo. 
Randomization will be performed utilizing permuted block randomization via an interactive 
response technology (IRT) system. Randomization will be stratified by systemic corticosteroid 
use at baseline (yes/no).    
2.5.2. 
Blinding 
The PCP is considered double-blind through PCP Week 12, as the study will be unblinded to the 
Sponsor at the time of the PCP Week 12 Analysis. The Sponsor (with exceptions described 
below) will be blinded to individual subject treatment assignments until the PCP Week 12 
Analysis. Subjects, investigators and site personnel, personnel performing central endoscopic 
and histologic evaluations, and personnel performing central laboratory and ECG evaluations 
will remain blinded to individual subject treatment assignments throughout the PCP.   
Sponsor (or designee) personnel will have access to unblinded individual subject treatment 
assignments prior to unblinding of the Sponsor at the time of the PCP Week 12 Analysis for the 
purposes of study-required activities, including management of IP inventory, production of 
summaries of data for DRC review, performance of bioanalytical analysis of PK and 
gene/protein concentrations, and performance of population pharmacokinetic modeling, for 
which subject level treatment assignment data will be provided to clinical pharmacology 
personnel performing the modeling using only pseudonymized (also known as dummy) subject 
identifiers. These personnel will not be directly involved in the conduct of the study. The DRC, 
comprised of Sponsor representatives not directly involved in the conduct of the study and 
external expert physicians, will have access to unblinded study results and data during the course 
of the study.     
2.6. 
Sample Size Determination 
A total sample size of approximately 195 subjects (approximately 65 per treatment group, 
randomized 1:1:1, with stratification by systemic corticosteroid use at baseline [yes/no]) is 
estimated to provide approximately 80% power to detect a difference of 20.4% between each 
GB004 treatment group and placebo for the primary endpoint of proportion of subjects with 
clinical remission at PCP Week 12 based on a chi-squared test at an 0.050 two-sided level of 
significance. This assumes the proportion of subjects with clinical remission at PCP Week 12 is 
10% in the placebo group and 30.4% in each GB004 treatment group and a dropout rate by PCP 
Week 12 of approximately 8%. Subjects with missing clinical remission status at PCP Week 12 
will be considered as having not met the primary endpoint. 
Using the same sample size assumptions as above for the primary endpoint of proportion of 
subjects with clinical remission at PCP Week 12 (ie, a difference of 20.4% between each GB004 
treatment group and placebo, with a 10% proportion in the placebo group), there will be 
approximately 80% power for the secondary endpoint of the proportion of subjects with clinical 
remission at PCP Week 36 based on a chi-squared test at an 0.050 two-sided level of 


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significance. Subjects with missing clinical remission status at PCP Week 36 will be considered 
as having not met the endpoint.  
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
Three separate formal statistical analyses will be performed as described in Protocol Section 9.4: 
• The PCP Week 12 Analysis will be conducted after all subjects either complete the 
PCP Week 12 visit or withdraw from the study prior to completion of the PCP 
Week 12 visit. This analysis will evaluate endpoints at or up through PCP Week 12. 
• The PCP Final Analysis will be conducted after all subjects either complete the PCP 
or withdraw from the study prior to completion of the PCP; This analysis will 
evaluate all PCP endpoints. 
• The OLE Final Analysis will be conducted after all subjects either complete the OLE 
period or withdraw from the study prior to completion of the OLE period. This 
analysis will evaluate all OLE endpoints. 
This SAP governs the PCP Week 12 Analysis and the PCP Final Analysis. 
All analyses will be performed using SAS® System (SAS Institute Inc., Cary, NC) version 9.4 or 
later. 
By-subject listings described in this SAP will be produced for the PCP Final Analysis only. 
Categorical variables (ie, those with discrete categories or levels, whether nominal or ordinal) 
will generally be summarized using descriptive statistics of counts (n) and percentages (%) and 
will be presented in the format “n (xx.x)”. To ensure completeness, summaries for categorical 
variables may include all categories, even if no subjects had a value in a particular category.  
Additionally, for missing data, a category of “Missing” will be presented as needed. Percentages 
will be rounded to one decimal place. If a count is zero, no percentage will be shown, and if a 
percentage is 100%, 100.0% will be shown. 
Continuous variables will generally be summarized using descriptive statistics: number of 
subjects with non-missing data (n), mean, standard deviation (SD), median, 25th and 75th 
percentiles, minimum, and maximum. Descriptive statistics on select measures may also include 
stool standard errors (SEs) and two-sided, 95% confidence intervals (CIs). In general, rounding 
rules for reporting continuous descriptive summary statistics are as follows: 
• If the original values have 0 or 1 decimal places: mean, median, 25th and 
75th percentiles will be reported to one more decimal place than the original values, 
and SD and SE will be reported to 2 more decimal places than the original values. 
• If the original values have 2 or more decimal places: mean, median, 25th and 75th 
percentiles, SD, and SE will all be reported to 3 decimal places. 
Original values include both reported raw data values and derived values. In the case of derived 
values, an appropriate determination for precision will be made based on the reported raw data 
values used for derivation. Minimum and maximum will always be reported to the same number 
of decimal places as the original values, up to a maximum of 3 decimal places. Percent change 


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from baseline will be reported to 1 more decimal place than change from baseline, up to a 
maximum of 3 decimal places. 
Efficacy results will be summarized by various measures, including, but not limited to, absolute 
differences in proportions, odds ratios (ORs), least squares (LS) means, differences in LS means, 
SEs, p-values, and two-sided, 95% CIs. Absolute differences in proportions and corresponding 
CIs will be reported to 1 decimal place. ORs and their corresponding CIs will be reported to 
3 decimal places. Least squares means and differences in LS means and their corresponding CIs 
and SEs will be reported per the rules above, with the CIs following the same rounding rules as 
the corresponding means. P-values will be reported to 4 decimal places, with values less than 
0.0001 displayed as < 0.0001 and values greater than 0.9999 displayed as > 0.9999. All 
statistical hypothesis testing for efficacy endpoints will be at an 0.050 two-sided level of 
significance.     
Summaries of subject disposition, major protocol deviations, demographic and other baseline 
characteristics, UC treatment history, and concomitant UC background medications at baseline 
will be presented by randomized treatment group and will also include an overall column 
combining all treatment groups. Summaries of medical history and prior medications will be 
presented by actual treatment group and will include an overall column combining all treatment 
groups. Summaries of concomitant medications, duration of study treatment, compliance, 
prescribed dose modifications, and time on study will be presented by actual treatment group and 
will also include a total GB004 column combining both GB004 treatment groups. Efficacy tables 
will be presented by randomized treatment group only. Safety tables will be presented by actual 
treatment group and, in general, will also include a total GB004 column combining both GB004 
treatment groups.   
When appropriate, sorting of non-ordinal categorical variables in tables will be based on 
decreasing frequency within the overall column. In general, adverse event (AE) tables that are 
displayed by system organ class (SOC) and preferred term (PT) will be sorted by the 
internationally agreed order for SOC, and by decreasing incidence and then alphabetically for PT 
within SOC in the total GB004 column. Otherwise, AE tables, when applicable, will be sorted by 
decreasing incidence within the total GB004 column. 
In general, assessments at the PCP Day 1 visit are to be performed prior to the first dose of study 
treatment at the PCP Day 1 visit. Therefore, the baseline value is defined as the last non-missing 
value on or before the first dose of PCP study treatment, unless otherwise specified. 
For analyses of change from baseline and percent change from baseline parameters, only subjects 
with a baseline value and at least one post-baseline value will be included. For maximum 
post-baseline analyses, only subjects with at least one post-baseline value will be included. 
Analyses of shift from baseline, outliers, and abnormalities will generally be based on the 
number of subjects at risk. 
Values with “<” or “>” signs will be analyzed without the signs in tables and figures. In by-
subject data listings, values will be reported as collected with the sign. 
Dates in by-subject data listings will be displayed as yyyy-mm-dd (eg, 2021-01-24). In general, 
by-subject data listings will be sorted by treatment group, subject number, and study day. 


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3.1. 
Determination of Data for Inclusion in Placebo-Controlled Period 
Analyses 
In general, statistical analyses described in this SAP will be performed separately for the PCP 
Week 12 Analysis and for the PCP Final Analysis. The PCP Week 12 Analysis is intended to 
analyze endpoints at or up through PCP Week 12, and the PCP Final Analysis is intended to 
evaluate all PCP endpoints. Therefore, a determination of study data to be included in the PCP 
Week 12 Analysis and the PCP Final Analysis is required. 
3.1.1. 
Placebo-Controlled Period Week 12 Analysis 
For subjects who consent only to version 1.0 of the protocol, which includes only a 12-week 
placebo-controlled treatment period, all data reported will be included in the PCP Week 12 
Analysis.   
For subjects who consent to version 2.0 of the protocol, which includes a 36-week placebo-
controlled treatment period and a 24-week OLE treatment period, data to be included in the PCP 
Week 12 Analysis will generally be dependent upon whether a subject continues in the PCP 
beyond PCP Week 12 as follows: 
• For subjects who withdraw from the PCP prior to PCP Week 12 and subjects who 
withdraw from the PCP at PCP Week 12 without transitioning into OLE, all data 
reported, including data from the PCP Follow-up visit, will be included in the PCP 
Week 12 Analysis.   
• For subjects who withdraw from the PCP and transition into the OLE at PCP Week 
12, all data up through the date and time (where ascertainable) of first dose of OLE 
study treatment will be included in the PCP Week 12 Analysis. 
• For subjects who continue in the PCP beyond PCP Week 12, all data reported up 
through and including PCP Week 12 will be included in the PCP Week 12 Analysis.     
3.1.2. 
Placebo-Controlled Period Final Analysis 
For subjects who consent only to version 1.0 of the protocol, all data reported will be included in 
the PCP Final Analysis.   
For subjects who consent to version 2.0 of the protocol, data to be included in the PCP Final 
Analysis will generally be dependent on whether a subject is dosed in the OLE as follows: 
• For subjects not dosed in the OLE, all data reported will be included in the PCP Final 
Analysis.   
• For subjects dosed in the OLE, all data up through the date and time (where 
ascertainable) of first dose of OLE study treatment will be included in the PCP Final 
Analysis. 
3.2. 
Analysis Visit Windowing 
Subjects do not always strictly adhere to the visit schedule timing in the protocol. Therefore, the 
designation of analysis visits (or timepoints) will generally be based on the actual day of 
evaluation relative to the date of first dose of PCP study treatment (Day 1), rather than the 


