Conditions: Ulcerative Colitis
Keywords: ulcerative colitis inflammatory bowel disease PROPEL Propel Study
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 98
Healthy volunteers: no

Brief summary:
The main objectives of this study are to evaluate the efficacy, safety, and tolerability of daily doses of PTG-100 in subjects with moderate to severe ulcerative colitis (UC).

Detailed description:
This is a Phase II multi-centre, double blind, randomised, placebo-controlled, clinical study to evaluate the efficacy, safety, and tolerability of an oral peptide, PTG-100, administered as capsules for 12 weeks in subjects with moderate to severe UC.

Following screening procedures and confirmation of subject eligibility, subjects will be randomised 1:1:1:1 to one of three daily doses of PTG-100 (150, 300 or 900 mg) or placebo. Stratification will be based on subjects' prior treatment with anti-TNF agents, with a maximum of 50% of subjects with prior unsuccessful anti-TNF agent treatments. Subjects will be treated with study drug for 12 weeks. Sigmoidoscopies will be performed at the Screening Visit and on Week 12. A final Follow Up Visit will occur on Week 16, when subject has been off study treatment for 4 weeks. Clinical, safety, pharmacokinetic (PK) and pharmacodynamic (PD) parameters will be evaluated on an ongoing basis during the 16 week study.

Arms:
arm 1: Low dose arm 2: Medium dose arm 3: High dose arm 4: Placebo control

Interventions: intervention 1: PTG-100 intervention 2: Placebo
Intervention descriptions: intervention 1: Daily dosing of PTG-100 by subject for a 12 week treatment period. intervention 2: Daily dosing of Placebo capsules by subject for a 12 week treatment period.

Protocol document:
Prot_000.pdf: 
Clinical Protocol 
Covance Study 8347353 
CONFIDENTIAL 
Protocol PTG-100-02 
 
 
 
Final Protocol Amendment 3: 16 November 2017 
Page 1 of 101 
 
 
 
A PHASE 2B RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL ADAPTIVE 2-STAGE, MULTI-CENTRE STUDY TO EVALUATE 
THE SAFETY AND EFFICACY OF ORAL PTG-100 INDUCTION IN SUBJECTS 
WITH MODERATE TO SEVERE ACTIVE ULCERATIVE COLITIS 
 
 
Document Version: Final Protocol Amendment 3:  16 November 2017 
Final Protocol Amendment 2:  01 November 2016 
Final Protocol Amendment 1:  26 September 2016 
Final Protocol:  08 September 2016 Study Drug: PTG-100 
Protocol PTG-100-02 
Covance Study 8347353 
 
 
IND No. 129348 
EudraCT No. 2016-003452-75 
 
 
for 
 
Protagonist Therapeutics, Inc. 
7707 Gateway Boulevard, Suite 140 
Newark, California 94560 
 
 
by 
 
Covance Early Clinical Segment 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704 
 
 
 


Clinical Protocol 
Covance Study 8347353 
CONFIDENTIAL 
Protocol PTG-100-02 
 
 
 
Final Protocol Amendment 3: 16 November 2017 
Page 2 of 101 
 
STUDY IDENTIFICATION 
Sponsor 
Protagonist Therapeutics, Inc. 
 
+1 (510) 474-0170 (Main Telephone No.) 
 
 
 
Sponsor’s Study Contact 
Lucio A. D. Tozzi 
 
+1 (510) 474-0899 (Office Telephone No.) 
 
 
Sponsor’s Medical Monitor Bittoo Kanwar, MD 
 
+1 (510) 474-0854 (Office Telephone No.) 
 
 
 
 


Clinical Protocol 
Covance Study 8347353 
CONFIDENTIAL 
Protocol PTG-100-02 
 
 
 
Final Protocol Amendment 3: 16 November 2017 
Page 3 of 101 
 
TABLE OF CONTENTS 
 
1 
SYNOPSIS ...............................................................................................................9 
2 
INTRODUCTION .................................................................................................19 
2.1 
Background and Rationale .........................................................................19 
2.2 
Study Rationale ..........................................................................................23 
2.3 
Dose Rationale ...........................................................................................24 
2.4 
Rationale for Target Population .................................................................26 
2.5 
Rationale for Endpoints .............................................................................26 
3 
STUDY OBJECTIVES ..........................................................................................27 
4 
INVESTIGATIONAL PLAN ................................................................................28 
4.1 
Study Design Overview .............................................................................28 
5 
SUBJECT SELECTION ........................................................................................32 
5.1 
Inclusion Criteria .......................................................................................32 
5.2 
Exclusion Criteria ......................................................................................34 
5.3 
Removal of Subjects from Study Participation ..........................................37 
5.4 
Management of Subject Safety ..................................................................37 
6 
STUDY PROCEDURES .......................................................................................38 
6.1 
Schedule of Study Procedures ...................................................................38 
6.2 
Study Treatment .........................................................................................42 
6.2.1 Drug Supplies and Accountability .................................................42 
6.2.2 Subject Number and Identification ................................................43 
6.2.3 Dose Preparation and Administration ............................................43 
6.2.4 Blinding..........................................................................................44 
6.3 
Study Restrictions ......................................................................................45 
6.3.1 Diet, Fluid, and Activity Control ...................................................45 


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Protocol PTG-100-02 
 
 
 
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6.3.2 Concomitant Medications ..............................................................45 
6.3.3 Contraception .................................................................................47 
6.4 
Screening Procedures (Days -42 to -7) ......................................................47 
6.5 
Clinical Site Admission (Day 0) ................................................................49 
6.5.1 Predose Procedures ........................................................................49 
6.5.2 Postdose Procedures.......................................................................50 
6.6 
Clinical Site Visits (Days 14, 28, 42, and 56) ............................................50 
6.7 
Day 70 (Phone Visit) .................................................................................51 
6.8 
Final Treatment Day Clinical Site Visit (Day 84 or Early Termination) ..51 
6.9 
Follow-up/End of Study Visit (Day 112)...................................................52 
6.10 
6 Months Post-Treatment (Final Phone Follow-up) ..................................53 
6.11 
Efficacy Assessments.................................................................................53 
6.11.1 Mayo Score ....................................................................................53 
6.11.2 Colonic Biopsy...............................................................................54 
6.11.3 Faecal Calprotectin ........................................................................54 
6.11.4 IBDQ ............................................................................................55 
6.12 
Pharmacokinetic and Pharmacodynamic Assessments ..............................55 
6.12.1 Pharmacokinetic Blood Sample Collection, Processing, and 
Analysis..............................................................................55 
6.12.2 Pharmacodynamic Blood Sample Collection, Processing, and 
Analysis..............................................................................55 
6.12.3 Anti-drug Antibody Blood Sample Collection and Processing .....56 
6.13 
Safety Monitoring ......................................................................................56 
6.13.1 PML Monitoring ............................................................................57 
6.13.2 Adverse Events ..............................................................................58 
6.13.3 Clinical Laboratory Evaluations ....................................................58 
6.13.4 Vital Signs ......................................................................................59 
6.13.5 Twelve-lead Electrocardiograms ...................................................59 


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6.13.6 Physical Examinations ...................................................................59 
6.14 
Study Termination .....................................................................................60 
7 
DATA ANALYSES AND SAMPLE SIZE ...........................................................60 
7.1 
Sample Size ................................................................................................60 
7.2 
Interim Analysis .........................................................................................61 
7.3 
Study Populations ......................................................................................62 
7.4 
Statistical Analysis of Efficacy Data .........................................................62 
7.5 
Statistical Analysis of Safety Data .............................................................64 
7.6 
Pharmacokinetic Analysis ..........................................................................65 
7.7 
Pharmacodynamic Analysis .......................................................................66 
7.8 
Immunogenicity Analysis ..........................................................................66 
7.9 
Data Handling and Record Keeping ..........................................................67 
7.10 
Quality Control and Quality Assurance .....................................................68 
8 
ADMINISTRATIVE ASPECTS ...........................................................................68 
8.1 
Change in Protocol .....................................................................................68 
8.2 
Site Initiation Visit/Investigator Meeting ..................................................69 
8.3 
Disclosure ..................................................................................................69 
8.4 
Publication .................................................................................................69 
8.5 
Monitoring .................................................................................................70 
8.6 
Institutional Review Board/Institutional Ethics Committee ......................70 
8.7 
Informed Consent.......................................................................................71 
8.8 
Records ......................................................................................................71 
8.9 
Reference to Declaration of Helsinki/Basic Principles ..............................72 
8.10 
Investigator Responsibilities ......................................................................72 
8.11 
Financing and Insurance ............................................................................73 
SPONSOR AGREEMENT ................................................................................................74 
INVESTIGATOR AGREEMENT.....................................................................................75 


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REFERENCES ..................................................................................................................76 
APPENDIX A - COMPONENTS OF THE MAYO SCORE ...........................................79 
APPENDIX B - CLINICAL LABORATORY EVALUATIONS.....................................81 
APPENDIX C - TB SCREENING CRITERIA .................................................................82 
APPENDIX D - PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY 
(PML) ASSESSMENT  .........................................................................................83 
APPENDIX E - BLOOD SAMPLING SUMMARY ........................................................86 
APPENDIX F - ADVERSE EVENTS ..............................................................................87 
APPENDIX G - INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE (IBDQ).91 
 


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ABBREVIATIONS 
 
5-ASA 
5-aminosalicylic acid 
6-MP 
6-mercaptopurine 
ADA 
anti-drug antibody 
ADRC 
Adaptive Design Review Committee 
AE 
adverse event 
AUC 
area under the concentration-time curve 
AUC0-t 
area under the concentration-time curve from time 0 to the time of the 
last sample collection 
BP 
blood pressure 
CD 
Crohn’s disease 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
Ctrough 
trough (predose) concentration  
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Agency 
FACS 
fluorescence-activated cell sorter 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HCV 
Hepatitis C Virus 
HIV 
human immunodeficiency virus 
IA 
interim analysis 
IB 
Investigator’s Brochure 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IV 
intravenous 
IXRS 
interactive web/voice response system 
JCV 
John Cunningham virus 
LTBI 
latent tuberculosis infection 
MAD 
multiple ascending dose 
MAdCAM-1 
mucosal addressin cell adhesion molecule 1 


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CONFIDENTIAL 
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NOAEL 
no observed adverse effect level 
NOEL 
no observed effect level 
PB 
phosphate buffer 
PD 
pharmacodynamic 
PGA 
physician’s global assessment 
PK 
pharmacokinetic 
PML 
progressive multifocal encephalopathy 
QD 
once daily 
RBC 
red blood cell 
RE 
receptor expression 
RO 
receptor occupancy 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOP 
standard operating procedure 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
Tmax 
time of maximum observed concentration 
TNF-α 
tumour necrosis factor-alpha 
UA 
urinalysis  
UC 
ulcerative colitis 
ULN 
upper limit of normal 
US(A) 
United States (of America) 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
 


Clinical Protocol 
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CONFIDENTIAL 
Protocol PTG-100-02 
 
 
 
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1 SYNOPSIS 
Title of Study: 
A Phase 2b Randomised, Double-blind, Placebo-controlled, Parallel Adaptive 
2-stage, Multi-centre Study to Evaluate the Safety and Efficacy of Oral PTG-100 
Induction in Subjects with Moderate to Severe Active Ulcerative Colitis 
Study Phase: 
Phase 2b 
Indication: 
Ulcerative colitis (UC) 
Objectives: 
The primary objectives of this study are: 
1. To evaluate the safety and tolerability of PTG-100  
2. To evaluate the efficacy of PTG-100 in the induction treatment of 
subjects with moderate to severe active UC compared to placebo.  
 
The secondary objectives are: 
1. To evaluate the dose-response relationship and select PTG-100 induction 
regimens for continued development 
2. To evaluate the pharmacokinetics (PK) of PTG-100 in subjects with 
active UC 
3. To evaluate the pharmacodynamic (PD) effects of PTG-100 including 
the assessment of receptor occupancy (RO) and α4β7 receptor expression 
(RE) in peripheral blood lymphocytes  
4. To evaluate changes in faecal calprotectin levels for subjects receiving 
PTG-100 compared to placebo 
5. To evaluate the incidence of positive anti-drug antibodies (ADAs) in 
subjects receiving PTG-100. 
 
The exploratory objectives are: 
1. To evaluate the ability of subjects receiving PTG-100 to achieve 
histological improvement in colonic tissue biopsies compared to placebo 
2. To characterise immunologic biomarkers in the target population and to 
evaluate changes in immunological/PD biomarkers in subjects receiving 
PTG-100 compared to placebo. 
Methodology/Study 
Design: 
This will be a randomised, double-blind, placebo-controlled, multi-centre, parallel 
adaptive 2-stage design study. 
 
Subjects will be screened for eligibility within 42 days of dosing. Eligible subjects 
will return for sigmoidoscopy/ biopsy and baseline Mayo Score within 14 days of 
randomisation (with all attempts made for this visit to occur as close to 
randomisation as possible; however, subjects may have a combined Screening 
visit that includes endoscopy). Randomisation must occur within 7 days of dosing. 
On Day 0, assessments including physical examination, safety labs, 
electrocardiogram (ECG), progressive multifocal encephalopathy (PML) 
assessment, PK, PD, ADA, faecal calprotectin, and Inflammatory Bowel Disease 
Questionnaire (IBDQ) will be performed predose followed by dosing and physical 
examination, adverse event (AE) assessment, and blood sampling for PK and PD 
analysis. 
 
Treatment duration will be 12 weeks in order to optimise duration of induction 
dosing for continued development. There will be a total of 9 visits to the clinical 
site, including: 2 Screening visits (one for general inclusion/exclusion criteria 
assessment and a second including recording baseline Mayo scoring and 
sigmoidoscopy/ biopsy, with the latter occurring within 14 days of randomisation; 


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CONFIDENTIAL 
Protocol PTG-100-02 
 
 
 
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Day -42 to Day -7; however, subjects may have a combined Screening visit that 
includes endoscopy); dose initiation (Day 0); and assessment visits on Days 14, 
28, 42, 56, and 84. Post-treatment sigmoidoscopy/biopsy will be performed on 
Day 84 (Week 12). Day 70 will be a phone visit in which subjects will be 
instructed to record the stool frequency and rectal bleeding data preceding 
Day 70. A final Follow-up visit will occur on Day 112 and a phone call for 
assessing PML signs and symptoms will occur approximately 6 months after the 
completion of treatment (or 6 months after discontinuation of treatment if the 
subject terminates early).  
 
Subjects are to be randomised 1:1:1:1 by interactive web/voice response system 
(IXRS) in Stage 1. Subjects will be stratified by prior treatment with tumour 
necrosis factor-alpha (TNF-α) antagonist use. Subject enrolment will occur in 
2 stages relative to an interim analysis (IA), the purpose of which will be to 
conduct a futility analysis and to identify which study arms provide optimal data 
in order to select one (or 2) PTG-100 dose levels and placebo to continue 
enrolling subjects to the most informative and effective dose arms. After the 
unblinded IA (Stage 1, see below) by the Adaptive Design Review Committee, 
additional subjects will be randomised equally (1:1 or 1:1:1, as appropriate) to the 
selected doses of PTG-100 and placebo with stratification maintained (Stage 2). 
 
The IA will be performed after approximately 60 to 80 subjects have been dosed 
and completed 12 weeks of dosing or terminated early (Stage 1). The IA 
guidelines for dose selection will be defined in the Data Monitoring Committee 
charter and will be made in consideration of safety data and sound clinical 
judgment. Subjects will continue to be randomised across the 4 arms during the 
IA until dose(s) are selected for Stage 2 of the trial, at which time the 
randomisation of remaining subjects to be enrolled will be modified to the 
remaining trial arms. Final analyses will combine all observed data from both 
stages of the trial. 
 
It should be noted that for subjects in the Netherlands, only subjects who have had 
prior exposure to anti-TNF agents will be allowed to enrol in the study. 
Number of Subjects: 
It is anticipated that approximately 240 male and non-gravid female subjects aged 
18 to 80 years with moderate to severe active UC will be randomised.  
 
No study-site target enrolment numbers will be set so as to allow for competitive 
enrolment among sites. 
Number of Study Sites: Approximately 100 to 120 sites worldwide. 
Criteria for Inclusion: 
The following are the inclusion criteria. Subjects must meet ALL of the following 
inclusion criteria to be enrolled. Subjects may be screened up to 3 different times 
separated by at least 14 days. 
1. Male and female subjects aged 18 to 80 years, inclusive. 
2. Diagnosis of UC for ≥ 2 months prior to screening, with a history of 
disease activity extending beyond the rectum; if the UC has been present 
for > 10 years, a total colonoscopy with biopsy must have been 
performed within 2 years of screening to rule out dysplasia. Subjects 
with a family history of colorectal cancer, personal history of increased 
colorectal cancer risk, age > 50 years, or other known risk factor must be 
up-to-date on colorectal cancer surveillance per local standards and 
guidelines (may be performed during screening). Subjects with extensive 
colitis or pancolitis of > 8 years duration must have documented 
evidence that a surveillance colonoscopy was performed within 12 


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CONFIDENTIAL 
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Final Protocol Amendment 3: 16 November 2017 
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months of the initial Screening visit (may be performed during 
screening). 
3. Moderate to severe active UC as defined by complete Mayo Score of 6 to 
12, inclusive (range 0 to 12), at baseline (pre-randomisation) with 
endoscopy score of at least 2 (range 0 to 3), extending 15 cm or more 
from the anal verge, as determined by blinded central read, within 
14 days of randomisation. 
4. Demonstrated, over the previous 5-year period, an inadequate response 
to, loss of response to, or intolerance of at least 1 of the following agents 
as defined below: 
a. 
Immunomodulators 
i. Signs and symptoms of persistently active disease 
despite a history of at least one ≥ 8-week regimen of 
oral azathioprine (≥ 1.5 mg/kg) or 6-mercaptopurine 
(6-MP) (≥ 0.75 mg/kg), OR 
ii. History of intolerance of at least 1 immunomodulator 
(including, but not limited to, nausea/vomiting, 
abdominal pain, pancreatitis, liver function test 
abnormalities, lymphopaenia, thiopurine 
S-methyltransferase genetic mutation, and/or infection) 
b. TNF-α antagonists 
i. Signs and symptoms of persistently active disease 
despite a history of at least 1 induction regimen of at 
least 6 weeks duration, OR 
ii. Recurrence of symptoms during maintenance dosing 
following prior clinical benefit (discontinuation despite 
clinical benefit does not qualify), OR 
iii. History of intolerance (including, but not limited to, 
infusion- or injection-related reaction, demyelination, 
congestive heart failure, and infection)  
Note: A maximum of 50% of randomised subjects 
may have had prior treatment with TNF-α 
antagonists. For subjects in the Netherlands, only 
subjects who have had prior exposure to anti-TNF 
agents will be allowed to enrol in the study (as 
confirmed by medical record documentation or by 
self-reporting). 
c. 
Corticosteroids  
i. Signs and symptoms of persistently active disease 
despite a history of at least one 4-week induction 
regimen that included a dose equivalent to prednisone 
30 mg daily orally for 2 weeks or intravenous (IV) for 
1 week, OR 
ii. Two failed attempts to taper corticosteroids to below a 
dose equivalent to prednisone 10 mg daily orally on 2 
separate occasions, OR 
iii. History of intolerance of corticosteroids (including, but 
not limited to, Cushing’s syndrome, osteopaenia/ 
osteoporosis, hyperglycaemia, insomnia, and 
infection). 
5. Subject is unlikely to conceive, as indicated by at least one “yes” answer 
to the following criteria: 
a. 
Subject is a male 


Clinical Protocol 
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CONFIDENTIAL 
Protocol PTG-100-02 
 
 
 
Final Protocol Amendment 3: 16 November 2017 
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b. Subject is a surgically sterilised female (at least 90 days prior to 
Screening) 
c. 
Subject is a post-menopausal female ≥ 45 years of age with 
> 1 year since last menses; if a female subject is < 45 years of 
age, or cessation of menses is < 1 year and > 6 months, 
follicle-stimulating hormone must be documented as elevated 
into the post-menopausal range at Screening 
d. Subject is a non-sterilised, premenopausal female with a 
non-sterile male partner and agrees to abstain from heterosexual 
activity, use adequate hormonal contraception, OR use double 
barrier contraception (ie, a combination of male condom with 
either cervical cap, diaphragm, or sponge with spermicide) as 
per local regulations and guidelines during the study and for 
28 days after the last dose of study drug. 
e. 
If subject is a non-sterilised, premenopausal female with a 
sterile male partner, the above requirements for contraception 
do not apply. 
6. For women of childbearing potential, a negative serum pregnancy test at 
Screening and a negative urine pregnancy test within 24 hours prior to 
the first dose of study medication. 
7. Subject is eligible according to tuberculosis screening criteria.  
8. Subject understands the study procedures and agrees to participate in the 
study by giving written informed consent. 
 