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nominal visit, for analyses conducted by visit or analyses conducted at a visit, unless otherwise 
stated. 
Mutually exclusive analysis visit windows containing no gaps will generally be utilized to assign 
analysis visits corresponding to scheduled post-baseline visits specified in the protocol and will 
be based on data from both scheduled and unscheduled visits/assessments. Analysis visits will be 
assigned by using a windowing scheme as described below. 
The target day for analysis visits for the PCP Week 2, 4, 8, 12, 18, 24, 30 and 36 visits is the 
week number multiplied by 7 plus 1 (eg, target day for the PCP Week 2 analysis visit is Day 15).  
The protocol-specified Follow-up visit in the PCP will have an analysis visit designation of 
Week 40 (Follow-up), and therefore, the week number for the Follow-up visit will be considered 
to be Week 40 for analysis visit windowing (ie, target day of 281).   
The upper bound of the baseline analysis visit window is Day 1 (up to and including the time of 
first dose of PCP study treatment for assessments with time collected), and the lower bound of 
the first post-baseline visit window is Day 1 after the time of first dose of PCP study treatment 
(for assessments with time collected) or Day 2 (for assessments without time collected). For all 
other lower and upper bounds of analysis visit windows, with the exceptions noted below, 
windows will end at the midpoint between scheduled visit timepoints, with the midpoint itself 
assigned to the latter visit window.  
The upper bound of the PCP Week 12 analysis visit window for assessments collected per the 
protocol SoA at both the PCP Week 12 and PCP Week 18 visits and for the PCP Week 12 
flexible sigmoidoscopy with biopsy will be Day 107 (allowing for a 22-day upper analysis visit 
window after the target day of Day 85). This upper analysis visit window incorporates the 
protocol-specified 5-day visit window for the PCP Week 12 visit, the additional protocol-
specified 14-day allotment to allow for any delay in endoscopy assessment due to a pandemic 
(eg, Coronavirus Disease 2019 pandemic) or other global health emergency, and the protocol-
specified requirement that the PCP Week 12 visit be conducted in-clinic within 3 days post-
endoscopy. 
Similarly, the upper bound of the PCP Week 36 analysis visit window for assessments collected 
per the protocol SoA at both the PCP Week 36 and PCP Follow-up visits and for the PCP 
Week 36 flexible sigmoidoscopy with biopsy will be Day 275 (allowing for a 22-day upper 
analysis visit window after the target day of Day 253). This upper analysis visit window 
incorporates the protocol-specified 5-day visit window for the PCP Week 36 visit, the additional 
protocol-specified 14-day allotment to allow for any delay in endoscopy assessment due to a 
pandemic (eg, Coronavirus Disease 2019 pandemic) or other global health emergency, and the 
protocol-specified requirement that the PCP Week 36 visit be conducted in-clinic within 3 days 
post-endoscopy. 
If a subject’s last assessment is after the date of first dose of PCP study treatment but prior to the 
first scheduled post-baseline visit/assessment, that assessment will be assigned to the first 
post-baseline scheduled visit. If two or more assessments occur in the same visit window, the 
assessment closest to the target visit day will be selected for inclusion in the analysis. If multiple 
assessments are equally close to the target visit day, then the latest assessment will be selected 
for inclusion in the analysis. If multiple assessments occur on the same day, the average of these 
assessments will be used for analysis (for evaluations with continuous values), excluding 


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analyses evaluated at any time post-baseline (eg, maximum post-baseline, shift from baseline, 
abnormality, and outlier analyses).     
Further details regarding analysis visit windowing for efficacy endpoints are described in 
Section 8.5.1.  
3.3. 
Standard Calculations 
Standard calculations are described as follows:  
Age: 
Either date of birth or age at informed consent (as an integer) is collected in the IRT system for a 
given subject.  If date of birth is collected, age at time of first dose of PCP study treatment will 
be calculated in years as [(date of first dose of PCP study treatment – date of birth +1)]/365.25, 
rounded down to the nearest integer. If age at informed consent is collected, age at time of first 
dose of PCP study treatment will be set equal to the reported age at informed consent. 
Change/Percent Change from Baseline: 
Change from baseline will be calculated as:  Value at post-baseline visit – value at baseline. 
Percent change from baseline will be calculated as:  (Change from baseline/value at baseline) * 
100%. 
If the value at baseline is 0, percent change from baseline will be missing. 
Study Day: 
Study day will be calculated as follows: 
Date of assessment – Date of first dose of PCP study treatment, where date of assessment is prior 
to the date of first dose of PCP study treatment 
Date of assessment  – Date of first dose of PCP study treatment + 1, where date of assessment is 
on or after the date of first dose of PCP study treatment. 
Duration: 
Where needed, the duration between two dates Date1 and Date2 will be calculated as follows: 
Date2 – Date1 + 1, when expressed in days 
(Date2 – Date1 + 1)/7, when expressed in weeks. 
 
3.4. 
Considerations Related to the COVID-19 Pandemic 
Screening of subjects for this study began in September 2020.  As such, this study’s conduct may 
be affected by the global Coronavirus Disease 2019 (COVID-19) pandemic. Prospectively 
specified measures to allow for adjustment in study conduct due to the COVID-19 pandemic (eg, 
measures addressing missed visits, alternative methods of performing study procedures, and 
alternative methods of supplying IP to subjects), with the objectives of maximizing subject 
monitoring, data collection, and endpoint ascertainment, are described in Protocol Appendix 9. 


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Several regulatory authorities have issued guidances related to clinical trial conduct and 
associated methodological issues related to the effect of the COVID-19 pandemic, including, but 
not limited to, the Food and Drug Administration (FDA) (FDA, 2020a, Guidance on Conduct of 
Clinical Trials of Medical Products during COVID-19 Pandemic and FDA, 2020b, Statistical 
Considerations for Clinical Trials During the COVID-19 Public Health Emergency) and 
European Medicines Agency (EMA) (EMA, 2021, Guidance on the Management of Clinical 
Trials during the COVID-19 (Coronavirus) pandemic, Version 4 and EMA, 2020, Points to 
consider on implications of Coronavirus disease (COVID-19) on methodological aspects of 
ongoing clinical trials). 
Potential effects on conduct of this study related to the COVID-19 pandemic include, but are not 
limited to, the following: subject discontinuation of study treatment and/or withdrawal from 
study; temporary site closure; inability or reduced ability for subjects to continue on IP due to 
disruptions in IP dispensing; extending protocol-defined windows for visits to enable endpoint 
ascertainment, which is addressed in Protocol Appendix 9; missed visits or missed assessments; 
and alternative ascertainment methods (eg, remote ascertainment via a telephone visit or virtual 
visit) used in visits or assessments for collection of data contributing to efficacy and/or safety 
endpoints. 
A determination will be made at the end of study if additional statistical analyses are warranted, 
should conduct of the study have been affected by the COVID-19 pandemic to a substantial 
degree. This determination may be made by assessing various aspects, such as the number of 
subjects with missed visits or assessments for reasons related to the COVID-19 pandemic, the 
number of subjects with alternative ascertainment methods used in visits or assessments, the 
number of subjects who discontinued study treatment and/or withdrew from the study for reasons 
related to the COVID-19 pandemic, and the number of subjects for whom IP dispensing was 
affected (eg, interruption in IP dispensing or alternative methods for supplying IP) for reasons 
related to the COVID-19 pandemic. Summary tables and/or by-subject data listings may be 
provided as part of this assessment. 
If the determination of this assessment is that conduct of the study was substantially affected by 
the COVID-19 pandemic, additional statistical analyses may be undertaken to enable an 
understanding of the potential impact of the COVID-19 pandemic on study results, particularly 
in the scenario of statistically significant results for the primary and/or secondary endpoints. 
A non-exhaustive list of examples of such additional statistical analyses is as follows: 
• Analysis of compliance: 
− By subgroup of subjects for whom IP dispensing or accountability was affected 
for reasons related to the COVID-19 pandemic versus subjects for whom IP 
dispensing was not affected; 
• Analyses of primary and select secondary efficacy endpoints: 
− By subgroup of subjects whose study participation was affected by the COVID-19 
pandemic versus subjects whose study participation was not affected; 
− Excluding only data that is missing for reasons related to the COVID-19 
pandemic (but including imputation of data missing for other reasons); and 


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− By subgroup of subjects who had an alternative method of collection for an 
assessment contributing to a particular endpoint (eg, mobile endoscopy) versus 
subjects who did not have an alternative method of collection 
• Analysis of AEs: 
− Incidence of AEs by subgroup of subjects whose study participation was affected 
by the COVID-19 pandemic versus subjects whose study participation was not 
affected; 
− Incidence of AEs that were collected via an alternative method versus incidence 
of AEs that were not collected via an alternative method 
• Analysis of laboratory values: 
− By subgroup of subjects whose study participation was affected by the COVID-19 
pandemic versus subjects whose study participation was not affected; and 
− Excluding values resulting from local collection due to reasons related to the 
COVID-19 pandemic. 
4. 
ANALYSIS POPULATIONS 
4.1. 
All Enrolled Population  
The all enrolled population will include all subjects with a non-missing date of informed consent.  
The all enrolled population will be utilized for analysis of subject disposition. 
4.2. 
PCP Intent-to-Treat Population 
The PCP intent-to-treat (ITT) Population will include all subjects who are randomized and  
receive at least 1 dose of PCP study treatment. Subjects will be grouped according to their 
randomized treatment, regardless of the treatment actually taken or received.   
The PCP ITT population will be used for analyses of major protocol deviations, demographic 
and other baseline characteristics, UC treatment history, concomitant UC background 
medications at baseline, and efficacy. 
4.3. 
PCP Safety Population 
The PCP safety population will include all subjects who receive at least 1 dose of PCP study 
treatment, with subjects grouped according to their actual treatment.   
Determination of actual treatment will be as follows. Subjects who are randomized to placebo or 
GB004 480 mg QD will be grouped according to their randomized treatment group, except for 
cases where a subject receives and takes IP from one or more misdispensed IP bottle(s) (defined 
as an IP bottle which was not assigned to the subject by the IRT system) whose treatment group 
identity differs from randomized treatment. In such cases, subjects randomized to placebo will be 
grouped in the GB004 480 mg QD or GB004 480 mg BID treatment groups only if GB004 was 
actually taken, with treatment grouping determined according to the greater frequency (QD or 
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randomized to GB004 480 mg QD will be grouped in the GB004 480 mg BID treatment group 
only if GB004 was actually taken BID based on study treatment accountability data. 
The PCP safety population will be utilized for analyses of medical history, prior and concomitant 
medications, duration of study treatment, compliance, prescribed dose modifications, time on 
study, and safety. 
5. 
STUDY SUBJECTS 
5.1. 
Disposition of Subjects 
The disposition of subjects will be summarized.  Disposition and screen failure data will also be 
presented in by-subject data listings. In addition, a listing of the randomization scheme will be 
presented.   
5.1.1. 
Placebo-Controlled Period Week 12 Analysis 
The following counts and percentages of subjects will be summarized: 
• Screened 
• Screen failures, including screen failure reasons 
• Randomized 
• Randomized in Error, defined as randomized subjects who have any 
inclusion/exclusion criteria not met, including those specific inclusion/exclusion 
criteria not met 
• Treated 
• Analysis populations (All Enrolled, PCP ITT, and PCP Safety) 
• Protocol version of informed consent (Version 1.0 or Version 2.0) 
• Completed PCP Week 12 on study treatment  
− Met protocol-defined UC disease activity criteria at PCP Week 12 
• Did not complete PCP Week 12 on study treatment, including reasons for study 
treatment discontinuation prior to PCP Week 12  
• Completed PCP Week 12 
• Did not complete PCP Week 12, including reasons for withdrawal prior to PCP 
Week 12 
If a subject who consented to version 2.0 of the protocol did not complete study treatment in the 
PCP, a determination of whether the subject completed PCP Week 12 on study treatment will be 
made based on the subject’s date of last dose of study treatment in the PCP relative to the 
subject’s nominal PCP Week 12 visit date or relative to the target day of Day 85 for the PCP 
Week 12 visit if the nominal PCP Week 12 visit date is missing.   