Note: Subjects may be permitted to enrol in the study on stable doses of oral 
5-aminosalicylic acid (5-ASA) agents, oral corticosteroids, antidiarrhoeals, 
azathioprine/ 6-MP, or probiotics according to specifications noted in the 
protocol. 
Exclusion Criteria: 
The following are the exclusion criteria; subjects must meet NONE of the 
following exclusion criteria to be enrolled. 
 
Gastrointestinal exclusion criteria 
1. Subject with Crohn’s disease (CD), indeterminate colitis, or presence or 
history of fistula consistent with CD. 
2. History of toxic megacolon, abdominal abscess, symptomatic colonic 
stricture, or stoma; history of extensive colonic resection, or subtotal or 
total colectomy; or is at imminent risk of colectomy. 
3. History or current evidence of colonic dysplasia or adenomatous colonic 
polyps. Note: Subjects will not be excluded from the study because of a 
pathology finding of indefinite dysplasia with reactive atypia. Subjects 
with resected adenomatous polyps may be enrolled. 
Infectious disease exclusion criteria 
4. Current bacterial or parasitic pathogenic enteric infection, including 
Clostridium difficile (confirmed by toxin result), current infection with 
hepatitis B or C virus (subjects treated for HCV infection must have 
evidence of sustained virologic response 12 weeks after the end of 
treatment [SVR12], infection requiring hospitalisation or IV 
antimicrobial therapy, opportunistic infection within 6 months of dosing, 
any infection requiring antimicrobial therapy within 2 weeks of dosing, 
history of more than one episode of herpes zoster, history of infection 
with human immunodeficiency virus (HIV), or any episode of 
disseminated zoster. Note: Subjects with a history of C. difficile infection 


Clinical Protocol 
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CONFIDENTIAL 
Protocol PTG-100-02 
 
 
 
Final Protocol Amendment 3: 16 November 2017 
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treated with antibiotics with or without faecal microbial transplant may 
be rescreened after 2 weeks following completion of treatment. 
5. Live virus vaccination within 1 month prior to screening. 
General exclusion criteria 
6. Subject has a concurrent clinically significant, unstable, or uncontrolled 
cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, 
haematological, coagulation, immunological, endocrine/metabolic, or 
other medical disorder that, in the opinion of the Investigator, might 
confound the results of the study or pose additional risk to the subject by 
their participation in the study. 
Note: Subjects with a history of uncomplicated kidney stones, childhood 
asthma, or concurrent stable and well-controlled asthma may be enrolled 
in the study at the discretion of the Investigator.  
7. Known primary or secondary immunodeficiency. 
8. History of myocardial infarction, unstable angina, transient ischaemic 
attack, decompensated heart failure requiring hospitalisation, congestive 
heart failure (New York Heart Association Class 3 or 4), uncontrolled 
arrhythmias, cardiac revascularisation, stroke, uncontrolled hypertension 
(systolic blood pressure [BP] > 160 mmHg or diastolic BP > 100 mmHg 
at Screening), or uncontrolled diabetes (haemoglobin A1c > 9% or > 1 
episode of severe hypoglycaemia) within 6 months of screening. 
9. Clinically meaningful laboratory abnormalities at Screening including, 
but not limited to, the ranges below: 
a. 
Absolute neutrophil count < 1000/µL 
b. Platelet count < 100,000/µL 
c. 
Haemoglobin < 9 g/dL 
d. Creatinine ≥ 1.5 mg/dL  
e. 
alanine aminotransferase or aspartate aminotransferase ≥ 2.5 x 
upper limit of normal (ULN) or bilirubin > 1.5 x ULN 
10. Pregnant or lactating females. 
11. Any surgical procedure requiring general anaesthesia within 1 month 
prior to screening, or planned elective surgery during the study. 
12. History of malignant neoplasms or carcinoma in situ within 5 years prior 
to screening. (Subjects who are cancer-free for the previous 5 years may 
be enrolled. Subjects with adequately treated non-metastatic basal cell 
skin cancer, squamous cell skin cancer that has not recurred for at least 1 
year prior to screening, or history of adequately treated cervical 
dysplasia/cervical intraepithelial neoplasia or cervical carcinoma in situ 
that has not recurred at least 3 years prior to screening may be enrolled.) 
13. History of any major neurological disorders, as judged by the 
Investigator, or positive PML subjective symptom checklist. 
14. Current or recent history of alcohol dependence or illicit drug use within 
1 year prior to screening. 
15. Subject is mentally or legally incapacitated at the time of Screening visit 
or has a history of clinically significant psychiatric disorders that would 
impact the subject’s ability to participate in the trial according to the 
Investigator. Note: Subjects who have had situational depression or 
adjustment disorder or treated depression may be enrolled at the 
discretion of the Investigator. 
16. Unable to attend study visits or comply with procedures. 
17. Concurrent participation in any other interventional study. 
Medication exclusion criteria 


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18. Use of topical 5-ASA or corticosteroid enemas/suppositories within 
2 weeks of administration of the screening endoscopy. 
19. Use of TNF-α antagonists within 60 days prior to screening. 
20. Use of ustekinumab within 3 months prior to screening. 
21. Use of cyclosporine, thalidomide, tacrolimus, sirolimus, or 
mycophenolate mofetil within 1 month prior to screening. 
22. Have received any investigational or biologic agent within 1 month (or 5 
half-lives of the agent, whichever is longer) prior to screening. 
23. Prior treatment with vedolizumab or natalizumab. 
Test Product(s), Dose, 
and Mode of 
Administration: 
Subjects will receive the following treatments according to a randomisation 
schedule generated by IXRS: 
• 
PTG-100 (150 mg) once daily (QD) by oral administration 
• 
PTG-100 (300 mg) QD by oral administration 
• 
PTG-100 (900 mg) QD by oral administration 
• 
Placebo QD by oral administration 
 
Matching PTG-100 (150 mg or 300 mg unit dose) and placebo capsules will be 
provided to subjects in prepackaged individual study drug kits, identical in 
appearance, according to the randomisation schedule. During the double-blind 
treatment period, subjects will take a total of 3 capsules QD, as indicated below, 
without regard to meals. 
• 
150 mg PTG-100: 1 × 150-mg capsule, 2 × placebo capsules 
• 
300 mg PTG-100: 2 × 150-mg capsules, 1 × placebo capsule 
• 
900 mg PTG-100: 3 × 300-mg capsules 
• 
Placebo: 3 x placebo capsules 
Duration of 
Treatment: 
Planned Enrolment/Screening Duration: up to 42 days (Days -42 to -1). 
Outpatient Visits: Days 14, 28, 42, 56, and 84.  
A telephone visit will be conducted on Day 70. 
Follow-up Visit: approximately 28 days (Day 112) after the last dose of study 
drug. 
Planned Study Conduct Duration (Screening to Follow-up visit): approximately 
17 to 20 months (up to 42 days of screening + 12- to 15-month enrolment 
+ 12 weeks treatment + 28 days follow-up). 
Criteria for 
Evaluation: Efficacy 
The primary efficacy endpoint is the: 
1. Proportion of subjects receiving PTG-100 with clinical remission at 
Week 12 compared with placebo 
 
Clinical remission is defined as follows, using the Mayo subscores of stool 
frequency, rectal bleeding, and endoscopy: 
• 
Stool frequency subscore of 0 or 1 with a pre-specified change of 1 or 
more from baseline 
• 
Rectal bleeding subscore of 0 
• 
Endoscopy subscore of 0 or 1 (modified so that a score of 1 does not 
include friability) 
 
The secondary efficacy endpoints (all based on comparison of individual 
PTG-100 dose levels to placebo) are: 
1. Proportion of subjects with endoscopic response at Week 12 (Day 84) 
(defined as an endoscopic subscore of 0 or 1) 
2. Proportion of subjects with clinical response at Week 12 (Day 84) 
(defined as at least 1 point and 30% reduction from baseline in rectal 


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bleeding and stool frequency subscores) 
3. Mean change in endoscopy subscore from baseline to Week 12 
4. Mean change in rectal bleeding and stool frequency subscores from 
baseline to Weeks 2, 4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 70, 84, 
and 112) 
5. Proportion of subjects with endoscopic remission at Week 12 (Day 84) 
(defined as an endoscopic subscore of 0) 
6. Mean change in complete Mayo Score (including all 4 subscores) from 
baseline to Week 12 (Day 84) 
7. Mean change in partial Mayo Score (excluding endoscopy subscore) 
from baseline to Weeks 2, 4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 
70, 84, and 112) 
8. Mean change in faecal calprotectin levels from baseline to Weeks 6 
(Day 42), 12 (Day 84), and 16 (Day 112) 
9. Mean change in IBDQ score from baseline to Week 12 (Day 84) 
10. Proportion of subjects developing ADA by Weeks 12 (Day 84) and 16 
(Day 112) 
 
The exploratory efficacy endpoints (all based on comparison of individual 
PTG-100 dose levels to placebo) are: 
1. Mean change in histological score from baseline to Week 12 (Day 84) 
2. Effects of ADA on PK, safety, and efficacy in subjects with positive 
ADA 
Criteria for 
Evaluation: Safety 
The primary safety endpoint is: 
1. Proportion of subjects with at least 1 AE comparing individual PTG-100 
dosing groups with placebo 
 
The secondary safety endpoints (all based on comparison of individual PTG-100 
dose levels to placebo) are: 
1. Frequency and type of AEs (affecting ≥ 5% of subjects)  
2. Proportion of subjects with at least 1 serious AE (SAE)  
3. Number and type of SAEs 
4. Frequency of AEs of special interest including serious or opportunistic 
infection (viral, bacterial, fungal including systemic/gut localization), 
allergic/drug reactions, immune system disorders, and suspected PML. 
5. Clinically significant changes in safety labs, ECGs, or physical 
examination findings (including vital signs) 
Criteria for 
Evaluation: PK, PD, 
and ADA 
The PK/PD/ADA endpoints are: 
1. PTG-100 plasma levels 
2. Blood α4β7 RO (peripheral blood T cells)  
3. Blood α4β7 RE (peripheral blood T cells) 
4. Proportion of subjects developing ADA by Weeks 12 (Day 84) and 16 
(Day 112) 
 
The exploratory PD endpoints are: 
1. Analysis of peripheral blood lymphocytes in subjects on individual 
PTG-100 dose levels compared to placebo 
2. Number of β7 positive cells in colonic biopsies as assessed by 
immunohistochemistry in subjects on individual PTG-100 dose levels 
compared to placebo 
3. Characterisation of immunologic biomarkers in the target population 
(selected sites only) 
Statistical Methods: 
Treatment population definitions: 


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• 
All randomised participants who receive any amount of study drug (Safety 
Population) will be included in the safety analyses.  
• 
All randomised participants who receive a Day 0 dose of study drug and who 
have sufficient PK data for analysis (PK Analysis Population) will be 
included in the PK analyses.  
• 
All randomised participants who receive any amount of study drug and who 
have results from baseline and from ≥ 1 post-baseline assessment (Full 
Analysis Set) will be included in the PD and efficacy analyses.  
 
Safety and Tolerability: 
Continuous safety data will be summarised with descriptive statistics (arithmetic 
mean, standard deviation [SD], median, minimum, and maximum) by dose level. 
Categorical safety data will be summarised with frequency counts and percentages 
by dose level. Adverse events will be coded using the most current Medical 
Dictionary for Regulatory Activities available. A by-participant AE data listing, 
including verbatim term, preferred term, system organ class, treatment, severity, 
and relationship to study drug, will be provided. The number of participants 
experiencing treatment-emergent AEs (TEAEs) and number of individual TEAEs 
will be summarised by treatment group, system organ class, and preferred term. 
The TEAEs will also be summarised by severity and by relationship to study drug. 
 
Laboratory evaluations, vital signs assessments, and ECG parameters will be 
summarised by treatment group and protocol-specified collection time point. A 
summary of change-from-baseline at each protocol-specified time point by 
treatment group will also be presented. 
 
Clinically significant changes in physical examinations will be listed for each 
participant and described in the text of the final report. 
 
Concomitant medications will be listed by participant and coded using the most 
current World Health Organization drug dictionary. 
 
Medical history will be listed by subject. 
 
Further details regarding presentation and analysis of safety data will be detailed 
in the Statistical Analysis Plan (SAP). 
 
Anti-drug Antibodies: 
Serum samples will be evaluated for the presence of ADAs through use of a 
bridging immunoassay. The evaluation will include assessment of neutralising 
ADAs, as well as the potential of ADA to cross-react with endogenous mucosal 
addressin cell adhesion molecule 1. If ADA is detected in clinical samples, the 
effect of ADA on PK, safety, and efficacy may be explored for all subjects who 
demonstrate evidence of ADAs.  
 
Pharmacokinetics: 
Individual PTG-100 concentration data will be listed and summarised by 
treatment group with descriptive statistics (sample size, arithmetic mean, SD, 
median, minimum, maximum, geometric mean, and geometric coefficient of 
variation). Individual and mean PTG-100 concentration-time profiles for each 
treatment group will also be presented graphically. 
 
Plasma PTG-100 noncompartmental PK parameters including maximum observed 


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concentration (Cmax), trough (predose) concentration (Ctrough), time of Cmax (Tmax), 
and area under the concentration-time curve from time 0 to the time of the last 
sample collection (AUC0-t) will be estimated. 
 
Correlations between PTG-100 drug levels and PD or efficacy responses may be 
explored. 
 
Details regarding the statistical analyses of PK data will be provided in the SAP. 
 
Pharmacodynamics: 
Individual data will be listed for each subject and summarised by nominal 
sampling time point and treatment group with descriptive statistics (arithmetic 
mean, SD, median, minimum, and maximum). A summary of change-from-
baseline at each protocol-specified time point by treatment group will also be 
presented. The change of PD indicators over time will be demonstrated 
graphically and will be compared among the dose levels. 
 
Receptor occupancy and α4β7 RE in peripheral blood will be listed for each 
subject and summarised by frequency counts for discrete categories. 
 
Additional population PK-PD modelling and immunologic assessment may be 
performed if deemed necessary. 
 
Details regarding the statistical analyses of PD data will be provided in the SAP. 
It should be noted that PD samples are to be collected at selected sites only. 
 
Efficacy Evaluations: 
Descriptive statistics will be used to evaluate differences in demographic and 
baseline characteristics.  
 
For the primary analysis, proportions of subjects with clinical remission will be 
compared between each dose and placebo using Cochran-Mantel-Haenszel test, 
with adjustment for stratification factors. Multiplicity will be addressed via closed 
testing procedure with combined p-values computed for each of the 2 stages of the 
trial (Stage 1 and Stage 2; IA and post IA). Each stage p-value will be adjusted as 
appropriate by a closed testing multiple comparison approach that controls the 
overall type 1 error at alpha=0.025, 1-sided. 
 
All analyses will be based on combined Stage 1 and Stage 2 data and include data 
from the dose(s) that is (are) dropped for Stage 2. Exploratory analyses will be 
carried out to assess consistency of results between Stages 1 and 2. Analyses of 
other binary endpoints will be carried out similarly. 
 
Subjects who discontinue prematurely will be considered treatment failures.  
 
Rates of clinical response, endoscopic response, and endoscopic remission will be 
evaluated similarly.  
 
Changes from baseline complete Mayo Score, partial Mayo Score, rectal bleeding 
subscore, stool frequency subscore, endoscopy subscore, IBDQ score, and faecal 
calprotectin levels will be analysed using repeated measures mixed analysis of 
covariance model adjusted for treatment, time point, treatment-by-time point 
interaction, stratification factors, and baseline values. For subjects who withdraw 


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prematurely, the last observation will be carried forward. These analyses will be 
based on the Stage 1 and Stage 2 combined data for exploratory purposes. 
 
 
 


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2 INTRODUCTIONa 
2.1 Background and Rationale 
Protagonist Therapeutics, Inc. is developing PTG-100 as a potential oral therapy for 
patients with moderate to severe active ulcerative colitis (UC). PTG-100, a peptide dimer 
comprised of natural and unnatural amino acids and a homologated amide bond, is an 
orally-stable peptide that binds specifically to α4β7 integrin on leukocytes.  
 
PTG-100 is designed to be stable against various forms of gastrointestinal (GI) 
degradation and to target α4β7 integrin within the GI tissue compartment. Animal 
pharmacokinetic (PK) studies have shown these peptides are orally stable because they 
can be detected as full-length intact peptides in gut tissues and faeces after oral 
dosing. The PK studies have also shown the oral peptides have high exposure in the 
colon, small intestine, and to a lesser extent in the mesenteric lymph nodes with less than 
0.5% systemic bioavailability; therefore, its presence is largely restricted to the GI tract.   
 