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Similarly, if a subject who consented to version 2.0 of the protocol did not complete the PCP, a 
determination of whether the subject completed PCP Week 12 will be made based on the 
subject’s last assessment date relative to the subject’s nominal PCP Week 12 visit date or relative 
to the target day of Day 85 for the PCP Week 12 visit if the nominal PCP Week 12 visit date is 
missing. 
5.1.2. 
Placebo-Controlled Period Final Analysis 
In addition to the above described counts and percentages for the PCP Week 12 Analysis, the  
following counts and percentages of subjects will also be presented for the PCP Final Analysis: 
• Completed PCP study treatment 
• Did not complete PCP study treatment, including reasons for PCP study treatment 
discontinuation 
• Completed PCP 
• Did not complete PCP, including reasons for withdrawal from PCP 
5.2. 
Major Protocol Deviations 
Protocol deviations will be identified and reviewed on an ongoing basis by the study team and 
entered into a Clinical Trial Management System. Major protocol deviations are defined as those 
that can affect efficacy and/or safety assessments, the safety or mental integrity of a subject, or 
the scientific value of the study. Protocol deviations will be prospectively classified as major or 
minor. 
The number and percentage of subjects with a major protocol deviation overall and for each 
major protocol deviation type will be summarized.  In addition, COVID-19 related and non-
COVID-19 related major protocol deviations will be summarized.   
Protocol deviations will also be presented in a by-subject data listing.  
In addition, subjects who were randomized in error and subjects who were mis-stratified (defined 
as subjects for whom the value of the randomization stratification factor, systemic corticosteroid 
use at baseline [yes/no], is different than the actual value of the stratification factor at 
randomization) will be presented in by-subject data listings. 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
6.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized: 
• Age (years), both continuously and categorically (≥ 18 - < 50, ≥ 50 - < 65, ≥ 65) 
• Sex (male, female) 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, Other, White) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 


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• Weight (kg) 
• Height (cm) 
• Body mass index (BMI) (kg/m2), both continuously and categorically (< 18.5, 
≥ 18.5 - < 25, ≥ 25 - < 30, ≥ 30) 
• Region/Country (Australia, Europe [Czech Republic, Georgia, Italy, Moldova, 
Poland, Romania, Russia, Serbia, Ukraine], South Korea, and United States) 
Demographic and baseline characteristics will also be presented in a by-subject data listing.  
6.2. 
Baseline Disease Characteristics 
The following baseline disease characteristics will be summarized:  
• Extent of disease (left side of colon, extensive) 
• Time since UC symptom onset (years), both continuously and categorically, using 
categories of < 1, ≥ 1 - < 3, ≥ 3 - < 7, and ≥ 7 
• Time since UC diagnosis (years), both continuously and categorically, using the same 
categories as time since UC symptom onset 
• Systemic corticosteroid use (yes, no) 
− Per randomization stratum  
− Actual value 
• Systemic corticosteroid dependent 
• Smoking history (current , former, never) 
• Fecal calprotectin (mg/kg), both continuously and categorically (normal [< 50], high 
[≥ 50]; ≤ 250, > 250; and ≤ 500, > 500) 
• Fecal lactoferrin (µg/g), both continuously and categorically (normal [≤ 7.24], high 
[> 7.24]) 
• C-reactive protein (mg/L), both continuously and categorically (normal [≤ 5.0], high 
[>5.0]) 
• UC-100 index 
Baseline disease characteristics will also be presented in a by-subject data listing.  
6.3. 
Baseline Mayo Score and Subscores 
Baseline Mayo score and subscores will be summarized based on the following:  
• Mayo score, both continuously and categorically 
− 0 - 2 (Quiescent disease), including individual categories of 0, 1, and 2 
− 3 - 5 (Mild disease), including individual categories of 3, 4, and 5 
− 6 - 10 (Moderate disease), including individual categories of 6, 7, 8, 9, and 10 


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− 11 - 12 (Severe disease), including individual categories of 11 and 12 
• Mayo subscores, both continuously and categorically 
− Stool frequency subscore (SFS) 
− 
0 (Normal number of stools) 
− 
1 (1 - 2 stools more than normal) 
− 
2 (3 - 4 stools more than normal) 
− 
3 (5 or more stools than normal) 
− Rectal bleeding subscore (RBS) 
− 
0 (No blood seen) 
− 
1 (Streaks of blood with stool less than half the time) 
− 
2 (Obvious blood with stool most of the time) 
− 
3 (Blood alone passes) 
− Endoscopic subscore 
− 
0 (Normal or inactive disease) 
− 
1 (Mild disease [erythema, decreased vascular pattern]) 
− 
2 (Moderate disease [marked erythema, absent vascular pattern, friability, 
erosions]) 
− 
3 (Severe disease [spontaneous bleeding, ulceration]) 
− Physician’s Global Assessment (PGA) 
− 
0 (Normal) 
− 
1 (Mild disease) 
− 
2 (Moderate disease) 
− 
3 (Severe disease) 
• Modified Mayo score, both continuously and categorically 
− 0 - 1 (Quiescent disease), including individual categories of 0 and 1 
− 2 - 4 (Mild disease), including individual categories of 2, 3, and 4 
− 5 - 7 (Moderate disease), including individual categories of 5, 6, and 7 
− 8 - 9 (Severe disease), including individual categories of 8 and 9 
• Partial Mayo score, both continuously and categorically 
− 0 - 1 (Quiescent disease) 


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− 2 - 4 (Mild disease) 
− 5 - 7 (Moderate disease)  
− 8 - 9 (Severe disease) 
• 6-Point Mayo score, both continuously and categorically 
− 0 (Quiescent disease) 
− 1 - 2 (Mild disease) 
− 3 - 4 (Moderate disease)  
− 5 - 6 (Severe disease) 
• Reference normal stool frequency (number of stools per day), continuously and 
categorically 
− When in remission 
− Prior to UC symptom onset/diagnosis 
Baseline Mayo scores and subscores will also be presented in a by-subject data listing.  
6.4. 
Baseline Histologic Activity 
Baseline histologic activity will be summarized based on the following:  
• RHI, both continuously and categorically 
− 0 - 3 (Quiescent) 
− 4 - 10 (Mild) 
− 11 - 18 (Moderate) 
− 19 - 33 (Severe) 
• RHI subscores, both continuously and categorically 
− Chronic inflammatory infiltrate RHI subscore 
− 
0 (No increase) 
− 
1 (Mild but unequivocal increase) 
− 
2 (Moderate increase) 
− 
3 (Marked increase) 
− Lamina propria neutrophils RHI subscore 
− 
0 (None) 
− 
1 (Mild but unequivocal increase) 
− 
2 (Moderate increase) 


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− 
3 (Marked increase) 
− Neutrophils in epithelium RHI subscore 
− 
0 (None) 
− 
1 (< 5% crypts involved) 
− 
2 (< 50% crypts involved) 
− 
3 (> 50% crypts involved) 
− Erosion or ulceration RHI subscore 
− 
0 (No erosion, ulceration or granulation tissue) 
− 
1 (Recovering epithelium + adjacent inflammation; Probable Erosion - focally 
stripped) 
− 
2 (Unequivocal erosion) 
− 
3 (Ulcer or granulation tissue) 
• Lamina propria neutrophils RHI subscore and neutrophils in epithelium RHI 
subscore, categorically (> 0 and > 0, > 0 and 0, 0 and > 0, 0 and 0, respectively) 
• Geboes score 
− 0 (architectural changes) 
− 1 (chronic inflammatory infiltrate) 
− 2 (lamina propria neutrophils) 
− 3 (neutrophils in epithelium)  
− 4 (crypt destruction)  
− 5 (erosions or ulcerations) 
Baseline histologic activity will also be presented in a by-subject data listing.  
6.5. 
UC Treatment History 
UC treatment history will be summarized as the number and percentage of subjects with any 
prior use of the following medication types since UC diagnosis, including information on 
specific medications taken for each medication type: 
• Aminosalicylates; 
• Corticosteroids; and  
• Immunomodulators. 
The number and percentage of subjects with prior failure to respond and/or prior intolerance, 
with prior failure to respond, and with prior intolerance will be summarized for each of the above 
medication types. 


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Ulcerative colitis treatment history will also be presented in a by-subject data listing. 
6.6. 
Medical History 
Medical history (including surgical history) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 24.0 or later. Medical history will be summarized by 
SOC and PT, with sorting by the internationally agreed order for SOC, and by decreasing 
frequency and then alphabetically for PT within SOC in the overall column. Counting will be at 
the subject level for each level of summarization (eg, any medical history, SOC, and PT), with 
subjects experiencing more than one occurrence of a SOC or PT counted only once.   
Medical history will also be presented in a by-subject data listing.   
6.7. 
Prior and Concomitant Medications 
Prior medications are defined as all medications that started prior to the date of first dose of PCP 
study treatment. Concomitant medications are defined as all medications that started on or after 
the date of first dose of PCP study treatment or that started prior to the date of first dose of PCP 
study treatment and stopped on or after the date of first dose of PCP study treatment or are 
ongoing at any time during the PCP. A medication may be considered as both prior and 
concomitant (ie, prior and concomitant medications are not mutually exclusive). 
In general, if it is not clear whether a medication is prior and/or concomitant due to missing or 
incomplete medication start and/or stop dates, the medication will be considered to be prior 
and/or concomitant for the given analysis, unless the non-missing portions of the medication start 
and/or stop dates indicate otherwise.   
For subjects who consent to version 2.0 of the protocol, in cases where a medication has a non-
missing start date equal to the date of PCP Week 12, the medication will be considered 
concomitant for the PCP Week 12 Analysis if it is reported on the appropriate concomitant 
medication eCRF intended to capture medications through PCP Week 12. If the date of PCP 
Week 12 is missing, then the target day for PCP Week 12 (Day 85) will be utilized for the 
purpose of determining concomitancy. 
In cases where a medication has a non-missing start date equal to the date of first dose of OLE 
study treatment, the medication will be considered concomitant to the PCP if it is reported on the 
appropriate concomitant medication eCRF(s) intended to capture medications in the PCP. 
Verbatim prior and concomitant medication terms will be coded to a drug class (anatomical 
therapeutic chemical classification level 2 [ATC2]) and preferred name using World Health 
Organization (WHO) Drug Global B3 March 2021 or later. 
Separate summaries will be presented for prior medications and concomitant medications. 
Counting will be at the subject level for each level of summarization (eg, any medication, drug 
class, and preferred name), with subjects receiving more than one medication counted only once. 
Prior and concomitant medications will also be presented in a by-subject data listing and will include 
an indicator, identifying each medication as prior and/or concomitant.   
Concurrent procedures such as colectomy and ostomy will be presented in a separate by-subject data 
listing. 


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6.7.1. 
Concomitant Background UC Medications 
Concomitant background UC medications at baseline will be summarized as the number and 
percentage of subjects with concomitant use of aminosalicylates and concomitant use of systemic 
corticosteroids at baseline, including specific medications taken for each medication type. 
The number and percent of subjects who are steroid-free at PCP Week 36, defined as not 
requiring any treatment with a systemic corticosteroid for a minimum duration prior to PCP 
Week 36, will be evaluated in the subset of subjects in the ITT population with an actual 
stratification value of yes for systemic corticosteroid use at baseline. Two different minimum 
durations will be evaluated, 2 weeks and 4 weeks. Steroid-free duration prior to PCP Week 36 
may be summarized continuously as well. 
7. 
EXTENT OF EXPOSURE, COMPLIANCE, AND TIME ON 
STUDY 
7.1. 
Duration of Study Treatment 
Duration of PCP study treatment will be summarized, both as a continuous parameter (in units of 
days and weeks, as well as total number of subject-years) and as a categorical parameter as 
follows: 
• PCP Week 12 Analysis 
− < 2 weeks, < 4 weeks, ≥ 2 weeks, ≥ 4 weeks, ≥ 8 weeks, ≥ 11 weeks, 2 days 
(which is the beginning of the protocol-specified visit window for the PCP 
Week 12 visit), and ≥ 12 weeks 
• PCP Final Analysis 
− The above categories for the PCP Week 12 Analysis, plus ≥ 18 weeks, 
≥ 24 weeks, ≥ 35 weeks, 2 days (which is the beginning of the protocol-specified 
visit window for the PCP Week 36 visit), and ≥ 36 weeks  
Other categories of duration of PCP study treatment may be utilized for summary purposes as 
needed. 
Duration of PCP study treatment in days will be calculated for the PCP Week 12 Analysis as 
follows: 
• For subjects who consent only to protocol version 1.0 and for subjects who consent to 
protocol version 2.0 and do not complete PCP Week 12 on study treatment:  
− If the subject’s time of last dose of PCP study treatment is prior to 12:00 noon:  
Date of last dose of PCP study treatment – Date of first dose of PCP study 
treatment + 0.5 
− If the subject’s time of last dose of PCP study treatment is after 12:00 noon or is 
missing:  Date of last dose of PCP study treatment – Date of first dose of PCP 
study treatment + 1. 
• For subjects who complete PCP Week 12 on study treatment:  


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− If the subject received in clinic dosing at the PCP Week 12 nominal visit:  Date of 
PCP Week 12 nominal visit – Date of first dose of PCP study treatment + 0.5 (due 
to the last dose of PCP study treatment as of the PCP Week 12 visit being 
administered per protocol as a morning dose in clinic at the PCP Week 12 
nominal visit) 
− If the subject had a PCP Week 12 nominal visit but did not receive in clinic 
dosing at the PCP Week 12 nominal visit:   
• If the subject did not continue dosing in the PCP beyond the PCP Week 12 
nominal visit: 
• If the subject’s time of last dose of PCP study treatment is prior to 
12:00 noon:  Date of last dose of PCP study treatment – Date of first 
dose of PCP study treatment + 0.5 
• If the subject’s time of last dose of PCP study treatment is after 12:00 
noon or is missing:  Date of last dose of PCP study treatment – Date of 
first dose of PCP study treatment + 1 
• If the subject continued dosing in the PCP beyond the PCP Week 12 nominal 
visit: 
• Date of PCP Week 12 nominal visit – Date of first dose of PCP study 
treatment 
− If the subject has a missing date for the PCP Week 12 nominal visit, then duration 
of PCP study treatment will be imputed to 84.5.   
Duration of PCP study treatment in days will be calculated for the PCP Final Analysis as 
follows: 
• If the subject entered OLE and the subject’s date of last dose of PCP study treatment 
is the same as the subject’s first dose of OLE study treatment:  Date of last dose of 
PCP study treatment – Date of first dose of PCP study treatment + 0.5 
• If the subject entered OLE and the subject’s date of last dose of PCP study treatment 
is not the same as the subject’s first dose of OLE study treatment, or if the subject did 
not enter OLE: 
− If the subject’s time of last dose of PCP study treatment is prior to 12:00 noon:  
Date of last dose of PCP study treatment – Date of first dose of PCP study 
treatment + 0.5 
− If the subject’s time of last dose of PCP study treatment is on or after 12:00 noon 
or is missing:  Date of last dose of PCP study treatment – Date of first dose of 
PCP study treatment + 1 
Duration of study treatment will also be presented in a by-subject data listing.     


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7.2. 
Compliance 
Compliance will be assessed using the following formula: 
Compliance (%) = (Number of actual tablets taken/Number of expected tablets) x 100, 
where: 
Number of actual tablets taken = (Number of tablets dispensed – Number of tablets returned); 
and Number of expected tablets is based on actual duration of study treatment as described in 
Section 7.1. 
Compliance will be calculated using two different parameters, for which the determination of the 
number of expected tablets differs. The first parameter, termed compliance with prescribed PCP 
study treatment, will be calculated taking into account prescribed dose modifications to calculate 
the number of expected tablets;  that is, the number of prescribed tablets will be used as the value 
for the number of expected tablets. This first parameter represents the extent to which a subject 
complies with prescribed PCP study treatment. The second parameter, termed compliance with 
randomized PCP study treatment, will be calculated without taking into account prescribed dose 
modifications to calculate the number of expected tablets. This second parameter therefore 
represents the extent to which a subject adhered to randomized PCP study treatment.   
Compliance will be summarized using descriptive statistics and categorically (eg, < 80%, ≥ 80 -
100%, > 100 - < 120%, ≥ 120%).  Further analyses of compliance may be performed according 
to compliance with tablets versus delayed-release tablets. 
Compliance will also be presented in a by-subject data listing. In addition, IP accountability 
including bottle information will be presented in a by-subject data listing. 
7.3. 
Prescribed Dose Modifications 
Provisions for permitted prescribed dose modifications of IP are described in Protocol Section 
6.5.1. 
The number and percentage of subjects with a prescribed dose modification, defined as the 
occurrence of a prescribed dose reduction or prescribed dose interruption, will be summarized.    
Subjects with occurrence of a prescribed dose modification will be summarized according to: 
• Reasons for prescribed dose modification (liver chemistry abnormality, treatment-
related AE other than liver chemistry abnormality, and other).  
• Prescribed dose modification type: 
− Those who had only a first step prescribed dose reduction (defined as a reduction 
in IP dose by 2 tablets BID to a total of 6 tablets BID), and those who had a 
second step prescribed dose reduction (defined as a further reduction in IP dose 
by 1 tablet BID to a total of 5 tablets BID). 
− Those who had a prescribed dose interruption.   
• Prescribed dose resumption following a prescribed dose modification: 
− Those who resumed a higher dose. 


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− Those who resumed the original dose. 
• Completion of PCP study treatment following a prescribed dose modification: 
− Those who completed PCP study treatment following a prescribed dose 
modification, broken down by those who completed at a reduced dose versus 
those who completed at the original dose. 
− Those who discontinued PCP study treatment following a prescribed dose 
modification.   
For the PCP Week 12 Analysis, this will be summarized with respect to completion 
of PCP Week 12 on study treatment, and for the PCP Final Analysis, this will be 
summarized with respect to completion of PCP Week 12 on study treatment and 
completion of PCP on study treatment. 
• Duration of prescribed dose modification, defined as time in days from the start of a 
prescribed dose modification to resumption of original dose (for subjects who resume 
original dose) or to last dose of study treatment (for subjects who do not resume 
original dose at time of last dose).  For subjects with multiple occurrences of 
prescribed dose modification, the total duration of prescribed dose modification will 
be summarized. 
Prescribed dose modification information will also be presented in a by-subject data listing. 
7.4. 
Time on Study 
Duration of time on study in the PCP will be summarized, both as a continuous parameter (in 
units of days and weeks, as well as total number of subject-years) and as a categorical parameter 
as follows: 
• PCP Week 12 Analysis 
− < 2 weeks, < 4 weeks, ≥ 2 weeks, ≥ 4 weeks, ≥ 8 weeks, ≥ 11 weeks, 2 days 
(which is the beginning of the protocol-specified visit window for the PCP Week 
12 visit), ≥ 12 weeks, and ≥ 16 weeks 
• PCP Final Analysis 
− The above categories for the PCP Week 12 Analysis through ≥ 12 weeks 
inclusive, plus ≥ 18 weeks, ≥ 24 weeks, ≥ 35 weeks, 2 days (which is the 
beginning of the protocol-specified visit window for the PCP Week 36 visit), 
≥ 36 weeks, ≥ 39 weeks, 4 days (which is the beginning of the protocol-specified 
visit window for the PCP Week 40 Follow-up visit), and ≥ 40 weeks 
Other categories of duration of PCP time on study may be utilized for summary purposes as 
needed. 
Duration of PCP time on study in days will be calculated as: 
• PCP Week 12 Analysis:   
− For subjects who consent only to protocol version 1.0 and for subjects who 
consent to protocol version 2.0 and withdraw from PCP at or prior to PCP 


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Week 12: Date of last assessment in PCP – Date of first dose of PCP study 
treatment + 1 
− For subjects who consent to protocol version 2.0 and do not withdraw from PCP 
at or prior to PCP Week 12: Date of PCP Week 12 nominal visit – Date of first 
dose of PCP study treatment + 1; if the date of PCP Week 12 nominal visit is 
missing, then time on study will be imputed to 85. 
• PCP Final Analysis:   
− For subjects who are dosed in the OLE:  Date of first dose of OLE study treatment 
– Date of first dose of PCP study treatment + 1 
− For subjects who are not dosed in the OLE:  Date of last assessment in PCP – 
Date of first dose of PCP study treatment + 1. 
Duration of PCP time on study will also be presented in a by-subject data listing.   
8. 
EFFICACY EVALUATION 
8.1. 
Overview of Efficacy Analysis Issues 
8.1.1. 
Handling of Dropouts or Missing Data 
The below approaches for handling of missing data will be applied after employing the approach 
for handling intercurrent events (ICEs) (ie, treatment failure rules) described in Section 8.1.4 
below. 
8.1.1.1. 
Proportion-Based (Binary) Efficacy Endpoints 
The primary analysis approach for handling of missing data for proportion-based (binary) 
efficacy endpoints will be non-responder imputation (NRI), wherein subjects with a missing 
value due to insufficient data for determination of endpoint status, including missing baseline 
value(s) and/or post-baseline value(s), will be considered as having not met the endpoint.   
8.1.1.2. 
Change from Baseline (Continuous) Efficacy Endpoints 
As all change from baseline (continuous) efficacy endpoints are exploratory endpoints, primary 
analyses of change from baseline efficacy endpoints will not employ imputation for missing data. 
Additional analyses of change from baseline efficacy endpoints (eg, mixed-effects model with 
repeated measures, methods utilizing imputation for missing data) may be explored. 
8.1.2. 
Multicenter Studies 
Data from all countries and sites will be pooled for the purpose of analyses. 
8.1.3. 
Multiple Comparisons/Multiplicity 
In general, statistical hypothesis testing for efficacy endpoints will be made without any 
adjustments for multiplicity, and all statistical hypothesis tests will be performed using a two-
sided significance level of 0.050. 