PTG-100 binds specifically to α4β7 integrin on leukocytes, the same target as the 
approved antibody therapeutic vedolizumab (Entyvio®).  PTG-100 is a potent and 
selective inhibitor of α4β7 integrin with binding selectivity identical to the antibody 
product vedolizumab. PTG-100 does not bind to α4β1 integrin. The α4β7 integrin, which 
is primarily involved in the recruitment of leukocytes to the GI tract, is present on the cell 
surface of a small population of circulating T- and B-lymphocytes. The major ligand for 
α4β7, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), is selectively 
expressed on the endothelium of the intestinal vasculature and is present in increased 
concentrations in inflamed tissue. Through blockade of leukocyte trafficking in the gut, 
PTG-100 may inhibit inflammation in the GI tract, potentially reducing the signs and 
symptoms of active UC.  
 
Vedolizumab (Entyvio®), an intravenously administered monoclonal antibody that 
similarly targets α4β7 integrin, has been approved for the treatment of adult patients with 
moderate to severe active UC who have had an inadequate response with, lost response 
to, or were intolerant to a tumour necrosis factor-alpha (TNF-α) blocker or 
immunomodulator; or had an inadequate response with, were intolerant to, or 
                                                 
a Information supplied by the Sponsor. 


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demonstrated dependence on corticosteroids.1 Vedolizumab has also been approved for 
treatment of patients with Crohn’s disease (CD).2 Therefore, it is considered that 
blockade of this interaction is a safe and effective therapy for inflammatory bowel 
disease.  
 
Ulcerative colitis is a chronic inflammatory bowel disease characterised by bloody 
diarrhoea, abdominal cramps, and fatigue.3 Current medical therapy has important 
limitations. Aminosalicylates are only modestly effective; glucocorticoids can cause 
unacceptable adverse events (AEs) and do not provide a benefit as maintenance 
therapy.4-6 Tumour necrosis factor-alpha antagonist antibody drugs, although efficacious, 
may predispose patients to serious infection, a risk of malignancy, and development of 
anti-drug antibodies (ADA).7-9 Vedolizumab (Entyvio®) is administered as an intravenous 
(IV) infusion with potential for systemic infection and risk of immunogenicity.1,2,10 
Therefore, new treatment strategies are needed for patients with UC.  
 
Due to the inconvenience of injectable therapies, associated safety risks of systemic 
treatment, and risk of development of ADA, PTG-100, an orally-stable, GI-restricted 
peptide therapeutic candidate that targets α4β7, may provide a significant benefit to 
patients with moderate to severe UC. 
 
Both in vitro and in vivo pharmacology studies have been conducted to assess the 
activity, mechanism of action, and toxicity of PTG-100. PTG-100 is a potent and 
selective inhibitor of α4β7 with binding properties highly similar to the antibody product 
vedolizumab. Similar to vedolizumab, PTG-100 does not bind α4β1 integrin. A dextran 
sulphate sodium-induced colitis mouse model demonstrated that PTG-100 administration 
induced a dose-dependent reduction in α4β7+ memory T cell homing to inflamed gut 
tissue and a significant improvement in mucosal damage as assessed by blinded 
endoscopy. Pharmacokinetic studies show that drug levels are much higher in GI tissues 
compared to blood, which suggests that drug exposure in the GI tissues is the principal 
driver for the in vivo pharmacology. Fluorescence-activated cell sorter (FACS) analysis 
of whole blood from healthy cynomolgus monkeys demonstrated that a peripheral blood 
receptor occupancy (RO) of less than 50% is correlated with in vivo efficacy in the 
mouse studies. Levels of circulating α4β7+ memory T cells were increased when 
normalised to total CD4 cells following PTG-100 dosing, confirming that blocking 
homing of α4β7+ memory T cells redistributes these cells to the blood. 
 


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In 42- and 90-day (Good Laboratory Practice [GLP]) toxicology studies, no adverse 
toxicological findings were observed at once daily (QD) doses up to 90 mg/kg/day and 
75 mg/kg/day in rats and monkeys, respectively. The no observed effect level (NOEL) in 
rats was 90 mg/kg/day, the highest level evaluated. In the monkey study, the no observed 
adverse effect level (NOAEL) was considered to be 75 mg/kg/day, the highest dose 
tested. Also, histology from the 90-day toxicology studies demonstrated no adverse 
testicular findings.   
 
Reproductive and developmental toxicity studies of limited scope (6 dams/group) in rats 
and rabbits have been completed. There were no maternal or developmental effects noted 
in either study. The maternal and developmental NOEL for PTG-100 was 90 mg/kg/day 
in pregnant rats and 75 mg/kg/day in pregnant rabbits, the highest dose levels tested in 
these studies. Definitive reproductive and developmental toxicity studies to evaluate 
embryo-foetal development will be completed prior to the Phase 3 clinical program.  
 
PTG-100 did not inhibit the human Ether-à-go-go Related Gene potassium channel 
current. No effects of PTG-100 were observed on the cardiovascular or respiratory 
systems in conscious monkeys, or in central nervous system functional assessment 
(Irwin) or GI motility studies in rats. In vitro GLP genotoxicity tests were negative, 
indicating a low genotoxic potential. 
 
Protagonist has completed a Phase 1 randomised, double-blind, placebo-controlled, 3-part 
study (Study PTG-100-01) of PTG-100 in 78 normal healthy male volunteers in 
Australia. Sixty-four of the 78 subjects were treated with PTG-100. Parts 1 and 2 
evaluated single and multiple ascending doses of PTG-100, respectively, up to a 
maximum daily dose of 1000 mg using a liquid phosphate buffer (PB) formulation of 
PTG-100. Doses up to 1000 mg/day were tested as a single dose and as QD dosing for 
14 days. Part 3 was a single dose cross-over study of PTG-100 capsule formulation 
compared to solution-based PB formulation. These data informed the selection of doses 
in Phase 2 (Section 2.2).  
 
In this Phase 1 study, PTG-100 was well tolerated; there were no serious AEs (SAEs) or 
dose-limiting toxicities observed. All AEs were mild to moderate in severity. No dose-
dependent increase in AEs was noted. There were no clinically significant abnormalities 
or trends in clinical labs, electrocardiograms (ECGs), or vital signs. The maximum dose 
tested for both single and multiple dosing was 1000 mg; no dose-limiting toxicities were 
observed at this or any doses.  


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Consistent with the preclinical data in mice, rats, and cynomolgus monkeys, in Study 
PTG-100-01, the plasma exposure to PTG-100 was extremely low (< 1%) as determined 
by the area under the concentration-time curve (AUC) and maximum observed 
concentration (Cmax), thus reflecting the GI-restricted nature of the drug. In a small cohort 
of subjects administered a single dose of PTG-100 (300 mg), the systemic exposure (as 
measured by Cmax and AUC from time 0 to the time of the last sample collection 
[AUC0-t]) of PTG-100 when given to participants after a high-fat meal was approximately 
30% of that for PTG-100 administered under fasted conditions. All subjects in the 
multiple ascending dose (MAD) cohorts in the trial were fed a standard diet. There was 
minimal drug accumulation at Day 14 in the MAD cohorts, related to the relatively short 
half-life in the blood.  
 
Dose-dependent increases in blood RO and reduction in receptor expression (RE; eg, 
receptor down-regulation), as reflecting target engagement in the GI tissue compartment, 
were observed, thus supporting evidence of sustained target engagement and 
pharmacologic activity of PTG-100 in healthy volunteers comparable to the data in 
mouse and cynomolgus monkey studies. Saturating levels of receptor down-regulation 
were observed at the 300-mg dose level following multiple dose exposure. Blood RO and 
RE levels in the healthy volunteers (at the 300-mg dose level) exceeded threshold levels 
in the healthy mice at comparable dose levels (based on allometric scaling; eg, 
approximately 50 mg/kg/day); this dose threshold also correlated with inhibition of 
lymphocyte trafficking and improvements in disease activity in the colitis mouse studies. 
Therefore, the data suggest a potentially efficacious dose of 300 mg in patients with UC.  
 
To support the use of the capsule formulation in Study PTG-100-02, in vivo PK bridging 
studies in cynomolgus monkey and normal healthy volunteers have demonstrated that the 
relative bioavailability of the capsule formulation compared to the liquid PB formulation 
(used in the GLP toxicology studies and Phase 1 single ascending dose and MAD 
cohorts) was approximately 60% based on AUC0-t and AUC from time 0 to infinity. 
Despite the lower plasma exposure of the capsule formulation compared to the liquid 
formulation, the pharmacodynamic (PD) effects (eg, blood RO and RE) were highly 
similar between the capsule and liquid formulations. These data support the use of the 
capsule formulation in the Phase 2b clinical trial at doses established by single and 
multiple dose cohorts using the liquid PB formulation. 
 


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Further information about the preclinical and Phase 1 studies are provided in the 
Investigator’s Brochure (IB). 
2.2 Study Rationale 
This is the first time PTG-100 will be administered to subjects with UC. The principle 
aims of this study are to evaluate the safety/tolerability and efficacy of PTG-100 
administered for 12 weeks as single daily oral doses to UC subjects with moderate to 
severe active disease. This information, together with PK/PD data, will help establish the 
doses and duration of induction dosing in subjects with moderate to severe active UC. 
 
The study design and target population described in this protocol is consistent with 
previous Phase 2 studies evaluating safety and efficacy in patients with moderate to 
severe active UC. In this trial, a parallel adaptive 2-stage methodology was selected to 
allow for interim assessment of futility and to drop one (or 2) study arms in order to most 
efficiently allocate subjects to the most informative dose arms.  
 
As is appropriate for such studies, a placebo group of UC subjects is included with 
multiple active dose groups to optimise dose finding during induction treatment. A 
blinded approach will be incorporated. 
 
Subjects will receive dose levels of PTG-100 within the range of doses supported by 
appropriate GLP toxicology studies and in a healthy volunteer population.  
 
The 12-week (84-day) duration of induction treatment is deemed sufficient for 
observation of appreciable, quantifiable symptom improvement and to characterise the 
optimal duration of induction treatment. Prior studies have suggested that shorter 
induction treatment periods may not be sufficient to identify optimal dose-response 
outcomes prior to changing to maintenance dosing regimens.1,11,12  In particular, the 
Phase 3 study of vedolizumab (Entyvio®), which was not designed to identify the time of 
maximal effect of vedolizumab as induction therapy, demonstrated greater efficacy 
beyond the induction treatment of 6 weeks.  
 
The primary endpoint of the trial will be the induction of clinical remission at 12 weeks, a 
well-established efficacy measure using Mayo Score assessment subscores for stool 
frequency, rectal bleeding, and endoscopy, but excluding the physician’s global 
assessment (PGA) subscore (see Section 7.4 for details). This definition is in accordance 


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with recent Food and Drug Administration (FDA) and European Medicines Agency 
(EMA) guidance. Secondary efficacy endpoints will include clinical response, 
endoscopic response, endoscopic remission, and changes in Mayo Score, partial Mayo 
Score, rectal bleeding subscore, stool frequency subscore, endoscopic subscore, faecal 
calprotectin, and Inflammatory Bowel Disease Questionnaire (IBDQ) from baseline. 
Further details may be found in the appendices and Section 7.4. 
2.3 Dose Rationale 
This Phase 2b study will initially consist of 4 arms: 3 dose levels of PTG-100 (150 mg, 
300 mg, and 900 mg QD) and one placebo arm QD. Following the interim analysis (IA; 
see Section 7.2), one (or 2) dose levels of PTG-100 will be dropped with additional 
subjects being randomised to the remaining dose arms.  The dose range of 150 to 900 mg 
is intended to bracket the 300-mg dose that may be a potentially efficacious dose based 
on translation of animal and Phase 1 PD data (see below). In order to optimise the 
duration of induction dosing, we will assess efficacy and safety over 12 weeks treatment. 
 
The selection of doses for this study is based on integration of toxicology and PK/PD 
data from preclinical studies and safety and PK/PD data from the Phase 1 clinical study 
(PTG-100-01), using exposure (dose levels, plasma exposure) and response data 
(inhibition of lymphocyte trafficking, disease activity improvement, α4β7 binding 
saturation, and α4β7 RE on peripheral blood T cells). In 42- and 90-day (GLP) 
toxicology studies, no adverse toxicological findings were observed with QD doses up to 
90 mg/kg/day and 75 mg/kg/day in both rats and monkeys. The NOEL in rats was 
90 mg/kg/day, the highest level evaluated.  In the monkey study, the NOAEL was 
considered to be 75 mg/kg/day, the highest dose tested.  The high doses used in the repeat 
dose GLP studies in rats (90 mg/kg/day) and monkeys (75 mg/kg/day) correlate to a 
human equivalent dose of 14.5 mg/kg and 24.2 mg/kg, respectively.  These dose levels in 
rats and monkeys correlate to doses of 871 mg and 1452 mg, respectively, based on 
allometric scaling in a 60 kg human. The 900-mg dose does not exceed the maximum 
dose of 1000 mg tested in the Phase 1 study (see Section 2.1). The blood RO and RE 
biomarkers have been shown to reflect primary target engagement in the GI tissues in the 
animal studies, since blood RO and RE measure recirculating lymphocytes with bound 
drug. At low dose levels, at time points earlier than 4 hours, RO levels in cells in the 
Peyer's patches and the mesenteric lymph nodes of mice are much higher than those 
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In mouse colitis models, inhibition of T cells trafficking to the gut and disease activity 
improvement were observed at doses between approximately 6 and 55 mg/kg/day with 
corresponding peak peripheral blood α4β7 receptor blockade of < 50%. Doses as low as 
6 mg/kg/day in the mouse significantly inhibited lymphocyte homing to the gut, while 
doses of approximately 55 mg/kg/day significantly reduced disease activity in the colitis 
mice. The dose range of 6 to 55 mg/kg/day in mouse may be extrapolated to a potentially 
efficacious dose range of approximately 35 to 300 mg daily dose in humans via 
allometric scaling by whole body surface area, a conservative assumption for a 
GI-restricted drug.  
 
Data from the Phase 1 healthy volunteer study (Study PTG-100-01) corroborated target 
blood RO and α4β7 RE levels that were observed in the mouse and cynomolgus monkey 
studies. Both blood RO and RE levels at the 300-mg dose level in healthy human 
volunteers at 24 hours following the last dose in the MAD cohorts (ie, trough exposure) 
exceeded threshold levels in the healthy mice at a comparable dose level (ie, 
approximately 50 mg/kg/day). Further, there was evidence of saturation of receptor 
down-regulation activity at the 300-mg dose in the multiple dose cohorts in Study 
PTG-100-01. Since inhibition of cell trafficking and mucosal healing was observed at a 
similar dose in the colitis mice (eg, dose range of 6 to 55 mg/ kg), the data conservatively 
suggest a potentially efficacious dose of approximately 300 mg in humans. Since 
PTG-100 exposure in blood and GI tissues of healthy mice is similar to that observed in 
colitis mice, it was determined that drug tissue exposure is unaffected by the 
inflammatory status of the mucosal layer. Thus, the highest efficacious dose in the colitis 
mice (approximately 55 mg/kg/day) corresponds to approximately 300 mg/day in the 
human.   
 
Based on these data, a dose range of 150 to 900 mg was selected for this Phase 2b study 
to target corresponding blockade of the α4β7 receptors and saturating levels of target 
expression in healthy human volunteers that correlated with dose levels inducing 
pharmacologic and clinical activity in the mouse colitis models. Sustained levels of blood 
RO and saturation levels of RE at 24 hours postdose in the MAD cohorts on Day 14 
(corresponding to trough levels), despite minimal plasma exposure of PTG-100, support 
the QD dosing regimen. 
 


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2.4 Rationale for Target Population 
PTG-100 is being developed for the treatment of patients with moderate to severe active 
UC, similar to the target population for the FDA-approved antibody vedolizumab 
(Entyvio®). In this study, the target population will include male and non-gravid female 
adult subjects with diagnosed UC for ≥ 2 months prior to screening and a Mayo Score of 
6 to 12, inclusive (total Mayo Score range 0 to 12), at baseline (pre-randomisation) with 
an endoscopy subscore of at least 2 (range 0 to 3) as determined by blinded central read. 
 
Eligible subjects will have failed treatment with at least 1 or more of the following 
agents: glucocorticoids, immunosuppressive medications (ie, azathioprine and 
6-mercaptopurine [6-MP]), and/ or TNF-α antagonists. A maximum of 50% of 
randomised subjects may have failed prior treatment with TNF-α inhibitor therapies. 
Subjects with prior exposure to vedolizumab or natalizumab will be excluded.  
 
As PTG-100 has minimal systemic absorption and a favourable safety/ tolerability profile 
in toxicology and human subjects to date, Protagonist believes that the proposed criteria 
define an appropriate population in which PTG-100 will be investigated. 
 
For subjects in the Netherlands, only subjects who have had prior exposure to anti-TNF 
agents will be allowed to enrol in the study. 
2.5 Rationale for Endpoints 
This Phase 2b study is designed to assess the safety and efficacy of induction treatment of 
PTG-100 in subjects with moderate to severe active UC.  The selection and definition of 
efficacy endpoints are consistent with recent FDA and EMA guidance and will be based 
on patient-reported and endoscopic outcomes. 
 
The study is modelled after other recent clinical studies of a wide range of drugs in mild 
to severe UC. The Mayo Score will be used as the primary assessment method and will 
be adapted based on the recent regulatory guidance documents for assessment of the 
primary and secondary endpoints (see below). Traditional outcome measures in UC trials 
consist of composite instruments that incorporate symptoms, laboratory criteria, and 
sigmoidoscopic findings. The Mayo Score is a composite instrument that includes both 
endoscopic and clinical items.13 The index has been used in multiple clinical trials of 
mesalamine, budesonide, infliximab, adalimumab, golimumab, and vedolizumab. In a 
recent meta-analysis, mucosal healing as assessed by sigmoidoscopy was associated with 


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long-term clinical remission, avoidance of colectomy, and corticosteroid-free clinical 
remission.14 In addition to the traditional endpoint of remission which incorporates 
symptomatic and endoscopic improvement, the Mayo Score has been adapted to 
functionally create co-primary endpoints in trials by separating components into 
symptom-based and endoscopic criteria of response and remission. Symptom-based 
criteria, that do not include endoscopy, have good correlation with the full Mayo Score.  
 