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8.1.4. 
Handling of Intercurrent Events (Treatment Failure Rules) 
For efficacy analyses, handling of intercurrent events (also known as treatment failure rules) will 
be applied as described below.   
Subjects with any of the following ICEs that occur prior to the timepoint of the endpoint will be 
considered as not meeting the endpoint for proportion-based (binary) endpoints and as having 
missing values for change from baseline-based endpoints: 
• Protocol-prohibited post-baseline initiation of a new UC rescue therapy medication   
− This includes post-baseline initiation of new UC rescue therapy medications such 
as systemic corticosteroids, azathioprine, 6-mercaptopurine, biologic therapies 
including anti-tumor necrosis factor agents or vedolizumab, tofacitinib, oral 
cyclosporine, sirolimus, mycophenolate mofetil, and per rectum therapy (eg, 
enemas or suppository formulations of steroids or 5-aminosalicylates) except 
those required for flexible sigmoidoscopy preparation.  Use of systemic 
corticosteroids and per rectum therapy initiated post-baseline must be for 
> 3 consecutive days in order to qualify for this ICE.    
− This ICE is considered to have occurred on the first start date of new UC rescue 
therapy medication use.   
• Protocol-prohibited post-baseline increase in a concomitant background UC therapy 
used at baseline (as described in Protocol Section 6.5.2) 
− This includes the following: 
− 
Post-baseline increase of ≥ 20% in the average total daily dose of concomitant 
background aminosalicylate UC treatment for ≥ 7 consecutive days, relative to 
the maximum total daily dose from 2 weeks prior to screening endoscopy up 
through and including the day prior to first dose of PCP study treatment 
(Day -1).     
− 
Post-baseline increase in the total daily dose of concomitant background 
systemic corticosteroid UC treatment for > 3 consecutive days, relative to the 
maximum total daily dose from 2 weeks prior to screening endoscopy up 
through and including the day prior to first dose of PCP study treatment 
(Day -1).  Protocol-permitted increases in systemic corticosteroid dose up to 
baseline dose for a subject on systemic corticosteroids at baseline in whom 
systemic corticosteroid taper is initiated after PCP Week 12 and who cannot 
tolerate the systemic corticosteroid taper without recurrence of clinical 
symptoms of either UC or steroid withdrawal will not be considered an ICE.    
− This ICE is considered to have occurred on the first date of qualifying dose 
increase. 
• Post-baseline prolonged course of systemic corticosteroids, where ‘prolonged’ is 
defined as consecutive use for > 7 days, for an indication other than UC.   
This ICE is considered to have occurred on the first start date of qualifying systemic 
corticosteroid use. 


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• A colectomy (partial or total) or an ostomy.   
This ICE is considered to have occurred on the procedure date for the colectomy or 
ostomy. 
• Discontinuation of PCP study treatment > 28 days prior to the timepoint of the 
endpoint.   
The approach for handling intercurrent events described above will be applied prior to 
employing the approaches for handling of missing data described in Section 8.1.1 above.   
Identification of ICEs may be performed by programmatic derivation and/or manual review. For 
the PCP Week 12 Analysis, this will be performed prior to Sponsor unblinding.    
The number and percentage of subjects with an ICE will be summarized overall and by each of 
the types of ICEs listed above. For the PCP Final Analysis, this will be further summarized with 
respect to ICE occurrence prior to PCP Week 12. A by-subject data listing of ICEs will be 
provided. 
8.2. 
Efficacy Endpoints 
Table 3 below provides a summary of the statistical models/methods of primary and sensitivity 
analyses to be used for primary, secondary, and exploratory efficacy endpoints.  
Table 3: 
Efficacy Endpoints and Analysis Methods 
Efficacy Endpoints 
CMH  
Logistic Regression 
ANCOVA 
Primary and Secondary   
Primary Analyses, 
Sensitivity Analyses 
Sensitivity Analyses 
 
Exploratory 
 
 
 
Proportion-based   
Primary Analyses 
 
 
Change from baseline   
 
 
Primary Analyses 
Abbreviations: ANCOVA, analysis of covariance; CMHI, Cochran-Mantel Haenszel 
Analyses of efficacy endpoints for the PCP Week 12 Analysis (ie, efficacy endpoints evaluated 
at or up to and including PCP Week 12) will be based on the ITT population, unless otherwise 
stated below.   
Analyses of efficacy endpoints for the PCP Final Analysis involving timepoints after PCP Week 
12 will be based on the subset of subjects in the ITT population who consent to version 2.0 of the 
protocol, unless otherwise stated below. 
Further analysis population details for specific efficacy endpoints are described below. 
Certain secondary and exploratory efficacy endpoints will only be evaluated in a subset of 
subjects in the ITT population in order to ensure that achievement of the endpoint can be 
attributed to study treatment and that treatment effect estimation is not affected by any potential 
imbalance across treatment groups with respect to subjects fully or partially meeting 
requirements for the endpoint at baseline.  This includes the following: 


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• Endpoints assessing histologic remission (including mucosal healing and disease 
clearance) will be evaluated in the subset of subjects in the ITT population with both 
baseline RHI lamina propria neutrophils and neutrophils in the epithelium subscores 
> 0.   
• Endpoints assessing histologic response will be evaluated in the subset of subjects in 
the ITT population with baseline RHI score ≥ 7. 
• Endpoints assessing subjects with a Geboes score ≤ 2 will be evaluated in the subset 
of subjects in the ITT population with a baseline Geboes score > 2. 
• The endpoint assessing steroid-free clinical remission at PCP Week 36 will be 
evaluated in the subset of subjects in the ITT population with an actual stratification 
value of yes for systemic corticosteroid use at baseline.   
• Endpoints assessing the proportion of subjects with RHI score ≤ 3 will be evaluated 
in the subset of subjects in the ITT population with baseline RHI score > 3. 
• Endpoints assessing the proportion of subjects with fecal calprotectin, fecal 
lactoferrin, or CRP values below a certain threshold value will be evaluated in the 
subset of subjects in the ITT population who baseline value is above the threshold 
value for the endpoint. 
For all applicable efficacy analyses, stratification factor values (systemic corticosteroid use at 
baseline [yes/no]) will be based on the values used for randomization, unless otherwise stated.   
8.3. 
Analysis Methods 
8.3.1. 
Primary Endpoint 
8.3.1.1. 
Primary Analysis 
The primary objective of the PCP will be evaluated by testing the superiority of each GB004 
treatment group to the placebo treatment group with respect to the primary endpoint of the 
proportion of subjects with clinical remission at PCP Week 12 based on a Cochran-Mantel 
Haenszel (CMH) chi-squared test (Mantel, 1959) stratified by the randomization stratification 
factor of systemic corticosteroid use at baseline (yes/no) with a two-sided 0.050 level of 
significance for each comparison.  
The Mantel-Fleiss criterion (Mantel, 1980) will be used to assess the validity of the chi-square 
approximation for the distribution of the CMH test statistic. In the case that the Mantel-Fleiss 
criterion is not at least 5, indicating lack of validity of the chi-square approximation due to 
stratum cell sizes that are too small, Pearson’s chi-squared test will be used instead of the CMH 
chi-squared test in the primary analysis of the primary endpoint. In the rare case that expected 
cell frequencies are too small, Fisher’s exact test will be used instead of Pearson’s chi-squared 
test.   
For the comparison of each GB004 treatment group versus placebo, the p-value from the CMH 
chi-squared test (or Pearson’s chi-squared test and/or Fisher’s exact test, as described above) will 
be reported. The number and proportion of subjects meeting the primary endpoint and 
corresponding 95% Wilson (Score) CIs (Wilson, 1927) will be summarized by treatment group. 


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The unstratified, absolute difference in proportion between each GB004 treatment group and 
placebo will be summarized, with the 95% CI for the unstratified, absolute difference based on 
the Newcombe continuity-corrected method (Newcombe, 1998). The estimated Mantel-Haenszel 
common odds ratio across strata and corresponding 95% CI will also be summarized. 
The primary analysis of the primary endpoint will be based on application of ICE handling 
followed by NRI. 
A bar graph of the proportion of subjects meeting the primary endpoint by treatment group will 
be presented. 
Primary endpoint data will be presented in a by-subject data listing. 
8.3.1.2. 
Sensitivity Analyses  
Sensitivity analyses of the primary endpoint will be conducted to evaluate the robustness of 
treatment effects observed in the primary analysis of the primary endpoint described in 
Section 8.3.1.1 above.  
Table 4 below provides an overview of the primary and sensitivity analyses of the primary 
endpoint. 


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Table 4: 
Summary of Primary and Sensitivity Analyses of the Primary Endpoint 
Analysis 
Description 
Primary Analysis: 
Analysis with both ICE Handling and 
NRI Applied 
• 
Analysis based on application of both ICE Handling 
and NRI. 
• 
P-value based on CMH chi-squared test.   
• 
Estimated treatment effect based on unstratified, 
absolute difference in proportion, with 95% CI based 
on the Newcombe continuity-corrected method. 
Sensitivity Analysis #1:  
Analysis with NRI Applied without 
ICE Handling Applied 
• 
Analysis based on application of NRI without 
application of ICE Handling. 
• 
P-value based on CMH chi-squared test.   
• 
Estimated treatment effect based on unstratified, 
absolute difference in proportion, with 95% CI based 
on the Newcombe continuity-corrected method. 
Sensitivity Analysis #2:  
Analysis with ICE Handling Applied 
without NRI Applied 
• 
Analysis based on application of ICE Handling 
without application of NRI. 
• 
P-value based on CMH chi-squared test.   
• 
Estimated treatment effect based on unstratified, 
absolute difference in proportion, with 95% CI based 
on the Newcombe continuity-corrected method. 
Sensitivity Analysis #3: 
As-Observed Analysis without ICE 
Handling or NRI Applied 
• 
Analysis using observed data, without application of 
ICE Handling or NRI. 
• 
P-value based on CMH chi-squared test.   
• 
Estimated treatment effect based on unstratified, 
absolute difference in proportion, with 95% CI based 
on the Newcombe continuity-corrected method. 
Sensitivity Analysis #4: 
Logistic Regression with ICE Handling 
and NRI Applied 
• 
Analysis based on application of Treatment Failure 
Rules and NRI. 
• 
Estimated treatment effect and p-value based on OR 
from logistic regression analysis.    
Abbreviations: CI, confidence interval; CMH, Cochran-Mantel Haenszel; ICE, intercurrent event; NRI, non-
responder imputation; OR, odds ratio. 
8.3.1.2.1. Sensitivity Analysis #1: NRI Applied without ICE Handling Applied  
In this sensitivity analysis, the primary endpoint will be analyzed similarly as in the primary 
analysis but with application of NRI without ICE handling.  
8.3.1.2.2. Sensitivity Analysis #2: ICE Handling without NRI Applied 
In this sensitivity analysis, the primary endpoint will be analyzed similarly as in the primary 
analysis, but with ICE handling applied without NRI applied. 


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8.3.1.2.3. Sensitivity Analysis #3: As-Observed Analysis without ICE Handling or NRI 
Applied 
In this sensitivity analysis, the primary endpoint will be analyzed similarly as in the primary 
analysis but based on observed data without application of ICE handling or NRI.  
8.3.1.2.4. Sensitivity Analysis #4: Logistic Regression with ICE Handling and NRI Applied 
In this sensitivity analysis, logistic regression modeling will be used to compare each GB004 
treatment group with the placebo treatment group, after handling of ICEs and NRI are applied.    
The logistic regression model will include covariates for treatment group, the randomization 
stratification factor of systemic corticosteroid use at baseline (yes/no), baseline Modified Mayo 
score, and region (Europe vs Rest of World).  
The odds ratio (OR), corresponding asymptotic 95% CI, and p-value from the logistic regression 
model will be presented for the comparison of each GB004 treatment group versus placebo.  
If the logistic regression model does not converge, covariates will be removed from the model, 
and the first reduced model that converges among reduced models with the below specified 
covariates will be utilized in the following order of priority: 
• Treatment group, randomization stratification factor, and baseline Modified Mayo 
score 
• Treatment group and randomization stratification factor 
• Treatment group only 
8.3.2. 
Secondary Endpoints 
8.3.2.1. 
Primary Analysis 
The secondary efficacy objectives of the PCP will be evaluated by testing the superiority of each 
GB004 treatment group to the placebo treatment group with respect to the secondary efficacy 
endpoints described and defined in Section 2 with a two-sided 0.050 level of significance for 
each comparison. The primary analyses of these secondary efficacy endpoints will be performed 
using the same approach as the primary analysis of the primary endpoint. 
Secondary efficacy endpoint data will be presented in a by-subject data listing. 
8.3.2.2. 
Sensitivity Analyses 
Sensitivity analyses of secondary efficacy endpoints will be conducted to evaluate the robustness 
of treatment effects observed in the primary analyses of secondary efficacy endpoints described 
in Section 8.3.2.1 above. These sensitivity analyses will be performed using the same approaches 
as the sensitivity analyses of the primary endpoint, with the differences described below.   
For Sensitivity Analysis #4 (Logistic Regression with ICE Handling and NRI Applied), 
covariates in the logistic regression models for secondary efficacy endpoints will be the same as 
for the primary endpoint with the following exceptions: 
• histologic remission will utilize the covariate of baseline RHI score instead of 
baseline Modified Mayo score; 


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• endoscopic improvement will utilize the covariate of baseline endoscopic subscore 
instead of baseline Modified Mayo score; 
• mucosal healing will utilize the covariates of baseline RHI score and baseline 
endoscopic subscore instead of baseline Modified Mayo score. 
If any of the logistic regression models for sensitivity analyses of secondary efficacy endpoints 
do not converge, the approach utilized for selection of a reduced model that converges will be 
similar to that for the primary endpoint. For mucosal healing, baseline endoscopic subscore will 
be removed from the model prior to removal of baseline RHI score. 
8.3.3. 
Potential Additional Sensitivity Analysis of Primary and Secondary Endpoints 
An additional sensitivity analysis of the primary and/or secondary endpoints may be performed, 
employing a hybrid imputation approach combining NRI and multiple imputation (MI) (Chen, 
2021), particularly in the scenario of substantial missingness assessed to be due to an underlying 
missing at random (MAR) missing data mechanism assumption. This hybrid imputation 
approach has the advantage of combining missing data handling techniques under different 
missing data mechanism assumptions, including missing at random (MAR) and missing not at 
random (MNAR) assumptions, in order to evaluate the impact of missingness due to different 
reasons.  
The MAR assumption is that missingness does not depend on the actual missing values, but that 
the missingness can be completely explained by the observed data. The MNAR assumption is 
that missingness does depend on the actual missing values even after conditioning on the 
observed data.   
The MNAR assumption will be made for missingness caused by withdrawals due to reasons such 
as AEs or lack of efficacy and for subjects with an ICE prior to the timepoint of the endpoint. 
Missingness for other reasons (e.g., missingness caused by withdrawals for other reasons such as 
withdrawal by subject or loss to follow-up, including missingness arising from force majeure 
events such as wars) will be assumed to be MAR. 
This hybrid imputation approach will be performed using the following 3 steps: 
• Step 1:   
Subjects with missing endpoint analysis values are categorized into MNAR and MAR 
based on the above. 
• Step 2:  
Missing endpoint analysis values are imputed using the statistical techniques under 
MNAR and MAR, respectively. 
NRI is used to impute subjects with missing endpoint analysis values under MNAR.   
For subjects with missing endpoint analysis values under MAR, MI is used to impute 
each Mayo subscore contributing to the endpoint using a fully conditional specification 
ordinal logistic regression method. Covariates included in this method may include Mayo 
subscores from all previous visits (including baseline), treatment group, and the 
randomization stratification factor. Multiple imputation will be utilized to compute a 


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number of multiply imputed datasets (e.g., 50) for each Mayo subscore. The Modified 
Mayo score and endpoint analysis values are then derived in each of the multiply imputed 
datasets. 
• Step 3:  
The multiply imputed datasets under MNAR and MAR from Step 2 are combined to 
obtain complete datasets with non-missing endpoint analysis values for all subjects in the 
analysis population. The primary analysis method is conducted within each multiply 
imputed dataset, and the analysis results from the multiply imputed datasets are combined 
using Rubin’s rules to obtain estimates for relevant statistics, including differences in 
proportion and associated 95% CIs and CMH p-values. Since the CMH test statistic is 
non-normally distributed, the Wilson-Hilferty transformation will be used for 
normalization before applying Rubin’s rules. 
8.3.4. 
Exploratory Endpoints 
8.3.4.1. 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoint data will be presented in a by-subject data listing. 
8.3.4.1.1. Proportion-Based (Binary) Exploratory Efficacy Endpoints 
Proportion-based (binary) exploratory endpoints will be analyzed similarly to the primary 
analysis of the primary endpoint.   
A subject will be considered to have met the exploratory efficacy endpoint of steroid-free clinical 
remission at PCP Week 36 if the subject achieves clinical remission at PCP Week 36 without 
requiring any treatment with a systemic corticosteroid for a minimum duration prior to PCP 
Week 36. Two different minimum durations will be evaluated, 2 weeks and 4 weeks. Since 
steroid-free clinical remission at PCP Week 36 will be evaluated in the subset of subjects in the 
ITT population with an actual stratification value of yes for systemic corticosteroid use at 
baseline, analysis of steroid-free clinical remission at PCP Week 36 will utilize Pearson’s chi-
squared test rather than CMH. 
8.3.4.1.2. Change from Baseline (Continuous) Exploratory Efficacy Endpoints 
Change from baseline (continuous) exploratory endpoints will be analyzed using analysis of 
covariance (ANCOVA) models at all applicable timepoints based on application of ICE handling 
(where subjects with an ICE that occurs prior to the timepoint of the endpoint will be considered 
as having missing values as described in Section 8.1.4). All ANCOVA models will include 
covariates for treatment group, the randomization stratification factor of systemic corticosteroid 
use at baseline (yes/no), and baseline value corresponding to the change from baseline endpoint.   
Descriptive statistics for change from baseline will be presented, along with the LS means, SEs, 
and corresponding 95% CIs for each treatment group from the ANCOVA models. The difference 
in LS means, SE, corresponding 95% CI, and p-value for each GB004 treatment group versus the 
placebo group from the ANCOVA models will also be presented.  


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8.3.4.2. 
Pharmacokinetic Concentrations 
By-subject data listings of pharmacokinetic plasma, tissue, and fecal concentrations for GB004 
(and its metabolites, as applicable) will be presented. 
8.4. 
Examination of Subgroups 
Subgroup analyses of the primary and secondary efficacy endpoints will be performed as 
described below. These subgroup analyses are aimed at evaluation of consistency of treatment 
effects across subgroup levels, rather than statistical inference within subgroup levels.   
Subgroup analyses will be performed similarly to the primary analysis methods for these 
endpoints with respect to application of ICE handling followed by NRI.  Pearson’s chi-squared 
test will be utilized to calculate within subgroup level p-values, unless expected cell frequencies 
are too small, in which case Fisher’s exact test will be used. The Breslow-Day test with Tarone’s 
adjustment (Tarone, 1985) will be used to evaluate the homogeneity of odds ratios across levels 
of each subgroup.   
Subgroup analyses will summarize, for each subgroup level, the numbers and proportions of 
subjects meeting the endpoint by treatment group and corresponding 95% Wilson (Score) CIs, 
absolute differences in proportions between each GB004 treatment group and placebo and 
corresponding 95% CIs based on the Newcombe continuity-corrected method, odds ratios and 
corresponding 95% CIs, and within subgroup level p-values (as described above), as well as p-
values from the Breslow-Day test with Tarone’s adjustment. Subgroup analyses will be 
presented in tables and forest plots.   
For any subgroup level that does not comprise ≥ 10% of the ITT population (or the applicable 
subset of the ITT population - eg, for histologic remission and mucosal healing), only within 
treatment group proportions and corresponding 95% Wilson (Score) CIs will be presented for 
that subgroup level, with no statistics for treatment effect comparisons within subgroup level.  
The Breslow-Day test with Tarone’s adjustment will still be performed in such cases if there are 
at least 2 subgroup levels comprising ≥ 10% of the ITT population (or the applicable subset of 
the ITT population).  
Subgroup analyses of interest are described in Table 5 below. 