The primary efficacy endpoint of the trial will be induction of clinical remission at 
12 weeks (see Section 7.4). Clinical remission will be based on the following patient-
reported and endoscopic criteria from the adapted Mayo Score assessment tool: 
1. Stool frequency subscore of 0 or 1 with a pre-specified change of 1 or more from 
baseline 
2. Rectal bleeding subscore of 0 
3. Endoscopy subscore of 0 or 1 (modified so that a score of 1 does not include 
friability) 
 
The secondary endpoints will include clinical response, endoscopic response, endoscopic 
remission and changes in endoscopy, rectal bleeding and stool frequency subscores, 
partial Mayo Score, complete Mayo Score, faecal calprotectin, and IBDQ score. 
Histological outcomes will also be assessed from colonic biopsy samples pre- and post-
treatment. Because observer variation in endoscopic assessments can result in differences 
in response rates compared to placebo, central reading of the recorded endoscopy scans 
will be performed to confirm eligibility and to assess key endpoints. In UC trials, central 
reading of endoscopic videos has been shown to be highly reliable and to reduce the rate 
of placebo response.15 
3 STUDY OBJECTIVES 
The primary objectives of this study are: 
1. To evaluate the safety and tolerability of PTG-100  
2. To evaluate the efficacy of PTG-100 in the induction treatment of subjects with 
moderate to severe active UC compared to placebo.  
 
The secondary objectives are: 
1. To evaluate the dose-response relationship and select PTG-100 induction 
regimens for continued development 
2. To evaluate the PK of PTG-100 in subjects with active UC 


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3. To evaluate the PD effects of PTG-100 including the assessment of RO and α4β7 
RE in peripheral blood lymphocytes  
4. To evaluate changes in faecal calprotectin levels for subjects receiving PTG-100 
compared to placebo 
5. To evaluate the incidence of positive ADAs in subjects receiving PTG-100. 
 
The exploratory objectives are: 
1. To evaluate the ability of subjects receiving PTG-100 to achieve histological 
improvement in colonic tissue biopsies compared to placebo 
2. To characterise immunologic biomarkers in the target population and to evaluate 
changes in immunological/PD biomarkers in subjects receiving PTG-100 
compared to placebo 
4 INVESTIGATIONAL PLAN 
4.1 Study Design Overview 
This Phase 2b study will be a randomised, double-blind, placebo-controlled, multi-centre, 
parallel adaptive 2-stage design to evaluate safety/tolerability and efficacy in subjects 
with moderate to severe active UC. 
 
Approximately 100 to 120 sites worldwide will participate in this study. No study-site 
target enrolment numbers will be set so as to allow for competitive enrolment among 
sites. It should be noted that for subjects in the Netherlands, only subjects who have had 
prior exposure to anti-TNF agents will be allowed to enrol in the study. 
 
Subjects will be screened for eligibility within 42 days of dosing (see Figure 4-1). 
Eligible subjects will return for sigmoidoscopy/ biopsy and recording baseline Mayo 
Score (within 14 days of randomisation; however, subjects may have a combined 
Screening visit that includes endoscopy). On Day 0, assessments including physical 
examinations, safety labs, ECG, progressive multifocal encephalopathy (PML) 
assessment, PK, PD, ADA, faecal calprotectin, and IBDQ, will be performed predose 
followed by dosing, physical examination, AE assessment, and blood sampling for PK 
and PD analysis.  
 


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Figure 4-1 Screening and Randomisation Design Schematic 
 
*Dosing to occur within 7 days of randomisation. 
 
Treatment duration will be 12 weeks in order to optimise the duration of induction dosing 
for continued development. A total of 9 visits to the clinical site will include: 2 Screening 
visits (one for general inclusion/exclusion criteria assessment and a second including 
recording baseline Mayo scoring and sigmoidoscopy/ biopsy, with the latter occurring 
within 14 days of randomisation; Day -42 to Day -7 for both Screening visits; however, 
subjects may have a combined Screening visit that includes endoscopy); dose initiation 
(Day 0); assessment visits on Days 14, 28, 42, 56, and 84; and Follow-up visit on 
Day 112. Day 70 will be a phone visit and subjects will be instructed to record stool 
frequency and rectal bleeding data preceding Day 70. A phone visit will be conducted at 
approximately 6 months after the end of study treatment period in which a PML 
assessment will be performed. Post-treatment sigmoidoscopy/ biopsy will be performed 
on Day 84 (Week 12). Study design schematics for the screening/randomisation period 
and overall study are shown in Figure 4-1 and Figure 4-2, respectively. A 3-day window 
(± 3 days) is allowable for each study visit following dosing with a 7-day window 
(± 7 days) allowed for the Follow-up visit on Day 112. 
 
Subjects will be randomised (1:1:1:1) using an interactive web/voice response system 
(IXRS; Almac, Craigavon, Northern Ireland) to one of the following treatments groups: 
• PTG-100 (150 mg) QD by oral administration 
 
• PTG-100 (300 mg) QD by oral administration 
 
• PTG-100 (900 mg) QD by oral administration 
 
• Placebo QD by oral administration 


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An IA will be performed after approximately 60 to 80 subjects have completed 12 weeks 
of dosing (Section 7.2). Subject enrolment will occur in 2 stages relative to the IA, the 
purpose of which will be to conduct a futility analysis and, if futility criteria are not met, 
to identify which study arms provide optimal data in order to select one (or 2) PTG-100 
dose levels and placebo to continue enrolling subjects to the most informative dose arms.   
 
The schematic of the study design is displayed in Figure 4-2. The start of the study is 
defined as the date the first subject enrolled in the study (ie, signs an Informed Consent 
Form [ICF]). A subject who completes the Day 112 Follow-up visit is considered to have 
completed the study. Completion of the study does not include any unplanned Follow-up 
visits (eg, return to the clinic for repeat clinical laboratory) or the phone visit 
approximately 6 months after the end of treatment. The end of the study is defined as the 
date the last subject completes the study (or completes an Early Termination visit). The 
planned duration of study conduct is approximately 17 to 20 months from Screening 
through the final subject’s Follow-up visit (up to 42 days of screening + 12- to 15-month 
enrolment + 12 weeks treatment + 28 days follow-up). 
 


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Figure 4-2 Study Design Schematic 
 
 
ADA = anti-drug antibodies; IBDQ = Inflammatory Bowel Disease Questionnaire; PD = pharmacodynamics; PK = 
pharmacokinetics; QD = once daily; TNFα = tumour necrosis factor-alpha; UC = ulcerative colitis. 
 
In this study, the primary efficacy endpoint is clinical remission as defined by the rectal 
bleeding, stool frequency, and endoscopic subscores of the Mayo Score; clinical 
response, endoscopic response, and endoscopic remission will be determined using 
designated subscores of the Mayo Score assessment (see Section 7.4 for details). Changes 
in complete and partial Mayo Score, rectal bleeding subscore, stool frequency subscore, 
and endoscopic subscore will be evaluated at designated time points. The IBDQ 
questionnaire will be assessed pre- and post-treatment; sigmoidoscopy and biopsy will be 
performed at baseline and Day 84 for evaluation of endoscopic response and remission 
and histological assessment. Stool samples will be collected for faecal calprotectin at 
designated time points. Subject blood samples will be obtained at designated time points 
from Day 0 through Day 112 for analysis of safety labs, PK, PD, and ADA parameters.  
 
Safety will be monitored with AE inquiries, assessment of concomitant medication use, 
clinical laboratory evaluations (Appendix B), vital sign measurements, 12-lead ECGs, 
and physical examination findings during the study. A PML assessment will also be done 
at designated time points. A study flow chart is presented in Table 6-1. 
 
Phase 2b in UC patients: 12 Week Induction
Randomised, Double-blind, Placebo-controlled Adaptive Design
Moderate to Severe
Active UC
∼100 sites 
• Biologics-naïve treatment failure 
or TNFα-refractory (up to 50%)
• Stratification: 
- Prior TNFα antagonist use 
300 mg QD
Placebo QD
900 mg QD
150 mg QD
Stage 1
300 or 900 mg QD
Placebo QD
150 or 300 mg QD
Stage 2b*
Interim
• PD
• Clinical Readouts
• Safety
*Drop 1 or 2 doses
Interim Analysis
• Clinical remission
• Clinical response
• Mayo Score
• Partial Mayo Score
• Endoscopic response
• Endoscopic remission
• Patient oriented 
outcomes (stool 
frequency, rectal 
bleeding)
• Faecal calprotectin
• IBDQ
• PD
• PK
• ADA
• Adverse events
Final Analysis
(Stage 1 + Stage 2)


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Pharmacokinetic analyses will be performed to characterise PTG-100 drug levels and PK 
parameters (AUC0-t, Cmax, trough [predose] concentration [Ctrough], and time of Cmax 
[Tmax]). Pharmacodynamic analyses will be performed to assess the blood PTG-100 RO 
and α4β7 RE in peripheral blood lymphocytes. The incidence of ADA will be assessed. 
 
Subjects will be stratified by prior treatment with TNF-α antagonist use. 
5 SUBJECT SELECTION 
Subjects who meet ALL of the inclusion criteria and for whom NONE of the exclusion 
criteria apply will be eligible to be enrolled into the study. Safety evaluations may be 
repeated at the Investigator’s (or designee’s) discretion. 
 
Approximately 240 subjects will be randomised in the trial.  
5.1 Inclusion Criteria 
The following are the inclusion criteria. Subjects must meet ALL of the following 
inclusion criteria to be enrolled. Subjects may be screened up to 3 different times 
separated by at least 14 days. 
 
1. Male and female subjects aged 18 to 80 years, inclusive. 
2. Diagnosis of UC for ≥ 2 months prior to screening, with a history of disease 
activity extending beyond the rectum; if the UC has been present for > 10 years, a 
total colonoscopy with biopsy must have been performed within 2 years of 
screening to rule out dysplasia. Subjects with a family history of colorectal 
cancer, personal history of increased colorectal cancer risk, age > 50 years, or 
other known risk factor must be up-to date on colorectal cancer surveillance per 
local standards and guidelines (may be performed during screening). Subjects 
with extensive colitis or pancolitis of > 8 years duration must have documented 
evidence that a surveillance colonoscopy was performed within 12 months of the 
initial Screening visit (may be performed during screening). 
3. Moderate to severe active UC as defined by complete Mayo Score of 6 to 12, 
inclusive (range 0 to12), at baseline (pre-randomisation) with endoscopy score of 
at least 2 (range 0 to 3), extending 15 cm or more from the anal verge, as 
determined by blinded central read, within 14 days of randomisation. 
4. Demonstrated over the previous 5-year period, an inadequate response to, loss of 
response to, or intolerance of at least 1 of the following agents as defined below: 


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a. Immunomodulators 
i. Signs and symptoms of persistently active disease despite a history 
of at least one ≥ 8-week regimen of oral azathioprine (≥ 1.5 mg/kg) 
or 6-MP (≥ 0.75 mg/kg), OR 
ii. History of intolerance of at least 1 immunomodulator (including, 
but not limited to, nausea/vomiting, abdominal pain, pancreatitis, 
liver function test abnormalities, lymphopaenia, thiopurine S-
methyltransferase genetic mutation, and/or infection) 
b. TNF-α antagonists 
i. Signs and symptoms of persistently active disease despite a history 
of at least 1 induction regimen of at least 6 weeks duration, OR 
ii. Recurrence of symptoms during maintenance dosing following 
prior clinical benefit (discontinuation despite clinical benefit does 
not qualify), OR 
iii. History of intolerance (including, but not limited to, infusion- or 
injection-related reaction, demyelination, congestive heart failure, 
and infection)  
Note: A maximum of 50% of randomised subjects may have 
had prior treatment with TNF-α antagonists. For subjects in the 
Netherlands, only subjects who have had prior exposure to 
anti-TNF agents will be allowed to enrol in the study (as confirmed 
by medical record documentation or by self-reporting). 
c. Corticosteroids  
i. Signs and symptoms of persistently active disease despite a history 
of at least one 4-week induction regimen that included a dose 
equivalent to prednisone 30 mg daily orally for 2 weeks or IV for 
1 week, OR 
ii. Two failed attempts to taper corticosteroids to below a dose 
equivalent to prednisone 10 mg daily orally on 2 separate 
occasions, OR 
iii. History of intolerance of corticosteroids (including, but not limited 
to, Cushing’s syndrome, osteopaenia/ osteoporosis, 
hyperglycaemia, insomnia, and infection). 
5. Subject is unlikely to conceive, as indicated by at least one “yes” answer to the 
following criteria: 
a. Subject is a male 


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b. Subject is a surgically sterilised female (at least 90 days prior to 
Screening) 
c. Subject is a post-menopausal female ≥ 45 years of age with > 1 year since 
last menses; if a female subject is < 45 years of age, or cessation of 
menses is < 1 year and > 6 months, follicle-stimulating hormone (FSH) 
must be documented as elevated into the post-menopausal range at 
Screening 
d. Subject is a non-sterilised, premenopausal female with a non-sterile male 
partner and agrees to abstain from heterosexual activity, use adequate 
hormonal contraception, OR use double barrier contraception (ie, a 
combination of male condom with either cervical cap, diaphragm, or 
sponge with spermicide) as per local regulations and guidelines during the 
study and for 28 days after the last dose of study drug. 
e. If subject is a non-sterilised, premenopausal female with a sterile male 
partner, the above requirements for contraception do not apply. 
6. For women of childbearing potential (WOCBP), a negative serum pregnancy test 
at Screening and a negative urine pregnancy test within 24 hours prior to the first 
dose of study medication. 
7. Subject is eligible according to tuberculosis (TB) screening criteria.  
8. Subject understands the study procedures and agrees to participate in the study by 
giving written informed consent. 
 
Note: Subjects may be permitted to enrol in the study on stable doses of oral 
5-aminosalicylic acid (5-ASA) agents, oral corticosteroids, antidiarrhoeals, 
azathioprine/6-MP, or probiotics according to specifications noted in the protocol. 
 
5.2 Exclusion Criteria 
The following are the exclusion criteria; subjects must meet NONE of the following 
exclusion criteria to be enrolled. 
 
Gastrointestinal exclusion criteria 
1. Subject with CD, indeterminate colitis, or presence or history of fistula consistent 
with CD. 


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2. History of toxic megacolon, abdominal abscess, symptomatic colonic stricture, or 
stoma; history of extensive colonic resection, or subtotal or total colectomy; or is 
at imminent risk of colectomy. 
3. History or current evidence of colonic dysplasia or adenomatous colonic polyps. 
Note: Subjects will not be excluded from the study because of a pathology finding 
of indefinite dysplasia with reactive atypia. Subjects with resected adenomatous 
polyps may be enrolled. 
Infectious disease exclusion criteria 
4. Current bacterial or parasitic pathogenic enteric infection, including Clostridium 
difficile (confirmed by toxin result), current infection with hepatitis B or C virus 
(subjects treated for HCV infection must have evidence of sustained virologic 
response 12 weeks after the end of treatment [SVR12], infection requiring 
hospitalisation or IV antimicrobial therapy, opportunistic infection within 
6 months of dosing, any infection requiring antimicrobial therapy within 2 weeks 
of dosing, history of more than one episode of herpes zoster, history of infection 
with human immunodeficiency virus (HIV), or any episode of disseminated 
zoster. Note: Subjects with a history of C. difficile infection treated with 
antibiotics with or without faecal microbial transplant may be rescreened after 
2 weeks following completion of treatment. 
5. Live virus vaccination within 1 month prior to screening. 
General exclusion criteria 
6. Subject has a concurrent clinically significant, unstable, or uncontrolled 
cardiovascular, pulmonary, hepatic, renal, GI, genitourinary, haematological, 
coagulation, immunological, endocrine/metabolic, or other medical disorder that, 
in the opinion of the Investigator, might confound the results of the study or poses 
additional risk to the subject by their participation in the study. 
Note: Subjects with a history of uncomplicated kidney stones, childhood asthma, 
or concurrent stable and well-controlled asthma may be enrolled in the study at 
the discretion of the Investigator.  
7. Known primary or secondary immunodeficiency. 
8. History of myocardial infarction, unstable angina, transient ischaemic attack, 
decompensated heart failure requiring hospitalisation, congestive heart failure 
(New York Heart Association Class 3 or 4), uncontrolled arrhythmias, cardiac 
revascularisation, stroke, uncontrolled hypertension (systolic blood pressure [BP] 
> 160 mmHg or diastolic BP > 100 mmHg at Screening), or uncontrolled diabetes 
(haemoglobin A1c > 9% or > 1 episode of severe hypoglycaemia) within 6 
months of screening. 


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9. Clinically meaningful laboratory abnormalities at Screening, including but not 
limited to, the ranges below: 
a. Absolute neutrophil count < 1000/µL 
b. Platelet count < 100,000/µL 
c. Haemoglobin < 9 g/dL 
d. Creatinine ≥ 1.5 mg/dL  
e. alanine aminotransferase or aspartate aminotransferase ≥ 2.5 x upper limit 
of normal (ULN) or bilirubin > 1.5 x ULN 
10. Pregnant or lactating females. 
11. Any surgical procedure requiring general anaesthesia within 1 month prior to 
screening, or planned elective surgery during the study. 
12. History of malignant neoplasms or carcinoma in situ within 5 years prior to 
screening. (Subjects who are cancer-free for the previous 5 years may be enrolled. 
Subjects with adequately treated non-metastatic basal cell skin cancer, squamous 
cell skin cancer that has not recurred for at least 1 year prior to screening, or 
history of adequately treated cervical dysplasia/cervical intraepithelial neoplasia 
or cervical carcinoma in situ that has not recurred at least 3 years prior to 
screening may be enrolled.) 
13. History of any major neurological disorders, as judged by the Investigator, or 
positive PML subjective symptom checklist. 
14. Current or recent history of alcohol dependence or illicit drug use within 1 year 
prior to screening. 
15. Subject is mentally or legally incapacitated at the time of Screening visit or has a 
history of clinically significant psychiatric disorders that would impact the 
subject’s ability to participate in the trial according to the Investigator. Note: 
Subjects who have had situational depression or adjustment disorder or treated 
depression may be enrolled at the discretion of the Investigator. 
16. Unable to attend study visits or comply with procedures. 
17. Concurrent participation in any other interventional study. 
Medication exclusion criteria 
18. Use of topical 5-ASA or corticosteroid enemas/suppositories within 2 weeks of 
administration of the screening endoscopy. 
19. Use of TNF-α antagonists within 60 days prior to screening. 
20. Use of ustekinumab within 3 months prior to screening. 
21. Use of cyclosporine, thalidomide, tacrolimus, sirolimus, or mycophenolate 
mofetil within 1 month prior to screening. 