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Table 5: 
Subgroup Analyses 
Subgroup Category 
Subgroups 
Efficacy Endpoints to be Evaluated 
Demographic and 
baseline 
characteristics 
• 
Age (years; < 50, ≥ 50) 
• 
Sex (male, female) 
• 
BMI (kg/m2; < 25, ≥ 25) 
• 
Region (Europe, Rest of 
World) 
• 
Proportion of subjects with clinical 
remission at PCP Week 12 
• 
Proportion of subjects with clinical 
response at PCP Week 12 
• 
Proportion of subjects with clinical 
remission at PCP Week 36 
• 
Proportion of subjects with clinical 
response at PCP Week 36 
Baseline disease 
characteristics 
• 
Extent of disease (left side of 
colon, extensive) 
• 
Time since UC diagnosis 
(years; < 3, ≥ 3) 
• 
Systemic corticosteroid use 
([per randomization stratum 
and per actual value]; no, yes) 
• 
Systemic corticosteroid 
dependent (no, yes) 
• 
Prior use of 
immunomodulators (no, yes) 
• 
Smoking history (never, 
former, current) 
• 
Fecal calprotectin (mg/kg; 
≤ Median, > Median, where 
median is based on the ITT 
population) 
• 
Fecal lactoferrin (mg/kg; 
≤ Median, > Median, where 
median is based on the ITT 
population) 
• 
CRP (mg/L; ≤ Median, 
> Median, where median is 
based on the ITT population) 
• 
Proportion of subjects with clinical 
remission at PCP Week 12 
• 
Proportion of subjects with clinical 
response at PCP Week 12 
• 
Proportion of subjects with clinical 
remission at PCP Week 36 
• 
Proportion of subjects with clinical 
response at PCP Week 36 
Baseline Mayo and 
Modified Mayo score 
subgroups 
• 
Baseline Mayo score 
− 
5, 6 - 10 
− 
5 - 7, 8 - 10 
• 
Baseline Modified Mayo 
score 
− 
4, 5 - 8 
− 
4, 5 - 7, 8 
− 
4 - 5, 6, 7 - 8 
• 
Proportion of subjects with clinical 
remission at PCP Week 12 
• 
Proportion of subjects with clinical 
response at PCP Week 12 
• 
Proportion of subjects with clinical 
remission at PCP Week 36 
• 
Proportion of subjects with clinical 
response at PCP Week 36 


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Subgroup Category 
Subgroups 
Efficacy Endpoints to be Evaluated 
Baseline endoscopic 
subscore subgroups 
• 
Baseline endoscopic 
subscore (2, 3) 
• 
Proportion of subjects with clinical 
remission at PCP Week 12 
• 
Proportion of subjects with clinical 
response at PCP Week 12 
• 
Proportion of subjects with 
histologic remission at PCP 
Week 12 
• 
Proportion of subjects with 
endoscopic improvement at PCP 
Week 12 
• 
Proportion of subjects with 
mucosal healing at PCP Week 12 
• 
Proportion of subjects with clinical 
remission at PCP Week 36 
• 
Proportion of subjects with clinical 
response at PCP Week 36 
• 
Proportion of subjects with 
histologic remission at PCP 
Week 36 
• 
Proportion of subjects with 
endoscopic improvement at PCP 
Week 36 
• 
Proportion of subjects with 
mucosal healing at PCP Week 36 
Baseline histologic 
activity subgroups 
• 
Baseline RHI score  
− 
0 - 3, > 3 
− 
0 - 10, > 10 
• 
Both baseline RHI lamina 
propria neutrophils and 
neutrophils in the epithelium 
subscores > 0 (yes, no) 
 
• 
Proportion of subjects with clinical 
remission at PCP Week 12 
• 
Proportion of subjects with clinical 
response at PCP Week 12 
• 
Proportion of subjects with 
histologic remission at PCP 
Week 12 
• 
Proportion of subjects with 
endoscopic improvement at PCP 
Week 12 
• 
Proportion of subjects with 
mucosal healing at PCP Week 12 
• 
Proportion of subjects with clinical 
remission at PCP Week 36 
• 
Proportion of subjects with clinical 
response at PCP Week 36 
• 
Proportion of subjects with 
histologic remission at PCP 
Week 36 
• 
Proportion of subjects with 
endoscopic improvement at PCP 
Week 36 


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• 
Proportion of subjects with 
mucosal healing at PCP Week 36 
Abbreviations: BMI, body mass index; CRP, c-reactive protein; ITT, intent-to-treat; PCP, placebo-controlled period; 
RHI, Robarts Histopathology Index; UC, ulcerative colitis. 
Subgroup analyses will only be performed for applicable endpoints (eg, subgroup analyses for 
histologic remission and mucosal healing will not be performed for the subgroup of baseline RHI 
lamina propria neutrophils and neutrophils in the epithelium subscores > 0 [yes, no]). Subgroup 
analyses for secondary and exploratory endpoints not listed in Table 5 may be performed. 
As exploratory analyses, the impact of baseline Mayo score on treatment effects for primary and 
secondary efficacy endpoints may be investigated via logistic regression models that include 
covariates for treatment group, baseline Mayo score, and the interaction between treatment group 
and baseline Mayo score. Odds ratio estimates and 95% CIs for the treatment effect of each 
GB004 treatment group according to baseline Mayo score may be presented. Predicted 
probabilities by treatment group according to baseline Mayo score may also be presented. These 
exploratory analyses may also be performed to assess the impact of baseline Modified Mayo 
score. 
8.5. 
Efficacy Assessments 
8.5.1. 
Mayo Score 
The Mayo score (adapted from Schroeder, 1987) Modified Mayo score, Partial Mayo score, 
Mayo subscores, and 6-point Mayo score are described in Protocol Section 8.1.2.  Calculation of 
the Mayo score, Modified Mayo score, Partial Mayo score, and 6-point Mayo score is 
summarized in Table 6 below: 
Table 6: 
Calculation of Mayo Scores 
Score 
Calculation 
Range Applicable Analysis Visits 
Mayo score 
Sum of SFS, RBS, PGA, 
and endoscopic subscore 
0 - 12 
Baseline, PCP Week 12, PCP Week 36 
Modified Mayo 
score 
Sum of SFS, RBS, and 
endoscopic subscore 
0 - 9 
Baseline, PCP Week 12, PCP Week 36 
Partial Mayo score 
Sum of SFS, RBS, and PGA 
0 - 9 
Baseline, PCP Week 2, PCP Week 4, 
PCP Week 8, PCP Week 12, 
PCP Week 18, PCP Week 24, 
PCP Week 30, PCP Week 36, 
PCP Week 40 (Follow-up) 
6-Point Mayo score 
Sum of SFS and RBS 
0 - 6 
Baseline, PCP Week 2, PCP Week 4, 
PCP Week 8, PCP Week 12, 
PCP Week 18, PCP Week 24, 
PCP Week 30, PCP Week 36, 
PCP Week 40 (Follow-up) 
Abbreviations: PCP, placebo-controlled period; PGA, Physician’s Global Assessment; RBS, rectal bleeding 
subscore; SFS, stool frequency subscore. 


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For calculation of Mayo score, Modified Mayo score, and applicable efficacy endpoints based on 
these scores at the analysis visits of PCP Week 12 and PCP Week 36, the first PGA on or after 
the date of the applicable endoscopic subscore in the analysis visit window will be used as the 
PGA subscore, and the corresponding PGA date will be used to determine the days of daily 
subject eDiary scores to be utilized for calculation of the SFS and RBS. If there are multiple 
endoscopic subscores in the analysis visit window, calculation will be based on the endoscopic 
subscore closest to the target visit day. If multiple endoscopic subscores are equally close to the 
target visit day, then the latest assessment will be utilized for calculation. 
For applicable efficacy endpoints, Mayo subscores comprising the Mayo score calculated at the 
analysis visits of PCP Week 12 and PCP Week 36 per the above will always be selected for 
inclusion in the analysis at the PCP Week 12 and PCP Week 36 analysis visits and will be 
ineligible for windowing to a different analysis visit window. Furthermore, Mayo subscores 
subsequent to those used for calculation at the analysis visits of PCP Week 12 and PCP Week 36 
will be ineligible for windowing to analysis visits prior to PCP Week 12 and PCP Week 36, 
respectively. 
For calculation of Partial Mayo score, 6-point Mayo score, PGA, SFS, and RBS Mayo subscores, 
and other applicable efficacy endpoints based on these scores at post-baseline analysis visits 
other than PCP Week 12 and PCP Week 36, the PGA closest to the target day will be used as the 
PGA subscore, and the corresponding PGA date will be used to determine the days of daily 
subject eDiary scores to be utilized for calculation of the SFS and RBS. If multiple PGA 
subscores are equally close to the target visit day, then the latest assessment will be utilized for 
calculation. 
At each applicable analysis visit, SFS and RBS will each be calculated based on the average of 
the most recent 3 days with non-missing data within 14 days prior to the PGA date. If the PGA at 
a given visit is missing, then the date of another assessment at the given visit (eg, vital signs) 
may instead be used to determine the 14 day calculation timeframe. If the date for a given visit is 
completely missing, then the 14 day calculation timeframe may be determined relative to the 
target visit day. For the analysis visits of Baseline, PCP Week 12, and PCP Week 36, the day of 
and the day after flexible sigmoidoscopy/colonoscopy and the day(s) of bowel preparation, if 
performed, will be excluded from eligible days for calculation. Days selected for SFS and RBS 
calculation may be different based on eDiary data availability. SFS and RBS will be considered 
missing for subjects with fewer than 3 available days of eDiary data in the relevant calculation 
timeframe at a given visit.   
Mayo scores and subscores will be presented in a by-subject data listing. 
8.5.1.1. 
Mayo Subscores 
8.5.1.1.1. Physician’s Global Assessment 
The PGA acknowledges the three other Mayo subscores, the subject’s recollection of abdominal 
discomfort and general sense of wellbeing, and other observations, such as physical findings and 
the subject’s performance status. The PGA is assessed on a 0-3 scale: 0 = Normal, 1 = Mild 
Disease, 2 = Moderate Disease, and 3 = Severe Disease, at the same applicable analysis visits as 
Partial Mayo score in Table 6 above. 


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8.5.1.1.2. Stool Frequency and Rectal Bleeding Score 
Daily eDiary scores will be collected from each subject to capture stool frequency and rectal 
bleeding. The SFS and RBS will be calculated at the same applicable analysis visits as Partial 
Mayo score in Table 6 above, using daily stool frequency scores and daily rectal bleeding scores.     
The SFS is calculated as follows:  
SFS = (average of the 3 daily stool frequency scores, rounded to the nearest integer) minus the 
reference normal stool frequency.   
A subject’s reference normal stool frequency is the number of stools in a 24-hour period when 
the subject was in remission from UC, or, if the subject does not report having previously 
achieved remission from UC, the number of stools the subject reports per day before initial onset 
of signs and symptoms of UC. 
The SFS is assessed on a 0-3 scale:  0 = Normal number of stools for this subject; 1 = 1 to 
2 stools more than normal; 2 = 3 to 4 stools more than normal; and 3 = 5 or more stools than 
normal. 
The RBS is calculated as follows: 
RBS = average of the 3 daily rectal bleeding scores, rounded to the nearest integer. 
The RBS is assessed on a 0-3 scale:  0 = No blood seen; 1 = Streaks of blood with stool less than 
half the time; 2 = Obvious blood with stool most of the time; and 3 = Blood alone passes. 
8.5.1.1.3. Endoscopic Subscore 
Endoscopic subscore of the sigmoid colon will be assessed by both a central reader (who is 
blinded to treatment assignment, visit, and subject symptoms) and a local endoscopist (who is 
blinded to treatment assignment). The same local endoscopist is to assess the endoscopic 
subscore for a particular subject throughout the study, if possible. Differences between the local 
endoscopist and the central reader will be adjudicated by a second blinded central reader as 
described in the study Imaging Charter. 
Centrally read endoscopic subscores (from adjudication, if applicable) will be used for both 
subject eligibility determination and all applicable analyses. 
The endoscopic subscore is assessed on a 0-3 scale: 0 = Normal or inactive disease; 1 = Mild 
disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, absent 
vascular pattern, friability, erosions); and 3 = Severe disease (spontaneous bleeding, ulceration),  
at the same applicable analysis visits as the Mayo score in Table 6 above. An endoscopic 
subscore of 1 does not include friability; an endoscopy with friability will be assessed an 
endoscopic subscore of at least 2.   
8.5.2. 
Histologic Assessments 
8.5.2.1. 
Robarts Histopathology Index 
The RHI (Mosli, 2017) is described in Protocol Section 8.1.3.   
RHI is evaluated by a blinded central reader for the sigmoid colon at Baseline, PCP Week 12, 
and PCP Week 36. The RHI score consists of four subscores: chronic inflammatory infiltrate, 








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• PCP Final Analysis:   
− For subjects not dosed in the OLE: AEs that start on or after the first dose of PCP 
study treatment; 
− For subjects dosed in the OLE:  AEs that start on or after the first dose of PCP 
study treatment and prior to the first dose of OLE study treatment. 
In general, if the treatment emergence of an AE is not clear due to a missing or incomplete AE 
start date/time and/or missing start time for first dose of PCP study treatment, the AE will be 
considered to be treatment-emergent for the given analysis, unless the non-missing portions of 
the AE start date/time and the end date/time and the date of first dose of PCP study treatment 
indicate otherwise. 
For subjects who consent to version 2.0 of the protocol, in cases where an AE has a non-missing 
start date equal to the date of PCP Week 12, the AE will be considered treatment emergent for 
the PCP Week 12 Analysis if it is reported on the appropriate AE eCRF intended to capture AEs 
through PCP Week 12. If the date of PCP Week 12 is missing, then the target day for PCP Week 
12 (Day 85) will be utilized for the purpose of determining treatment emergence. 
In cases where an AE has a non-missing start date equal to the date of first dose of OLE study 
treatment, but the AE start time and/or time of first dose of OLE study treatment is missing, the 
AE will be considered treatment-emergent to the PCP if it is reported on the appropriate AE 
eCRF intended to capture AEs in the PCP. 
In general, whenever a tabular summary of AEs is mentioned in this SAP, it is intended that the 
tabular summary is in reference to treatment emergent AEs, even though “treatment emergent” 
may not be explicitly mentioned. By-subject data listings of AEs will include all events 
regardless of treatment emergence.   
Counting will be at the subject level for each level of summarization (eg, any AE, SOC, and PT), 
with subjects experiencing more than one AE counted only once. For summary of AEs by 
severity, subjects will be counted once at the highest severity reported at each level of 
summarization. AEs that are missing severity will be presented in summary tables as “Missing”. 
AEs that are missing relationship to study treatment will be presented in summary tables as 
“Related”. 
The following AE summaries will be presented: 
• Overall Summary of AEs, showing the number and percentage of subjects with an 
AE; a moderate or severe AE; a severe AE; a serious adverse event (SAE) including 
UC SAEs (defined as the PT of ‘Colitis ulcerative’); an SAE excluding UC SAEs; a 
treatment-related AE; a treatment-related SAE; an AE leading to dose reduction, dose 
interruption, or discontinuation of PCP study treatment; an AE leading to dose 
reduction; an AE leading to dose interruption; an AE leading to discontinuation of 
PCP study treatment; an AE leading to withdrawal from PCP; and an AE resulting in 
death.  
• Incidence of AEs by SOC and PT 
• Incidence of AEs by PT  


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• Incidence of AEs ≥ 5% in Any Treatment Group by PT 
• Incidence of AEs ≥ 2% Higher in Either GB004 Treatment Group Relative to Placebo 
by PT 
• Incidence of SAEs by SOC and PT including UC SAEs 
• Incidence of SAEs by SOC and PT excluding UC SAEs 
• Incidence of AEs by SOC, PT, and maximum severity  
• Incidence of Treatment-Related AEs by SOC and PT 
• Incidence of AEs Leading to Dose Reduction of PCP Study Treatment by SOC and 
PT 
• Incidence of AEs leading to Dose Reduction of PCP Study Treatment by PT 
• Incidence of AEs Leading to Dose Interruption of PCP Study Treatment by SOC and 
PT 
• Incidence of AEs Leading to Dose Interruption of PCP Study Treatment by PT 
• Incidence of AEs Leading to Discontinuation of PCP Study Treatment by SOC and 
PT 
• Incidence of AEs Leading to Discontinuation of PCP Study Treatment by PT 
• Incidence of AEs Leading to Withdrawal from PCP by SOC and PT 
• Incidence of AEs Leading to Withdrawal from PCP by PT 
• Incidence of AEs Resulting in Death by SOC and PT 
In-depth summaries of nausea, dizziness, and/or other specific AEs may be presented, including 
information such as AE severity, treatment-related AEs, AEs requiring treatment, AEs leading to 
dose reduction, dose interruption, or discontinuation of PCP study treatment, AEs leading to 
withdrawal from PCP, onset timing, incidence over time, AE duration, prevalence over time, and 
duration of AE after last dose of PCP study treatment. 
All AEs, AEs leading to dose reduction of PCP study treatment, AEs leading to dose interruption 
of PCP study treatment, AEs leading to discontinuation of PCP study treatment and/or 
withdrawal from PCP, AEs resulting in death, and SAEs will be presented in by-subject data 
listings, regardless of treatment emergence, with those AEs that are treatment-emergent 
identified. A by-subject listing of SAEs occurring in screen failures may be presented, if any 
occur. 
9.2. 
Clinical Laboratory Evaluation 
Actual values, change from baseline values, and percent change from baseline values for 
quantitative laboratory parameters (hematology, clinical chemistry, plasma markers 
[erythropoietin (EPO) and vascular endothelial growth factor (VEGF)], urinalysis, and serum 
markers [iron, transferrin, total iron binding capacity, serum ferritin, hepcidin, and zinc]) will be 
summarized by visit. 


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The following quantitative clinical chemistry laboratory parameters will be derived based on 
reported laboratory parameters: 
• Indirect bilirubin, derived by subtracting direct bilirubin from total bilirubin 
• Estimated glomerular filtration rate (eGFR), derived using the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) 2021 equation (Inker, 2021): 
eGFR (ml/min/1.73m2) =  
142 x minimum (SCr/k, 1)α x maximum (SCr/k, 1)-1.200 x 0.9938Age x                    
1.012 [if female], 
where SCr is serum creatinine (in mg/dL), k is 0.7 for females and 0.9 for males, α is 
-0.241 for females and -0.302 for males, minimum (SCr/k, 1) indicates the lesser of 
SCr/k and 1, and maximum indicates the greater of SCr/k and 1, and Age is baseline 
age in years. 
Shift tables will be presented, summarizing shifts from baseline to high and low or shifts from 
baseline to abnormal/positive at any time post-baseline based on laboratory normal ranges.  
Summaries of maximum post-baseline values for liver chemistry parameters (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], ALT or AST, total bilirubin, 
concurrent ALT or AST and total bilirubin, total bilirubin, direct bilirubin, indirect bilirubin, 
alkaline phosphatase, gamma-glutamyl transferase [GGT]) according to categories based on 
multiples of upper limit of normal (ULN) will be presented.  Liver chemistry parameters 
according to categories based on multiples of ULN may also be presented by visit. 
The number and percentage of subjects with an increase from baseline in hemoglobin to a high 
(> ULN) value at any time post-baseline will be presented for the following categories:  > 0 g/L, 
> 20 g/L, and > 40 g/L.   
In addition, the following figures/plots will be provided: 
• Mean actual, change from baseline, and percent change from baseline values, 
including SE bars, by visit figures for select laboratory parameters (eg, hemoglobin,  
creatinine, eGFR, EPO, and VEGF) 
• Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) (Merz, 2014) plots for 
maximum ALT, maximum AST, and maximum ALT or AST versus total bilirubin 
Creatinine and eGFR may be further assessed in the subset of subjects with concomitant use of 
sensitive clinical substrates of organic cation transporter 2 (such as metformin or dalfampridine). 
Laboratory parameters will also be presented in by-subject data listings.   
9.3. 
Vital Signs 
Actual values and change from baseline values for vital sign parameters (systolic and diastolic 
blood pressure, heart rate, respiratory rate, temperature, and weight) will be summarized by visit. 
A summary table of the incidence of abnormalities in vital sign parameters will be presented 
according to the abnormality criteria listed below in Table 9. 


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Table 9: 
Vital Sign Parameter Abnormality Criteria 
Vital Sign Parameter 
Abnormality Criteria 
Systolic Blood Pressure 
High or Increased: > 180 mmHg post-baseline if ≤ 180 mmHg at 
baseline, or an increase from baseline of > 40 mmHg. 
Low or Decreased: < 90 mmHg post-baseline if ≥ 90 mmHg at 
baseline, or a decrease from baseline of > 30 mmHg. 
Diastolic Blood Pressure 
High or Increased: > 105 mmHg post-baseline if ≤ 105 mmHg at 
baseline, or an increase from baseline of > 30 mmHg. 
Low or Decreased: < 50 mmHg post-baseline if ≥ 50 mmHg at 
baseline, or a decrease from baseline of > 20 mmHg. 
Pulse Rate 
High or Increased: > 120 beats per minute (bpm) post-baseline if 
≤ 120 bpm at baseline, or an increase from baseline of > 20 bpm. 
Low or Decreased: < 50 bpm post-baseline if ≥ 50 bpm at baseline, 
or a decrease from baseline of > 20 bpm. 
Temperature 
> 38 degrees C and an increase from baseline of ≥1 degree C. 
Abbreviations: bpm, beats per minute; C, Celsius; mmHg, millimeters of mercury. 
Vital sign parameters will also be presented in a by-subject data listing, with abnormalities 
flagged. 
9.4. 
12-Lead ECGs 
Actual values and change from baseline values will be summarized by visit for the following 
quantitative ECG parameters: mean heart rate; RR interval; QT interval (uncorrected); 
Fridericia's correction formula for QT interval (QTcF); PR interval; and QRS duration.   
Outlier analyses for QTcF intervals in the PCP will be performed. This will consist of a summary 
of the number and percentage of subjects with a post-baseline QTcF interval greater than 450 
msec, 480 msec, and 500 msec and the number and percentage of subjects with an increase from 
baseline in QTcF interval of greater than 30 msec and 60 msec. 
Each ECG will be assessed by a blinded central reader with an overall interpretation of normal, 
abnormal, or unable to evaluate. Shift tables for overall interpretation will be presented, 
summarizing shifts from baseline to abnormal at any time post-baseline. 
ECG parameters will also be presented in a by-subject data listing with values meeting the above 
QTcF outlier criteria and values representing a shift from baseline to abnormal in overall 
interpretation flagged. 
10. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
There are no changes to the analyses planned in the protocol. 


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11. 
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