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22. Have received any investigational or biologic agent within 1 month (or 5 half-
lives of the agent whichever is longer) prior to screening. 
23. Prior treatment with vedolizumab or natalizumab. 
5.3 Removal of Subjects from Study Participation 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject 
has the right to withdraw from the study at any time and for any reason without prejudice 
to his or her future medical care by the physician or at an institution. The Investigator (or 
designee) may remove a subject from the study if, in the Investigator’s (or designee’s) 
opinion, it is not in the best interest of the subject to continue the study. Subjects may be 
withdrawn due to (but not limited to) any of the following:  
• change in compliance with inclusion/exclusion criterion that is clinically relevant 
and affects subject safety 
• at the subject’s request (withdrawal of consent) 
• protocol noncompliance 
• occurrence of AEs that, in the Investigator’s opinion, require subject removal 
• occurrence of pregnancy 
• intake of non-permitted concomitant medication that might affect subject safety or 
study assessments/objectives. 
 
Notification of withdrawal will be made to the Sponsor as soon as is practical. In case of 
withdrawal, all reasonable efforts will be made to perform all final study day assessments 
within 10 days of termination (eg, Early Termination visit) (Table 6-1). The date the 
subject is withdrawn from the study and the reason for withdrawal will be recorded on 
the subject’s Case Report Form (CRF). All withdrawn subjects will be followed until 
resolution of all their AEs or until the unresolved AEs are judged by the Investigator (or 
designee) to have stabilised.  
 
5.4 Management of Subject Safety 
Following dose administration and before leaving the site, each subject will be given a 
Patient Alert card to carry at all times in case of any emergency outside of the site. The 
card gives details of the study name and study drug used, name of the relevant 
Investigator, address and telephone number of the site, as well as emergency out of office 
contact details if a third party medical professional requires any details or safety 
information about the study or study drug in case of emergency. Subjects should retain 


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this card after they have completed or discontinued the study and during the follow-up 
phase, and destroy the card when directed by study personnel. 
6 STUDY PROCEDURES 
6.1 Schedule of Study Procedures 
A study flow chart is presented in Table 6-1. The total blood volume that will be taken 
during the study is outlined in Appendix E. 


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Table 6-1  Study Flow Chart 
 
Screening 
Random-
isation 
Period 
Treatment 
Follow up 
 
 
Days -42 
to -7 
Day -7 
to Day -
1 
Day 0 
(pre-
dose)1 
Day 0 
(dosing, 
post-dose)
Day 14 
±3 days 
Day 28 
±3 days 
Day 42 
±3 days 
Day 56 
±3 days 
Day 702 
±3 days 
Day 84 
±3 days 
Day 
112  
±7 days 
Day 
2522 
±30 
days 
Early 
Termi-
nation3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medications4 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
Physical Examination5 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
Vital Signs6 
X 
 
X 
X7 
X 
X 
X 
X 
 
X 
X 
 
X 
12-lead ECG6 
X 
 
X8 
 
X 
 
 
X 
 
X 
X9 
 
X 
Laboratory: 
Haematology, 
Coagulation, Serum 
Chemistry10 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
Stool C.diff, Culture, 
and Ova and Parasites 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (microscopy 
if abnormal) 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
PML Neurological 
Assessment11 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B & C; TB 
Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
(WOCBP) 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 


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Screening 
Random-
isation 
Period 
Treatment 
Follow up 
 
 
Days -42 
to -7 
Day -7 
to Day -
1 
Day 0 
(pre-
dose)1 
Day 0 
(dosing, 
post-dose)
Day 14 
±3 days 
Day 28 
±3 days 
Day 42 
±3 days 
Day 56 
±3 days 
Day 702 
±3 days 
Day 84 
±3 days 
Day 
112  
±7 days 
Day 
2522 
±30 
days 
Early 
Termi-
nation3 
Sigmoidoscopy 
X12 
 
 
 
 
 
 
 
 
X 
 
 
X 
Colonic Biopsy 
X12 
 
 
 
 
 
 
 
 
X 
 
 
X 
Mayo Score13 
X12 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
JCV Antibody 
Testing14 
X14 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
Eligibility 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Randomisation15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
IBDQ 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Faecal Calprotectin 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
Urine Pregnancy 
(WOCBP) 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
PK Blood Collection16 
 
 
X 
X17 
X 
X 
X 
X 
 
X17 
 
 
X17 
PD Blood Collection16 
 
 
X 
X17 
X 
X 
X 
X 
 
X17 
 
 
X17 
ADA Testing 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Exploratory 
Immunologic 
Assessment Blood 
Sample18 
 
 
X 
 
 
 
 
 
 
 
 
 
 
IP Administration19 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ADA = anti-drug antibodies; AE = adverse event; ECG = electrocardiogram; IBDQ = Inflammatory Bowel Disease Questionnaire; IP = investigational product; JCV= John 
Cunningham virus; PD = pharmacodynamics; PK = pharmacokinetics; PML = progressive multifocal leukoencephalopathy; TB = tuberculosis; WOCBP = women of childbearing 
potential. 
1 All predose procedures should be completed prior to dosing. 
2 Day 70 AE monitoring will be obtained via phone call and data to calculate rectal bleeding and stool frequency subscores will be obtained; 6-month follow-up PML assessment 
will be obtained via phone call (the phone call should occur 6 months following discontinuation of treatment if the subject terminates early). 
3 Procedures to be performed within 10 days of Early Termination.  


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4 All prior medications taken within 3 months before Screening should be recorded. 
5 Complete physical examinations (including a neurological examination) should be conducted at Screening. Complete physical examinations should also be conducted at Day 84, 
Day 112, and/or Early Termination. Directed physical examinations should be conducted at other time points. The Day 0 postdose examination will occur 4 hours postdose. 
6 Participants should be rested in a supine or semi-recumbent position for ≥ 5 minutes prior to recording of ECGs and vital signs. The ECGs and vital signs should be assessed prior 
to blood draws. Temperature by oral, axillary, or tympanic route may be permitted provided the same route is used for the participant throughout the study. 
7 Vital signs will be done at 1, 2, and 4 hours ± 20 minutes postdose following the first dose of study drug. 
8 Predose (baseline) ECGs should be repeated 3 times with 1- to 2-minute intervals between ECG readings, all within 2 hours prior to dosing.  
9 ECG only to be performed if previously abnormal. 
10 Laboratory samples collected at Screening and on Day 0 (predose), Day 28, Day 84 (or Early Termination), and Day 112 MUST be after the participant has FASTED from all 
food and drink except water for ≥ 8 hours (except for any dietary requirements that are part of sigmoidoscopy prep). Chemistry Panel at these fasting visits will include cholesterol 
and glucose analytes. All other non-fasting visits will have Chemistry Panel completed without cholesterol and glucose analytes. See Appendix B for list of analytes assessed. 
11 PML Assessment Questionnaire subjective checklist will be performed at Screening and at designated study visits (see Appendix D). If the Screening PML subjective checklist 
was performed within 14 days of Day 0, it will not need to be repeated on Day 0. At Day 0 (predose), subjects will be educated on the signs and symptoms of PML and advised to 
report if they experience any of those signs or symptoms at any time during the study.   
12 Sigmoidoscopy, biopsy, and a baseline complete Mayo Score are to be completed within 14 days of randomisation (as close to randomisation as possible; however, subjects may 
have a combined Screening visit that includes endoscopy) after confirmation of eligibility from other screening tests. Mayo Score for stool frequency and rectal bleeding should be 
done before the day of sigmoidoscopy. Mayo Score for physician’s global assessment will be completed on the day of the sigmoidoscopy. Sigmoidoscopy should be the last 
procedure before randomisation. Subjects must meet eligibility criteria of Mayo Score 6 to 12 and endoscopy subscore of ≥ 2 in order to be randomised. 
13 Complete Mayo Score (including all 4 subscores) to be assessed at Screening, Day 84, and Early Termination (if possible); partial Mayo Score (without endoscopy subscore) to 
be assessed at all other time points except Day 70 where only rectal bleeding and stool frequency subscores will be reported via phone. 
14 JCV antibody testing must be performed within 90 days prior to dosing. Testing will be performed at the time of the pretreatment sigmoidoscopy if no prior results (within the 
90-day timeframe) are available, and if the subject is eligible for study enrolment. Results will not determine eligibility for the trial. 
15Randomisation will occur after all subject eligibility has been confirmed in the screening period. Randomisation in the interactive web/voice response system must be completed 
in advance of Day 0. Dosing should occur within 7 days of randomisation. 
16 Baseline (Day 0 predose) PK and PD blood samples will be taken within 2 hours prior to dosing. PD samples to be taken at selected sites only. 
17 PK samples are to be collected at 1, 2, and 4 hours ± 20 minutes postdose on Day 0 and Day 84 or Early Termination (if possible) only. PD samples to be collected 4 hours ± 
20 minutes postdose on Day 0 and Day 84 or Early Termination (if possible) only. For every visit other than Day 0, a single PK and PD sample will be obtained within 1 hour prior 
to taking the regularly scheduled dose. 
18 A separate blood sample will be collected at selected sites (Day 0 predose only) for immunologic assessment. 
19 IP will be administered once daily for 84 days. The first drug will be administered at the study centre and subjects will be observed for at least 4 hours. On visits to study site, 
subjects should take the daily dose of study medication after completion of all blood collections. On Day 0, if the IP shipment is delayed, late dosing will not be considered a 
protocol deviation. 
 
 
 


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6.2 Study Treatment 
6.2.1 Drug Supplies and Accountability 
Specific instructions about the storage, dispensation, and administration of PTG-100 to 
subjects will be provided in the pharmacy manual. 
 
The Sponsor (or designee) will provide the Investigator (or designee) with adequate 
quantities of the study drugs (Table 6-2). 
 
Table 6-2  Study Drug 
Study Drug 
Placebo 
PTG-100 
PTG-100 
Forma 
Powder in a hard 
gelatin capsule 
Powder in a hard 
gelatin capsule 
Powder in a hard 
gelatin capsule 
Strength 
0 mg 
150 mg 
300 mg 
Supplier 
Protagonist 
Protagonist 
Protagonist 
Manufacturer 
Catalent 
Catalent 
Catalent 
a Specific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with the 
study drug. 
 
The lot numbers for the study drug will be provided to the clinical sites by the 
supplier/manufacturer. 
 
Study drugs will be supplied in blister packs and stored refrigerated at 2°C to 8°C 
under secure conditions. 
 
The Investigators (or designees) will maintain an accurate record of the receipt of the 
clinical trial materials as shipped by the Sponsor (or designee), including the date 
received. One copy of this receipt will be returned to the Sponsor (or designee) when the 
contents of the shipment have been verified. In addition, an accurate drug disposition 
record will be kept, specifying the amount dispensed to each subject and the date of 
dispensation. This drug accountability record will be available for inspection at any time. 
At the completion of the study, the original drug accountability record will be available 
for review by the Sponsor on request. 
 
At the completion of the study, all unused drug supplies will be returned to the Sponsor 
(or designee) or disposed of by the clinical site(s), per the Sponsor’s (or designee’s) 
written instructions. 


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6.2.2 Subject Number and Identification 
Subjects will be assigned a number by an Interactive Web Response System . Assignment 
of numbers will be in ascending order and no numbers will be omitted. Subject numbers 
will be used on all study documentation. For subjects who are withdrawn by the 
Investigator (or designee) or who voluntarily withdraw prematurely from the study, 
replacement subjects will be enrolled only if deemed necessary by the Sponsor. 
Replacement subjects will be assigned a subject number by adding 300 to the number of 
the subject they are replacing (eg, Subject No. 305 replaces Subject No. 005) and will be 
enrolled into the same randomisation arm as the subject whom they are replacing. 
6.2.3 Dose Preparation and Administration 
Study drug (PTG-100 or placebo) will be administered by subjects orally QD.  
 
Matching PTG-100 (150-mg or 300-mg capsule) and placebo capsules will be provided 
to subjects in prepackaged individual study drug wallet kits, identical in appearance, 
according to the randomisation schedule. Each prepackaged kit will be appropriately 
labelled. Each day during the double-blind treatment period (preferably in the morning), 
subjects will take a total of 3 capsules, without regard to meals, according to their blinded 
treatment assignment, as follows: 
• 
150 mg PTG-100 group will receive: 1 × 150-mg capsule, 2 × placebo capsules 
• 
300 mg PTG-100 group will receive: 2 × 150-mg capsules, 1 × placebo capsule 
• 
900 mg PTG-100 group will receive: 3 × 300-mg capsules 
• 
Placebo group will receive: 3 × placebo capsules 
 
Study drug will be prepared in blinded blister packs and dispensed by the pharmacist (or 
appropriate designee) at study site visits; the subject will return any unused study drug at 
site visits during which site personnel will record used and unused capsules.  
 
Subjects will be encouraged to take their daily study drug in the morning at 
approximately the same time each day. If the subject forgets to take a morning dose, the 
subject will be advised to take the dose on the same day. If it has been more than 
12 hours since they were due to take the dose, they will be advised to skip that dose and 
resume the daily schedule with the next dose. Subjects will be told to not “double-up” on 
the doses if doses are missed. 
 
All study personnel including the Sponsor, Contract Research Organization (CRO), 
Medical Monitors, Investigator, site pharmacist (or designee), site personnel involved in 


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study conduct, and subjects will remain blinded to study medication assignment. 
Appropriate unit doses, as described above, will be administered to 
consecutively-numbered subjects.  
 
For all site visit days, doses will be administered orally after PK and PD blood 
collections. Doses will be preceded by an overnight fast (ie, at least 8 hours) from food 
(not including water) on Days 0, 28, 84, and 112 only prior to safety lab collection. 
Subjects may resume food after the blood collection. 
 
At all other times during the study, subjects will have no water or meal restrictions or 
requirements.  
6.2.4 Blinding 
This will be a double-blind, placebo-controlled study. As such, the Sponsor, CRO, 
Medical Monitors, Investigator, site pharmacist (or designee), site personnel involved in 
study conduct, and subjects will remain blinded to study medication assignment.   
 
An independent Data Monitoring Committee (DMC) will monitor safety throughout the 
study period and may be unblinded as necessary. Limited personnel required for 
conducting the analyses may also be unblinded to allow necessary safety oversight. The 
DMC will also be involved in the IA. Limited personnel required for conducting the IA 
will also be unblinded. Unblinded personnel required for the IA will be defined in the 
DMC charter. 
 
Unblinding of individual subject treatment assignment may be permitted in the event of 
an emergency situation requiring knowledge of treatment assignment; however, subject 
assignment should not be routinely unblinded. Unblinding will be performed via the 
IXRS. This randomisation information may be opened and the randomisation for each 
individual subject made available to the Investigator (or designee) only in the event of a 
medical emergency or an AE that necessitates identification of the clinical trial material 
for the welfare of that subject. Except in a medical emergency, the Investigator (or 
designee) and blinded clinical site staff will remain blinded during the conduct of the 
study and until such time that all discrepancies in the clinical database are resolved (ie, at 
the database lock). The date/initials and reason for the Investigator (or designee) 
removing the study blind will be documented. Although the Investigator (or designee) 
will remain blinded as to treatment, the Investigator (or designee) will assess the data in 


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aggregate for safety and tolerability review. Unblinding for any other reason will be 
considered a protocol violation. 
6.3 Study Restrictions 
6.3.1 Diet, Fluid, and Activity Control 
Subjects will adhere to recommended dietary and activity restrictions prior to 
sigmoidoscopy/ biopsy according to the Investigator (or designee).  
 
Subjects will maintain their normal level of physical activity throughout the entire study 
(ie, will not begin a new exercise program or participate in any unusually strenuous 
physical exertion). There are no dietary restrictions throughout the study except for 
fasting for at least 8 hours prior to study visits on Days 0, 28, 84, and 112 (except for 
dietary requirements that are part of the preparations for a sigmoidoscopy). 
6.3.2 Concomitant Medications 
Subjects will refrain from participation in any other investigational study drug trial in 
which receipt of any investigational drug occurred within 5 half-lives or 1 month, 
whichever is longer, prior to Screening and during the entire study.  
 
Subjects will be expected to continue their existing medication regimen, provided those 
treatments are permitted in the protocol.  
 
Subjects may be receiving the following drugs at enrolment and must maintain stable 
doses throughout the treatment and follow-up period: 
• Oral 5-ASA therapy may be continued provided that subjects have been on 
treatment for at least 6 weeks with a stable dose for the 2 weeks immediately prior 
to screening endoscopy 
• Oral corticosteroid therapy (prednisone at a stable dose ≤ 20 mg/day, or 
equivalent steroid) may be continued provided that subjects have been on 
treatment for at least 4 weeks with a stable dose for at least 2 weeks immediately 
prior to screening endoscopy 
• Azathioprine or 6-MP may be continued provided that the dose has been stable 
for the 4 weeks immediately prior to screening endoscopy 
• Antidiarrhoeals (eg, loperamide, diphenoxylate with atropine) may be continued 
at a stable dose for control of chronic diarrhoea 


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• Probiotics (eg, Culturelle, Saccharomyces boulardii) may be continued provided 
that the dose has been stable for the 2 weeks immediately prior to screening.  
 
The following drugs must be discontinued and may not be used during the study: 
• Use of topical 5-ASA or corticosteroid enemas/suppositories must be 
discontinued within 2 weeks prior to the screening endoscopy  
• TNF-α antagonist drugs must not be used within 60 days prior to screening  
• Ustekinumab must not be used within 3 months prior to screening  
• Cyclosporine, thalidomide, tacrolimus, sirolimus, or mycophenolate mofetil must 
not be used within 1 month prior to screening  
• Investigational drugs or biologic agents must not be used within 1 month (or 5 
half-lives) prior to screening  
• Vedolizumab, natalizumab, or other biologic therapy must not be used during the 
study. Subjects with prior treatment with vedolizumab or natalizumab are not 
eligible for participation in the study. 
• No live viral vaccines should be administered within 1 month prior to screening 
• Subjects must have discontinued antibiotics for treatment of infection according 
to the criteria listed in Section 5.2.  
 
The Investigator (or designee) will review all subject medications prior to study entry and 
consult with the Medical Monitor if any questions or concerns arise. In general, subjects 
may continue concomitant treatments for stable or controlled concurrent medical 
conditions. 
 
When concomitant use of a medication is in doubt, an evaluation will be made by the 
Investigator(s) (or designee[s]) and Medical Monitor to allow on-study use of some 
medications that are stable and unlikely to interfere with study medications and 
assessments. 
 
Use of any newly prescribed, intermittent, or as-needed medication taken by a subject 
during the course of the study and the reason for its use (eg, to address an AE) will be 
documented in the source documents and the concomitant medication CRF. The 
administration of any of the disallowed concomitant medications noted above is 
prohibited.  


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6.3.3 Contraception 
Female participants must be unlikely to conceive according to the criteria listed in 
Section 5.1.  
 
Females of non-childbearing potential are defined as females who are ≥ 45 years of age 
with > 1 year since last menses. Female subjects who are of non-childbearing potential 
will not be required to use contraception. 
 
If a female subject is < 45 years of age, or cessation of menses is < 1 year and 
> 6 months, FSH must be documented as elevated into the post-menopausal range at 
Screening or the subject must have been surgically sterile (eg, bilateral oophorectomy, 
hysterectomy) for at least 90 days.  
 
Women of childbearing potential must have a negative serum pregnancy test at Screening 
and a negative urine pregnancy test within 24 hours prior to the first dose of study 
medication in order to receive study drug. 
 
Women of childbearing potential when sexually active with male partners who are not 
sterile will be required to use adequate hormonal contraception or use appropriate double 
barrier contraception (such as a combination of male condom with either cervical cap, 
diaphragm, or sponge with spermicide) as per local regulations and guidelines from the 
time of signing the ICF until 28 days after the last dose of study drug. 
 
Any subject who becomes pregnant during the study must immediately discontinue 
further treatment with study drug and will be followed through the pregnancy’s outcome 
(see Appendix F). 
6.4 Screening Procedures (Days -42 to -7) 
Subjects will undergo study-specific screening within 42 days prior to dosing (Day 0). 
Prior to the Screening visit, subjects will have fasted for ≥ 8 hours. 
 
Subjects will sign the study-specific consent form in the presence of a study site 
physician (or appropriate designee), prior to any screening procedures being performed. 
The information recorded for all subjects, regardless of their suitability for the study, will 
be retained and archived. 
 


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The following information and procedures will be recorded and performed as part of the 
screening assessments for the first Screening visit: 
• demographic data 
• medical history 
• prior medications (including all prescription medications within 3 months prior to 
screening) 
• review of inclusion/exclusion criteria 
• height and weight 
• complete physical examination, including neurological examination; any subject 
with abnormal neurological examination will be excluded from study 
participation 
• vital signs (including BP, heart rate, respiration rate, and temperature) 
• 12-lead ECG 
• clinical laboratory evaluations (including haematology, coagulation factors, serum 
chemistry, and C-reactive protein [CRP]; see Appendix B) 
• stool for C.difficile (confirmed by toxin result), culture, and ova and parasites 
• urinalysis (UA; see Appendix B) 
• PML subjective checklist (see Appendix D) 
• TB test (QuantiFERON-TB Gold assay or TB skin test) and chest x-ray (if 
indicated for positive TB test; see Appendix C) 
• hepatitis B and C testing 
• serum pregnancy test (for WOCBP) 
 
Subjects who meet all of the preceding screening criteria will attend a second Screening 
visit (however, subjects may have a combined Screening visit that includes endoscopy), 
where they will undergo: 
• sigmoidoscopy and biopsy (within 14 days of randomisation) 
• complete Mayo Score assessment (within 14 days of randomisation; see 
Appendix A). Eligibility/baseline Mayo Score and sigmoidoscopy/biopsy should 
be done as close to randomisation as possible. Mayo Score for stool frequency 
and rectal bleeding should be done before the day of sigmoidoscopy. However, if 
the subject has a combined Screening visit, then the Mayo Score for stool 
frequency and rectal bleeding should be done before the day of randomization for 
final determination of eligibility. Mayo Score for PGA will be completed on the 
day of the sigmoidoscopy. Sigmoidoscopy should be the last procedure before 
randomisation. Subjects must meet eligibility criteria of Mayo Score 6 to 12 and 
endoscopy subscore of ≥ 2 in order to be randomised 


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• John Cunningham virus (JCV) antibody testing (within 90 days prior to dosing; a 
sample will be obtained for testing at the second Screening visit in the absence of 
prior JCV testing). 
 
Subjects will be randomised within 7 days of dosing. 
6.5 Clinical Site Admission (Day 0) 
6.5.1 Predose Procedures 
On arrival at the study site on Day 0, subjects will undergo the following assessments 
prior to dosing (see Table 6-1): 
• confirmation of eligibility 
• prior and concomitant medications 
• AEs 
• weight 
• vital signs 
• 12-lead ECG  
• directed physical examination 
• clinical laboratory evaluations (including haematology, coagulation, serum 
chemistry [fasting], CRP, and UA; see Appendix B) 
• PML subjective checklist (see Appendix D); subjects will be educated on the 
signs and symptoms of PML and advised to report to designated site personnel if 
they experience any of those signs or symptoms at any time during the study 
• IBDQ (see Appendix G) 
• faecal calprotectin 
• urine pregnancy test (for WOCBP; subject must have negative pregnancy test to 
be dosed) 
• PK blood sample (within 2 hours prior to dosing) 
• PD blood sample (within 2 hours prior to dosing; at selected sites only) 
• ADA testing 
• blood sample for exploratory immunologic assessment (selected sites only)  
• dose administration (after completion of the preceding procedures); it should be 
noted that a delay to dosing on Day 0 due to IP shipment delay will not be 
considered a protocol deviation 


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6.5.2 Postdose Procedures 
Subjects will be observed for up to 4 hours after the first dose of study drug. Following 
dose administration, the following assessments will be performed in the clinic: 
• AEs 
• concomitant medications 
• vital signs (at 1, 2, and 4 hours ± 20 minutes postdose) 
• directed physical examination (4 hours postdose) 
• PK blood sample (1, 2, and 4 hours ± 20 minutes postdose) 
• PD blood sample (4 hours ± 20 minutes postdose; at selected sites only) 
6.6 Clinical Site Visits (Days 14, 28, 42, and 56) 
Subjects will be instructed to take the study drug QD, preferably in the morning. Subjects 
will be instructed not to take their study drug dose the morning of their study site visits to 
allow for predose blood sampling. On these visits, subjects will take the study drug dose 
following completion of the blood collection. Details on dosing times and allowable 
dosing windows will be provided in the pharmacy manual and explained to the subject 
prior to their dismissal from the study site. 
 
Subjects will return to the study site at designated visits according to the study schedule 
and will arrive without having taken their dose for the day. Subjects will have fasted for 
≥ 8 hours on Day 28 prior to arrival at the study site. The following assessments will be 
performed prior to dose administration: 
• AEs 
• concomitant medications 
• weight 
• vital signs 
• 12-lead ECG (Days 14 and 56 only) 
• directed physical examination 
• PML subjective checklist (see Appendix D); any positive responses to the PML 
subjective checklist will require that the PML objective checklist be performed by 
the Investigator according to Appendix D and the study manual   
• urine pregnancy test (for WOCBP). Subjects must have negative urine pregnancy 
test to proceed with dosing 
• partial Mayo Score assessment (rectal bleeding, stool frequency, PGA subscores 
only; see Appendix A) 
• PK blood sample (within 1 hour prior to dosing) 


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• PD blood sample (within 1 hour prior to dosing; selected sites only) 
• clinical laboratory evaluations (including haematology, coagulation, serum 
chemistry, CRP, and UA; see Appendix B) (Days 14, 28 [fasting], and 56 only) 
• ADA testing (Days 28 and 56 only) 
• faecal calprotectin (Day 42 only) 
6.7 Day 70 (Phone Visit) 
Sites will conduct the subject visit by phone.  
 
The following assessments should be performed during this phone visit: 
• AEs 
• concomitant medications 
• recording of rectal bleeding and stool frequency subscores only via diary record 
(see Appendix A) 
• PML subjective checklist (see Appendix D); any positive responses to the PML 
subjective checklist will require that the PML objective checklist be performed by 
the Investigator at the study site according to Appendix D and the study manual 
6.8 Final Treatment Day Clinical Site Visit (Day 84 or Early Termination) 
The following assessments should be performed: 
• AEs 
• concomitant medications 
• weight 
• vital signs 
• 12-lead ECG  
• complete physical examination 
• clinical laboratory evaluations (including haematology, coagulation, serum 
chemistry [fasting], CRP, and UA; see Appendix B) 
• PML subjective checklist (see Appendix D); any positive responses to the PML 
subjective checklist will require that the PML objective checklist be performed by 
the Investigator according to Appendix D and the study manual 
• serum pregnancy test (WOCBP) 
• sigmoidoscopy and biopsy 
• complete Mayo Score assessment (rectal bleeding, stool frequency, PGA, and 
endoscopy subscores; see Appendix A) 
• IBDQ (see Appendix G) 


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• faecal calprotectin 
• PK blood sample (within 1 hour prior to dosing and 1, 2, and 4 hours ± 20 
minutes postdose) 
• PD blood sample (within 1 hour prior to dosing and 4 hours ± 20 minutes 
postdose; at selected sites only) 
• ADA testing 
 
Subjects who experience a flare of UC requiring rescue treatment that is prohibited in the 
protocol (in the judgement of the Investigator) will be discontinued from further 
treatment with study drug. Subjects who terminate early from treatment may be placed on 
appropriate therapy by the treating physician. Subjects will complete an Early 
Termination visit (including endoscopy) within 10 days following discontinuation, 
undergo the study procedures detailed in the Study Flow Chart (Table 6-1), and will be 
encouraged to be followed for all safety assessments through 28 days. 
6.9 Follow-up/End of Study Visit (Day 112) 
Subjects will return to the study site having fasted for ≥ 8 hours, and the following 
assessments will be performed: 
• AEs 
• concomitant medications 
• weight 
• vital signs 
• 12-lead ECG (if previously abnormal) 
• complete physical examination 
• clinical laboratory evaluations (including haematology, coagulation, serum 
chemistry [fasting], CRP, and UA; see Appendix B)  
• PML subjective checklist (see Appendix D); any positive responses to the PML 
subjective checklist will require that the PML objective checklist be performed by 
the Investigator according to Appendix D and the study manual 
• serum pregnancy test (WOCBP) 
• partial Mayo Score assessment (rectal bleeding, stool frequency, PGA subscores 
only) 
• faecal calprotectin 
• ADA testing 
 


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Subjects will also be asked to confirm and provide all relevant contact information for the 
6-month phone visit. 
6.10 
6 Months Post-Treatment (Final Phone Follow-up) 
Study subjects will receive a follow-up phone call at the 6-month post-treatment 
time point (Day 252) or earlier if the subject terminates early from the study. During this 
call, the PML subjective checklist (Appendix D) will be administered and the data 
recorded in the CRF. Any positive responses to the PML subjective checklist will 
necessitate the scheduling of an additional site visit so that the PML objective checklist 
may be performed by the Investigator according to Appendix D and the study manual. 
6.11 
Efficacy Assessments 
6.11.1 Mayo Score 
Clinical remission, clinical response, endoscopic response, endoscopic remission, 
complete and partial Mayo Score and individual endoscopy, rectal bleeding, and stool 
frequency subscores will be assessed using the Mayo Score (see Appendix A).  
 
Subjects will record stool frequency and rectal bleeding subscores in an electronic subject 
diary each day through the entire treatment and follow-up periods. Subjects will be 
provided standardised instructions for recording the number of stools and their worst 
rectal bleeding over a 24-hour period (Appendix A). Each subscore ranges from 0 to 3, 
with higher scores indicating more severe disease. For visits that include a 
sigmoidoscopy, data collected on the day of the bowel preparation will not be used to 
assess the Mayo Score. The nearest 3 available days preceding the study visit (or bowel 
preparation) will be used to assess the Mayo Score, allowing for discontinuous days if a 
day is missing (eg, Day -4, Day -3, Day -1 [with Day -2 missing]). However, if the 
subject has a combined Screening visit, then the baseline Mayo Score for stool frequency 
and rectal bleeding should be done before the day of randomization for final 
determination of eligibility. 
 
Endoscopic subscore will be assessed by a central reading of recorded endoscopy scans. 
Sigmoidoscopy will be performed by the site endoscopist and scored by a blinded central 
reader reviewing video recordings of the procedure. Further details to standardise 
procedures, video recordings/equipment, and assessment of endoscopy will be provided 
in the laboratory manual. 


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The complete Mayo Score is a sum of 4 subscores (ie, stool frequency, rectal bleeding, 
endoscopic ﬁndings, and PGA). The complete Mayo Score ranges from 0 to 12 using all 
4 subscores.   
 
Partial Mayo Score (range 0 to 9) will include the PGA, stool frequency, and rectal 
bleeding subscores only. 
At baseline and Day 84 (or Early Termination), complete Mayo Score will be assessed 
and recorded.  
For evaluation of the primary endpoint clinical remission, the PGA subscore will not be 
evaluated, only the stool frequency, rectal bleeding, and endoscopic subscores will be 
assessed (Section 7.4). Clinical response will be assessed using the stool frequency and 
rectal bleeding subscores.  
6.11.2 Colonic Biopsy 
Colonic biopsies will be obtained from subjects during sigmoidoscopy at baseline (within 
14 days prior to randomisation) and at Week 12 (Day 84). Biopsies will be taken from the 
most inflamed area of the colon, while avoiding necrotic areas of ulcerated mucosa or 
suture sites in patients with previous colonic resection. Biopsies should be repeated from 
the same area at baseline and at Week 12. Biopsies will be placed into RNAlater® (Life 
Technologies Corporation, Carlsbad, CA, United States of America [USA]) or formalin 
for storage and subsequent processing. Further details regarding the biopsy collection, 
processing, storage, and shipment will be provided in the laboratory manual. Colonic 
biopsies will be subjected to histologic evaluation and immunohistochemistry. Histologic 
assessment will be performed.  
 
All biopsies will be read by a central laboratory. Further details will be provided in the 
laboratory manual. 
6.11.3 Faecal Calprotectin 
Stool samples will be collected by the study subjects and brought to the study centre for 
faecal calprotectin assessment at the designated time points. The stool should be a 
morning specimen. Subjects will be provided instructions regarding the proper means of 
collecting (including proper collection time), processing (eg, mixing), and storing the 
stool samples. 
 
Further details will be provided in the laboratory manual.  


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6.11.4 IBDQ 
Health-related quality of life will be assessed by the IBDQ (see Appendix G),16 a 
standardised validated questionnaire with scores ranging from 32 to 224 points, at time 
points designated in the study schedule (Table 6-1). 
6.12 
Pharmacokinetic and Pharmacodynamic Assessments 
6.12.1 Pharmacokinetic Blood Sample Collection, Processing, and Analysis 
Blood (4 mL) samples for PK analysis will be obtained in K2EDTA tubes according to 
the site standard operating procedures (SOPs) prior to dosing and at the time points 
delineated in the study schedule (Table 6-1). All samples (except those collected postdose 
on Days 0 and 84) should be obtained prior to the daily dosing of study drug (ie, Ctrough). 
The actual collection time of each sample must be recorded in the source data, collection 
tube, and on the electronic CRF (eCRF). The allowed time deviation window for blood 
sample collection is ± 20 minutes for the samples up to 4 hours postdose on Days 0 and 
84.  
 
The Sponsor will supply complete written instructions for collection, handling, 
processing, storage, and shipping of samples in the laboratory manual. 
 
Plasma PK sample analysis will be performed using validated procedures and methods. 
6.12.2 Pharmacodynamic Blood Sample Collection, Processing, and Analysis 
Pharmacodynamic assessments will be measured from 2 mL blood samples collected in 
heparinised blood collection tubes from subjects at selected sites according to the study 
schedule (Table 6-1). The blood samples will be analysed by FACS for PTG-100 RO and 
α4β7 RE in peripheral blood lymphocytes. The percentages of circulating lymphocytes 
will also be measured.   
 
An additional 3 mL blood sample will be collected in heparinised blood collection tubes 
at selected sites (Day 0 predose only) with plasma stored for exploratory immunologic 
assessments.  
 
The Sponsor will supply complete written instructions for the collection, handling, 
processing, storage, and shipping of samples in the laboratory manual. The samples will 
be analysed using validated assay methods. 


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6.12.3 Anti-drug Antibody Blood Sample Collection and Processing 
Blood samples (3 mL) will be collected in heparinised blood collection tubes according 
to the study schedule (Table 6-1) and serum will be evaluated for the presence of ADAs 
with a bridging immunoassay.  
 
The Sponsor will supply complete written instructions for the collection, handling, 
processing, storage, and shipping of samples in the laboratory manual. 
6.13 
Safety Monitoring 
Subjects will be monitored for AEs and concomitant medication use throughout the 
study. Physical examination (including weight and vital signs), clinical safety labs, PML 
assessments, and ECGs will be done periodically throughout the study according to the 
schedule specified in Table 6-1. Safety evaluations may be repeated at the Investigator’s 
(or designee’s) discretion. 
 
The following will constitute AEs of special interest that will be monitored at each visit: 
serious or opportunistic infection (viral, bacterial, fungal including systemic/gut 
localization), allergic/drug reactions, immune system disorders, and/or suspected PML. 
Adverse events of special interest will not constitute Investigational New Drug safety 
reports unless they are defined as serious events and there is evidence suggesting a causal 
relationship between the drug and the event.   
 
The JCV antibody testing must have been performed and documented on all randomised 
subjects within 90 days prior to dosing. All subjects will be closely monitored for signs 
and symptoms of PML through directed questionnaires that assess recent changes in 
vision, speech, gait, sensation, comprehension, coordination, and personality, with any 
positive responses prompting objective testing by the Investigator (see Appendix D).1,17  
 
An independent DMC will be appointed to monitor the safety of the subjects in the study. 
The DMC will meet approximately quarterly to review the safety data and will make 
recommendations regarding the continuation, modification, suspension, or termination of 
the study. Operational guidelines will be specified in the DMC charter. 
 
Every effort will be made to schedule and perform the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical 
restrictions, and the other procedures to be performed at the same time point. Acceptable 


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windows for study visits are provided in Section 6.1. The order of priority for scheduling 
procedures around a time point is (in descending order of priority): 
• dosing 
• PK blood sampling 
• PD blood sampling 
• vital sign measurements 
• ECGs 
• blood and urine samples for clinical laboratories 
• physical examinations 
6.13.1 PML Monitoring 
Any subject with abnormal neurological examination at Screening will be excluded from 
participation in the study.  
 
The JCV antibody testing must have been performed and documented on all randomised 
subjects within 90 days prior to dosing. 
 
All randomised subjects will be closely monitored for signs and symptoms of PML 
through directed questionnaires that assess recent changes in vision, speech, gait, 
sensation, comprehension, coordination, and personality, with any positive responses 
prompting objective testing by the Investigator (see Appendix D).1,17,26,27 All randomised 
study subjects will be closely monitored for the onset of any new neurological signs or 
symptoms or suspected PML during treatment and follow-up. The study’s monitoring 
program will include education of site personnel and subjects about the signs and 
symptoms of PML and will advise subjects to report to designated personnel should they 
experience any signs and symptoms suggestive of PML.  
 
Study sites will be provided a stepwise algorithm for the action plan for all subjects with 
suspected PML during the study and follow-up period; details regarding this algorithm 
will be provided in the study manual. Appropriately qualified site staff will complete the 
subjective PML checklist using the questionnaire (Appendix D) at all study visits per the 
schedule in Section 6.1. If any subject has a positive response based on the PML 
subjective checklist, the site will immediately schedule a visit where the Investigator will 
perform the PML objective checklist (involving tests of visual fields, ocular motility, 
speech, muscle strength, gait, memory, and sensation) per Appendix D and the study 
manual. If a study subject has both positive subjective and objective checklists, the 
subject will be referred to a local neurologist for further evaluation to rule out PML. If 


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the neurologist cannot rule out PML, the case will be referred to the Independent 
Adjudication Committee (that will include at least one neurologist) for the final 
determination of PML. 
6.13.2 Adverse Events 
Adverse event definitions; assignment of severity, causality, action taken, and outcome; 
and procedures for reporting SAEs are detailed in Appendix F. 
 
Subjects will be asked a nonleading question such as “Have there been any changes in 
your health status since Screening/since you were last asked?” at the time points specified 
in Table 6-1 to assess for the occurrence of AEs. Subjects will also be encouraged to 
voluntarily report AEs occurring at any other time during the study. 
 
All nonserious AEs, whether volunteered, elicited, or noted on physical examination, will 
be recorded from Day 0 until study completion. Serious AEs will be recorded from the 
time the subject signs the ICF until study completion. 
 
All AEs (nonserious and serious) should be followed until the event has resolved, 
returned to baseline, or is assessed as stable by the Investigator (or designee). 
6.13.3 Clinical Laboratory Evaluations 
Clinical laboratory evaluations (including clinical chemistry panel [fasted at least 8 hours 
on designated study days], coagulation parameters, haematology, and UA; Appendix B) 
will be collected at the time points specified in Table 6-1. Medically indicated laboratory 
tests (emergency or unscheduled tests) will be conducted at the local laboratory as 
needed. 
 
A blood sample will be taken from each subject for haematology, coagulation, and serum 
chemistry analysis at the time points delineated in the study schedules. Additional clinical 
laboratory tests may be performed at other times if deemed necessary. 
 
Urinalysis will be performed at the Screening visit and at other times according to the 
study schedule. Urine microscopy will be performed in the event of abnormal macro 
analysis. 
 
Screen for a hepatitis panel and TB testing (Appendix C) will be performed at Screening. 
Stool samples for C. difficile (confirmed by toxin result), culture, and ova, and parasite 


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examination will be obtained at Screening. An HIV antibody test will not be performed, 
but history of positive HIV test is exclusionary. Serum and urine pregnancy tests 
(WOCBP only) will be performed at the time points specified in Table 6-1. 
6.13.4 Vital Signs 
Vital sign measurements (including oral temperature, respiratory rate, and BP and pulse) 
will be obtained at the time points specified in Table 6-1. Blood pressure and pulse will 
be taken with the subject in a supine or semi-recumbent position; subjects will have 
rested in a supine or semi-recumbent position for at least 5 minutes prior to and during 
vital sign measurements. Temperature may be taken by oral, axillary, or tympanic route 
provided the same route is used for the participant throughout the study. When the time 
of vital sign measurements coincides with a blood draw, the vital signs will be taken 
before the scheduled blood draw where possible.  
6.13.5 Twelve-lead Electrocardiograms 
A 12-lead ECG will be obtained at the time points specified in Table 6-1. Additional 
ECG monitoring may be performed at other times if deemed necessary. Subjects will be 
supine or semi-recumbent for at least 5 minutes prior to obtaining an ECG measurement. 
 
The predose (baseline) ECG will be repeated 3 times with 1- to 2-minute intervals 
between ECG readings within 2 hours prior to dosing. The ECG measurements will be 
single measurements performed according to the study schedule. Electrocardiogram 
parameters (including heart rate; PR, QRS, and QT intervals; and QT interval corrected 
for heart rate using Fridericia’s formula) and the Investigator’s overall interpretation of 
the ECG will be recorded in the CRF. When the time of ECG monitoring coincides with 
a blood draw, the ECG will be taken before the scheduled blood draw. 
6.13.6 Physical Examinations 
A complete physical examination will be performed at the time points specified in 
Table 6-1. A directed exam (including exam of general appearance, skin, thorax/lungs, 
cardiovascular system, and abdomen) will be performed at the time points specified in 
Table 6-1. 
 
The time and date of the physical examination findings will be recorded in the CRF and 
any clinically significant findings will be recorded as AEs. 


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6.14 
Study Termination 
The study or specific participating sites may be terminated if significant violations of 
Good Clinical Practice (GCP) that compromise the ability to achieve the study objectives 
or compromise participant safety are observed at any time during the study. With regard 
to safety, the study may be temporarily suspended or terminated should the DMC 
determine that the safety of study participants is significantly jeopardised. Additional 
reasons for termination of the study may include: medical or ethical reasons affecting 
continued performance of the study, inability to recruit subjects, or suspension or 
cancellation of the drug development program. The decision for a temporary or 
permanent study hold will depend on the nature, frequency, and severity of AEs that were 
observed in all enrolled participants to date. In a temporary study hold, no additional 
participants will be enrolled into the study or dosed with study drug until the DMC 
determines it is safe to proceed with the study. 
7 DATA ANALYSES AND SAMPLE SIZE 
7.1 Sample Size 
Approximately 240 male and non-gravid female subjects aged 18 to 80 with moderate to 
severe active UC will be randomised. If only 2 arms are selected for continuation 
following the IA, then up to approximately 210 subjects will be randomised in the study; 
see Section 7.2. 
 
Prior studies1,17-21 suggest treatment effects of approximately 21 percentage point 
differences from placebo clinical remission rate of approximately 10%.  Those values 
were assumed for purposes of design of this 12-week trial. 
 
The table below shows power for representative scenarios of potential TRUE underlying 
dose-response relationships, as well as that for no drug effect to assess type 1 error 
(calculations via Cytel’s EAST COMPASS adaptive dose-finding software based on 
1000 simulations of each design, with each simulated trial analysed as described in the 
statistical methods section).22 
 
TRUE underlying response rates 
power (alpha=0.025, 1-sided) 
placebo 
150 mg 
300 mg 
900 mg 
N=260 
N=240 
N=220 
N=200 
0.1 
0.2 
0.31 
0.31 
93% 
91% 
90% 
84% 
0.1 
0.17 
0.24 
0.31 
83% 
82% 
78% 
75% 
0.1 
0.1 
0.1 
0.1 
3.4% 
2.2% 
1.7% 
2.1% 


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7.2 Interim Analysis 
An unblinded IA will be performed by the Adaptive Design Review Committee (ADRC) 
after approximately 60 to 80 subjects have been dosed and completed 12 weeks of dosing 
or terminated early (Stage 1).23 A futility analysis will be performed; if the trial does not 
meet criteria for futility, further analysis will be conducted in order to drop one (or 2) of 
the PTG-100 dose arms (Stage 1, see below). Following the IA, randomisation will 
continue to the remaining dose arms (Stage 2).  
 
Conditional power will also be computed at the IA. It is the probability that the trial will 
yield a statistically significant difference for clinical remission at the higher chosen dose 
for Stage 2 if the observed difference at the IA is the TRUE underlying difference and the 
trial is continued to completion. If this probability is low (eg, less than 10% to 20%), the 
decision could be made to stop the trial for futility.   
 
The PD, efficacy, and safety data will be analysed to model dose- and exposure-response 
from Stage 1 of the trial to allow dropping of an ineffective or redundant arm(s). Since 
the trial provides for a 12-week treatment period, it is expected that an additional 
approximately 60 subjects would be randomised in equal proportions to the 4 treatment 
groups while the first approximately 60 to 80 subjects' 12-week data are accumulated and 
analysed. Hence, in Stage 2, the remaining subjects would be randomised in equal 
proportions to the selected dose(s) and placebo. This would yield approximately 70 to 80 
subjects per treatment group for the selected doses. Final analysis will combine all 
observed data from both Stages 1 and 2.    
 
The IA guidelines for futility and dose selection will be defined in the DMC charter and 
will be made in consideration of safety data and sound clinical judgment. Dose selection 
for Stage 2 will be made by the ADRC, which will be comprised of the DMC and a 
representative of the Sponsor (not involved in the direct conduct of the study). No 
pre-specified algorithm will be defined for the IA, although specific guidelines for 
dropping a dose(s) will be provided in the DMC charter. Only the ADRC, which will 
make the dose selection for Stage 2, and the Independent Statistical Centre, which will 
perform the IA, will be unblinded. 
 
Stratification by prior treatment with TNF-α antagonist use will be maintained in both 
Stage 1 and 2. 


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7.3 Study Populations 
Safety Population: All randomised participants who receive any amount of study drug 
will be included in the safety analyses.  
 
Pharmacokinetic Analysis Population: All randomised participants who receive a Day 0 
dose of study drug and who have sufficient PK data (meeting the required minimum 
blood volume collected along with the sampling schedule, with an accurate record of 
dosing and sampling time, and without vomiting) for analysis will be included in the PK 
analyses.  
 
Full Analysis Set: All randomised participants who receive any amount of study drug and 
who have results from baseline and from ≥ 1 post-baseline assessment will be included in 
the PD and efficacy analyses.   
7.4 Statistical Analysis of Efficacy Data 
The primary efficacy endpoint for this study is the proportion of subjects receiving 
PTG-100 with clinical remission at Week 12 compared with placebo.  
 
Clinical remission is defined as follows, using the Mayo subscores of stool frequency, 
rectal bleeding, and endoscopy: 
• Stool frequency subscore of 0 or 1 with a pre-specified change of 1 or more from 
baseline 
• Rectal bleeding subscore of 0 
• Endoscopy subscore of 0 or 1 (modified so that a score of 1 does not include 
friability) 
 
The secondary endpoints, all based on comparison of individual PTG-100 dose levels 
with placebo, include: 
1. Proportion of subjects with endoscopic response at Week 12 (Day 84) (defined as 
an endoscopic subscore of 0 or 1) 
2. Proportion of subjects with clinical response at Week 12 (Day 84) (defined as at 
least 1 point and 30% reduction from baseline in rectal bleeding and stool 
frequency subscores) 
3. Mean change in endoscopy subscore from baseline to Week 12 (Day 84) 
4. Mean change in rectal bleeding and stool frequency subscores from baseline to 
Weeks 2, 4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 70, 84, and 112) 


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5. Proportion of subjects with endoscopic remission at Week 12 (Day 84) (defined 
as an endoscopic subscore of 0) 
6. Mean change in complete Mayo Score (including all 4 subscores) from baseline to 
Week 12 (Day 84) 
7. Mean change in partial Mayo Score (excluding endoscopy subscore) from 
baseline to Weeks 2, 4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 70, 84, and 112) 
8. Mean change in faecal calprotectin levels from baseline to Weeks 6, 12, and 16  
(Days 42, 84, and 112) 
9. Mean change in IBDQ score from baseline to Week 12 (Day 84) 
 
The exploratory endpoints (all based on comparison of individual PTG 100 dose levels to 
placebo) include: 
1. Mean change in histological score from baseline to Week 12 (Day 84) 
(assessment tool to be determined) 
2. Effects of ADA on PK, safety, and efficacy in subjects with positive ADA 
 
Descriptive statistics will be used to evaluate differences in demographic and baseline 
characteristics.  
 
For the primary analysis, proportions of subjects with clinical remission will be compared 
between each dose and placebo using Cochran-Mantel-Haenszel test, with adjustment for 
stratification factors. Rates of clinical response, endoscopic response, and endoscopic 
remission will be evaluated similarly.   
 
Multiplicity will be addressed via closed testing procedure with combined p-values 
computed for each of the 2 stages of the trial (IA and post-IA). Each stage p-value will be 
adjusted as appropriate by closed testing multiple comparison approach per Simes.24 This 
approach controls the overall type 1 error at alpha=0.025, 1-sided. 
 
All analyses will be based on combined Stage 1 and Stage 2 data and include data from 
the dose(s) that is (are) dropped for Stage 2. Exploratory analyses will be carried out to 
assess consistency of results between Stages 1 and 2. Analyses of other binary endpoints 
will be carried out similarly. 
 
Subjects who discontinue prematurely will be considered treatment failures.  
 
Changes from baseline complete Mayo Score, partial Mayo Score, rectal bleeding 
subscore, stool frequency subscore, endoscopic subscore, IBDQ score, and faecal 


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calprotectin levels will be analysed using repeated measures mixed analysis of covariance 
model adjusted for treatment, time point, treatment-by-time point interaction, 
stratification factors, and baseline values. For subjects who withdraw prematurely, the 
last observation will be carried forward. These analyses will be based on the Stage 1 and 
Stage 2 combined data for exploratory purposes. 
 
Details regarding the statistical analyses of efficacy data will be provided in the 
Statistical Analysis Plan (SAP). 
7.5 Statistical Analysis of Safety Data 
The primary safety endpoint is the proportion of subjects with at least 1 AE comparing 
individual PTG-100 dosing groups with placebo.  
 
The secondary endpoints (all based on comparison of individual PTG-100 dose levels to 
placebo) will include: 
1. Frequency and type of AEs (affecting ≥ 5% of subjects)  
2. Proportion of subjects with at least 1 SAE  
3. Number and type of SAEs  
4. Frequency of AEs of special interest including serious or opportunistic infection 
(viral, bacterial, fungal including systemic/gut localization), allergic/drug 
reactions, immune system disorders, and suspected PML  
5. Clinically significant changes in safety labs, ECGs, or physical examination 
findings (including vital signs). 
 
Continuous safety data will be summarised with descriptive statistics (arithmetic mean, 
standard deviation [SD], median, minimum, and maximum) by dose level. Categorical 
safety data will be summarised with frequency counts and percentages by dose level. 
Adverse events will be coded using the most current Medical Dictionary for Regulatory 
Activities available, which will be indicated in the Data Management Plan. A by-
participant AE data listing, including verbatim term, preferred term, system organ class, 
treatment, severity, and relationship to study drug, will be provided. The number of 
participants experiencing treatment-emergent AEs (TEAEs) and number of individual 
TEAEs will be summarised by treatment group, system organ class, and preferred term. 
The TEAEs will also be summarised by severity and by relationship to study drug. 
 
Laboratory evaluations, vital signs assessments, and ECG parameters will be summarised 
by treatment group and protocol-specified collection time point. A summary of change-


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from-baseline at each protocol-specified time point by treatment group will also be 
presented. 
 
Clinically significant changes in physical examinations will be listed for each participant 
and described in the text of the Clinical Study Report. 
 
Medical history will be listed by subject. 
 
Concomitant medications will be listed by participant and coded using the most current 
World Health Organization drug dictionary. 
 
Further details regarding presentation and analysis of safety data will be detailed in the 
SAP. 
7.6 Pharmacokinetic Analysis 
Noncompartmental PK analyses will be performed on individual PTG-100 plasma 
concentration data. The Cmax, Ctrough, and Tmax will be taken directly from the observed 
data. The AUC0-t will be calculated using the linear trapezoidal rule.   
 
The PK analyses will be performed using commercial software such as Phoenix™ 
WinNonlin® Version 6.4 or higher (Certara USA Inc.). All PK calculations will be 
performed using published noncompartmental relationships. Actual dose administration 
times and sample collection times will be used for the analyses as recorded on the CRF. 
Plasma concentrations below the lower limit of quantification will be set to zero for the 
analysis.  
 
As a secondary endpoint, individual PTG-100 concentration data will be listed and 
summarised by treatment group with descriptive statistics (sample size, arithmetic mean, 
SD, median, minimum, maximum, geometric mean, and geometric coefficient of 
variation). Mean and individual PTG-100 concentration-time profiles will be presented 
graphically on both linear and semilogarithmic scales. All statistical analyses will use 
non-rounded parameter estimates. Plasma concentration data and the PK parameter 
estimates will be presented by study group. Pharmacokinetic parameter estimates will be 
3 or 4 significant figures for presentation. No attempt will made to estimate missing data. 
Other parameters and data handling procedures may be added as appropriate. Final PK 
parameters reported and statistical approaches will be detailed in the SAP. 


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7.7 Pharmacodynamic Analysis 
Quantitation of PTG-100 RO and α4β7 RE on peripheral blood T cells will be evaluated 
as secondary endpoints.  
 
The exploratory endpoints will include: 
1. Analysis of peripheral blood lymphocytes in subjects on individual PTG-100 dose 
levels compared to placebo   
2. Number of β7 positive cells in colonic biopsies as assessed by 
immunohistochemistry in subjects on individual PTG-100 dose levels compared 
to placebo 
 
Individual data will be listed for each individual and summarised by nominal sampling 
time point and treatment group with descriptive statistics (arithmetic mean, SD, median, 
minimum, and maximum). A summary of change-from-baseline at each 
protocol-specified time point by treatment group will also be presented. The change of 
PD indicators over time will be demonstrated graphically and will be compared among 
the dose levels. Details regarding the statistical analyses of PD data will be provided in 
the SAP. 
 
Receptor occupancy and α4β7 RE in peripheral blood will be listed for each individual 
and summarised by frequency counts for discrete categories. 
 
Additional population PK-PD modelling may be performed and will be detailed in the 
SAP.  
 
Details regarding the statistical analyses of PD data will be provided in the SAP. 
7.8 Immunogenicity Analysis 
The proportion of subjects developing ADA by Weeks 12 (Day 84) and 16 (Day 112) 
will be characterised.  
 
Serum samples will be evaluated for the presence of ADA through use of a validated 
bridging immunoassay. This will involve conjugating PTG-100 to biotin or horseradish 
peroxidase (HRP) enzyme using a flexible PEG linker. The biotin conjugate will be used 
to immobilize PTG-100 to streptavidin coated wells of assay plates. Clinical serum 
samples containing anti-PTG-100 antibodies will bind to the plate and binding can be 
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we will spike positive control antibodies into the matrix selected for the assay to measure 
assay sensitivity and specificity as recommended by the FDA guidance.25 We will also 
establish a negative control by pooling the sera from 5 to 10 non-exposed individuals. 
The evaluation will include assessment of neutralizing ADAs, as well as the potential of 
ADA to cross-react with endogenous MAdCAM-1. If ADA is detected in clinical 
samples, the effect of ADA on PK, safety, and efficacy may be explored for all subjects 
who demonstrate evidence of ADAs. 
7.9 Data Handling and Record Keeping 
Any changes to the information in the trial progress notes and other source documents 
will be initialled and dated on the day the change is made by a clinical site staff member 
authorized to make the change. Changes will be made by striking a single line through 
erroneous data and clearly entering the correct data (eg, wrong data right data). If the 
reason for the change is not apparent, a brief explanation for the change will be written 
adjacent to the change by the clinician. 
 
The Data Management Plan will be approved by the Sponsor. 
 
Data will be validated during data entry by the clinical site and verified by the Study 
Monitor. Data will then be reviewed by the data management group to resolve any 
outstanding issues. Listings will be generated after the database is cleaned by Data 
Management and will be reviewed by the Covance scientific team. The CRF/eCRF and 
ancillary data will be converted into final SAS® datasets following Study Data Tabulation 
Model or client-provided specifications. The final datasets structure will be verified (eg, 
by using a data management system such as Web Submission Data Manager®) while the 
dataset content will be peer-reviewed by an independent programmer. 
 
The tables, figures, and listings (TFLs) will be programmed per the final SAP. All TFLs 
will be peer-reviewed by an independent programmer. In addition, draft TFLs will be 
reviewed by the Covance scientific team during the dry run and data review meetings. 
 
The peer-review will be performed by independent programmers following the quality 
control process and programming checklists. 


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7.10 
Quality Control and Quality Assurance 
Quality control and quality assurance will be performed according to Covance SOPs or 
per client request and as applicable according to the contract between Covance and the 
Sponsor. 
 
Prior to participation, investigational sites and Investigators will be evaluated for 
appropriate qualifications and ability to execute the study. Each investigational site must 
undergo appropriate training on the study protocol and ancillary study procedures and 
documents, through participation in an initiation visit or Investigator Meeting. Training 
must take place before any subjects are enrolled at that site. Initiation visits and 
Investigator Meetings will include (but may not be limited to) review of GCP guidelines, 
study drug dispensation and administration procedures, data collection requirements, and 
subject eligibility requirements. 
 
The Sponsor and/or its representative may make periodic visits to the investigational site 
to assess compliance with study procedures and regulatory requirements; to ensure that 
the safety, welfare, and privacy of subjects are being protected; and to verify the accuracy 
and integrity of the study data. In addition, independent quality assurance site audits may 
be conducted as verification of the quality and compliance of study conduct. 
 
The Sponsor and/or its representative will periodically review the study data to ensure that 
data are being appropriately collected and reported. Queries and corrections will be made 
as needed. 
8 ADMINISTRATIVE ASPECTS 
8.1 Change in Protocol 
There will be no alterations in the protocol without agreement between the Sponsor and 
the Investigator. 
 
There will be no alterations in the protocol affecting subject safety without the expressed 
written approval of the Sponsor, Investigator, and the Institutional Review Board (IRB; 
see Form FDA 1572) or Independent Ethics Committee (IEC). 


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8.2 Site Initiation Visit/Investigator Meeting 
Prior to the start of the clinical study, the representative(s) of the Sponsor will meet with 
the Investigator(s) and appropriate clinical staff to familiarise the Investigator(s) and 
clinical staff with the protocol and the materials necessary for conducting the clinical 
study. 
8.3 Disclosure 
All information provided regarding the study, as well as all information 
collected/documented during the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
8.4 Publication 
This study is intended for publication, even if terminated prematurely. Publication may 
include any or all of the following: posting of a synopsis online, abstract and/or 
presentation at a scientific conference, or publication of a full manuscript. The Sponsor 
will work with the authors to submit a manuscript describing study results within 
12 months after the last data become available. The Sponsor will post a synopsis of study 
results for approved products on www.clinicaltrials.gov by 12 months after the last 
patient’s last visit or within 7 days of product approval in any major markets (US, 
Europe, or Japan), whichever is later. These timelines may be extended for products that 
are not yet marketed, if additional time is needed for analysis, to protect intellectual 
property, or to comply with confidentiality agreements with other parties. 
 
Authors of the primary results manuscript will be provided the relevant results from the 
Clinical Study Report, subject to the confidentiality agreement. For this multicentre 
study, subsequent to the multicentre publication (or after public disclosure of the results 
online if a multicentre manuscript is not planned), an Investigator and his/her colleagues 
may publish their data independently. In most cases, publication of individual site data 
does not add value to complete multicentre results, due to statistical concerns. In rare 
cases, publication of single-site data prior to the main paper may be of value. Limitations 
of single-site observations in a multicentre trial should always be described in such a 
manuscript. 
 
Authorship credit should be based on 1) substantial contributions to conception and 
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or revising it critically for important intellectual content; 3) final approval of the version 
to be published; and 4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved. Significant contributions to study execution may 
also be taken into account to determine authorship, provided that contributions have also 
been made to all of the preceding authorship criteria. Contributors who do not meet the 
criteria for authorship will not be listed as authors, but should be acknowledged. The 
collection of data, or general supervision of the research group, by themselves, does not 
justify authorship. Although publication planning may begin before conducting the study, 
final decisions on authorship and the order of authors’ names will be made based on 
participation and actual contributions to the study and writing, as discussed above. The 
first author is responsible to defend the integrity of the data, method(s) of data analysis, 
and the scientific content of the manuscript. 
 
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or 
presentations regarding this study 60 days prior to submission for 
publication/presentation. Any information identified by the Sponsor as confidential must 
be deleted prior to submission. Sponsor review can be expedited to meet publication 
timelines. 
8.5 Monitoring 
The Sponsor will designate a Sponsor’s Study Monitor who will be responsible for 
monitoring this clinical trial. The Sponsor’s Study Monitor will monitor the study 
conduct, proper CRF and source documentation completion and retention, and accurate 
study drug accountability. To this end, the Sponsor’s Study Monitor will visit the clinical 
site at suitable intervals and be in frequent contact through verbal and written 
communication. It is essential that the Sponsor’s Study Monitor has access to all 
documents (related to the study and the individual participants) at any time these are 
requested. In turn, the Sponsor’s Study Monitor will adhere to all requirements for 
subject confidentiality as outlined in the ICF. The Investigator and Investigator’s staff 
will be expected to cooperate with the Sponsor’s Study Monitor, to be available during a 
portion of the monitoring visit to answer questions, and to provide any missing 
information. 
8.6 Institutional Review Board/Institutional Ethics Committee 
In accordance with US Title 21 Code of Federal Regulations (CFR) 56, the protocol, 
advertisement, ICF, and any other information provided to subjects will be reviewed and 


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approved by the IRB/IEC. The Sponsor will supply relevant material for the Investigator 
(or designee) to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB/IEC unconditional approval of the protocol and the written ICF 
statement will be transmitted to the Investigator (or designee). 
 
The IRB/IEC will be informed by the Investigator (or designee) of subsequent protocol 
amendments and of serious and unexpected AEs. Approval for protocol amendments will 
be transmitted in writing to the Investigator (or designee). If requested, the Investigator 
(or designee) will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
 
The Investigator (or designee) will provide the IRB/IEC with progress reports at 
appropriate intervals, as per local regulations, and a Study Progress Report following the 
completion, termination, or discontinuation of the Investigator’s participation in the 
study. 
8.7 Informed Consent 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are carried out. The ICF will be approved (along with the 
protocol) by the IRB/IEC and will be acceptable to the Sponsor. 
 
The Investigator (or designee) will explain the nature of the study and the action of the 
test product. The subjects will be informed that participation is voluntary and that they 
can withdraw from the study at any time. In accordance with 21 CFR 50, the informed 
consent process shall be documented by the use of a written ICF approved by the 
IRB/IEC and signed by the subject prior to protocol-specific procedures being performed. 
 
The subject will sign the ICF; a copy will be given to the subject, and the other will be 
maintained with the subject’s records. 
8.8 Records 
The results from data collected at Screening and during the study will be recorded in the 
subject’s CRF (paper or eCRF). To maintain confidentiality, the subjects will be 
identified only by numbers, initials, or both. 
 


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The completed CRFs will be transferred to the Sponsor (or designee). Copies of each 
CRF will be retained by the Investigator (or designee). All source documents, records, 
and reports will be retained by the clinical site in accordance with 21 CFR 312.62(c). 
 
All primary data, or copies thereof (eg, laboratory records, CRFs, data sheets, 
correspondence, photographs, and computer records), which are a result of the original 
observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report, will be retained in the clinical site archives. 
8.9 Reference to Declaration of Helsinki/Basic Principles 
The study procedures outlined in this protocol will be conducted in accordance with the 
US CFR governing Protection of Human Patients (21 CFR 50), Financial Disclosure by 
Clinical Investigators (21 CFR 54), IRB/IECs (21 CFR 56), Investigational New Drug 
Application (21 CFR 312), and Applications for FDA Approval to Market a New Drug 
(21 CFR 314), as appropriate. As such, these sections of US Title 21 CFR, along with the 
applicable International Council on Harmonisation (ICH; formerly International 
Conference on Harmonisation) Guidelines, are commonly known as GCP, which are 
consistent with the Declaration of Helsinki. 
8.10 
Investigator Responsibilities 
The Investigator agrees to: 
• Conduct the study in accordance with the relevant, current protocol and make 
changes only after notifying Sponsor or its representative, except where necessary 
to eliminate apparent immediate hazards to human subjects 
• Comply with the ICH Tripartite Guideline on GCP plus appropriate regional 
regulatory laws and requirements 
• Personally conduct or supervise the described investigation 
• Inform any subjects or persons used as controls that the study drugs are being 
used for investigational purposes 
• Ensure requirements relating to obtaining informed consent and regional IEC/IRB 
approval have been met 
• Report to the Sponsor or its representative any AEs that occur in the course of the 
investigations, as specified in Appendix F 
• Read and understand the IB, including potential risks and side effects of the drug 
• Ensure all associates, colleagues, and employees assisting in the conduct of the 
study are informed of their obligations in meeting their commitments 


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• Maintain adequate and accurate records and make these available for inspection 
by the Sponsor and/or its representative, or any regulatory agency authorised by 
law 
• Promptly report to the regional IEC/IRB all changes in research activity and all 
unanticipated problems involving risks to human subjects or others 
• Comply with all other requirements regarding the obligations of clinical 
Investigators and all other pertinent requirements 
• Administer study drug only to subjects who meet study entry criteria and are 
enrolled in the study, and only according to the guidelines set forth in this 
protocol 
8.11 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 


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SPONSOR AGREEMENT 
I have read the foregoing protocol and agree to conduct the study as described herein. 
Senior Medical Director 
Protagonist Therapeutics, Inc. 
Final Protocol Amendment 3: 16 November 2017 
Date 
I 7-
/\lDlJ 
Zol] 
Page 74of101 


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INVESTIGATOR AGREEMENT 
 
I have read the foregoing protocol and agree to conduct the study as described herein. 
 
 
 
 
 
 
 
 
Printed Name of PI 
 
 
 
 
 
 
 
Signature of PI 
 
 
Date 
 
 
 


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REFERENCES 
1. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and 
maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699-710. 
2. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and 
maintenance therapy for Crohn's disease. N Engl J Med. 2013;369(8):711-721. 
3. Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365(18):1713-1725. 
4. Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission 
in ulcerative colitis. Cochrane Database Syst Rev. 2012;10: CD000543. doi: 
10.1002/14651858.CD000543.pub3. 
5. Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of 
remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;10:CD000544. 
doi: 10.1002/14651858.CD000544.pub3. 
6. Ford AC, Khan KJ, Achkar JP, Moayyedi P. Efficacy of oral vs. topical, or 
combined oral and topical 5-aminosalicylates, in ulcerative colitis: systematic 
review and meta-analysis. Am J Gastroenterol. 2012;107(2):167-176.  
7. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a 
tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 
2001;345(15):1098-1104. 
8. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and 
maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353(23):2462-
2476. 
9. Sandborn WJ, Van Assche G, Reinisch W, et al. Adalimumab induces and 
maintains clinical remission in patients with moderate-to-severe ulcerative colitis. 
Gastroenterology. 2012;142(2):257-265.e1-3. 
10. ENTYVIO (Vedolizumab) for Injection, for Intravenous Use [package insert]. 
Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2014. Available at: 
http://general.takedapharm.com/content/file.aspx?FileTypeCode=ENTYVIOPI&c
acheRandomizer=1b94c181-3ea4-4aa4-8ac5-3a0592873792. 
11. Gies N, Kroeker KI, Wong K, Fedorak RN. Treatment of ulcerative colitis with 
adalimumab or infliximab: long-term follow-up of a single centre cohort. Aliment 
Pharmacol Ther. 2010;32(4):522-528. 
12. Kobayashi T, Suzuke Y, Motoya S, et al. First trough level of infliximab at week 
2 predicts future outcomes of induction therapy in ulcerative colitis – results from 
a multicenter prospective randomized controlled trial and its post hoc analysis. J 
Gastroenterol. 2016;51:241-251. 


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13. 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 Dec 24;317(26):1625-1629. 
14. Shah SC, Colombel JF, Sands BE, Narula N. Mucosal Healing is Associated with 
Improved Long-term Outcomes of Patients With Ulcerative Colitis: a Systematic 
Review and Meta-analysis. Clin Gastroenterol Hepatol. 2016;14(9):1245-
1255.e8. 
15. Feagan BG Sandborn WJ, D'Haens G, et al. The Role of Centralized Reading of 
Endoscopy in a Randomized Controlled Trial of Mesalamine for Ulcerative 
Colitis. Gastroenterology. 2013;145(1):149-157.e2. 
16. Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure 
of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian 
Crohn’s Relapse Prevention Trial Study Group. Gastroenterology. 
1994;106(2):287-296. 
17. Vermeire S, O’Byrne S, Keir M, et al. Etrolizumab as induction therapy for 
ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet. 2014;384:309-
318. 
18. Feagan BG, Greenberg GR, Wild G, et al. Treatment of ulcerative colitis with a 
humanized antibody to the α4β7 integrin. N Engl J Med. 2005;352(24):2499-
2507. 
19. Sandborn WJ, Feagan BG, Wolf DC, et al. Ozanimod induction and maintenance 
treatment for ulcerative colitis. N Engl J Med. 2016;374(18):1754-1762. 
20. Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral janus kinase inhibitor, 
in active ulcerative colitis. N Engl J Med. 2012;367:616-624. 
21. Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab induces 
clinical response and remission in patients with moderate-to-severe ulcerative 
colitis. Gastro. 2014;46:85-95. 
22. COMPASS User Manual, Cytel Inc., Cambridge, MA, 2012. 
23. Posch M, Koenig F, Branson M, Brannath W, Dunger-Baldauf C, Bauer P. 
Testing and Estimation in Flexible Group Sequential Designs with Adaptive 
Treatment Selection. Stat Med. 2005;24:3697-3714. 
24. Simes RJ.  An improved Bonferroni procedure for multiple tests of 
significance. Biometrika. 1986;73:751-754. 
25. Department of Health and Human Services, Food and Drug Administration. 
Assay Development and Validation for Immunogenicity Testing of Therapeutic 
Protein Products; Guidance for Industry. April 1, 2016. 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM192750.pdf. 


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26. Parikh A, Leach T, Wyant T, et al. Vedolizumab for the treatment of active 
ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm 
Bowel Dis. 2012;18:1470–9. doi:10.1002/ibd.21896. 
27. Parikh A, Mcauliffe M, Stephens K, Major E, Fox I, Milch C, et al. Risk 
assessment and minimization for progressive multifocal leukoencephalopathy 
(PML) (RAMP): a program to assess for potential early signs and symptoms of 
PML during clinical development of vedolizumab. Poster presented at: United 
European Gastroenterology Week 2013; 14 October 2013.


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APPENDIX A - COMPONENTS OF THE MAYO SCORE 
Stool Frequency 
0 = Normal 
1 = 1–2 stools/day more than normal 
2 = 3–4 stools/day more than normal 
3 = >4 stools/day more than normal 
 
Rectal bleedinga 
0 = None 
1 = Visible blood with stool less than half the time 
2 = Visible blood with stool half of the time or more 
3 = Passing blood alone 
 
Mucosal appearance at endoscopyb 
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 rating of disease activity 
0 = Normal 
1 = Mild 
2 = Moderate 
3 = Severe 
 
aA score of 3 for bleeding required patients to have at least 50% of bowel motions 
accompanied by visible blood and at least one bowel motion with blood alone. 
 
bThe mucosal appearance at endoscopy is not included in the partial Mayo Score. 
 
 


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Study sites will use the following standardised instructions to advise subjects on 
recording the stool frequency and rectal bleeding over a 24-hour period. 
 
 


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APPENDIX B - CLINICAL LABORATORY EVALUATIONS 
Clinical Chemistry Panel (Fasted): Haematology Parameters: 
Urinalysis: 
Alanine aminotransferase 
Haematocrit 
Bilirubin 
Albumin 
Haemoglobin 
Colour and appearance 
Alkaline phosphatase 
Mean corpuscular haemoglobin 
Glucose 
Aspartate aminotransferase 
Blood urea nitrogen 
Mean corpuscular haemoglobin 
concentration 
Ketones 
Leukocyte esterase 
Calcium 
Mean corpuscular volume 
Nitrite 
Chloride 
Platelet count 
Occult blood 
Cholesterol* 
Red blood cell (RBC) count 
pH and specific gravity 
Creatinine 
RBC distribution width 
Protein 
Glucose* 
White blood cell (WBC) count 
Urobilinogen 
Potassium 
Sodium 
 
WBC differential (absolute): 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Microscopic exam including 
bacteria, casts, crystals, 
epithelial cells, RBCs, and 
WBCs (if protein, leukocyte 
esterase, nitrite, or blood is 
positive) 
Total bilirubin 
 
 
Total protein 
Coagulation: 
 
Triglycerides 
Activated partial thromboplastin 
time 
 
Uric acid 
Prothrombin time  
 
 
 
 
Other Tests: 
 
 
Hepatitis B surface antigen 
Hepatitis C virus antibody 
 
 
Pregnancy test (females only; 
serum qualitative) 
 
 
Pregnancy test (females only; urine 
quantitative) 
 
 
Follicle-stimulating hormone 
(postmenopausal females only) 
 
 
C-reactive protein  
 
 
Enteric pathogens (stool sample) 
 
 
*Required only on visits requiring fasting, ie, Day 0 (predose), Day 28, Day 84 (Early Termination), and Day 112 
(Follow-up). 
 
 
 


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APPENDIX C - TB SCREENING CRITERIA 
Subject is eligible according to the following tuberculosis (TB) screening criteria: 
a. Has no history of untreated latent or active TB prior to screening. 
(Prophylactic treatment for latent TB as per local guidelines must be 
initiated within at least 28 days prior to first administration of study 
medication.) 
b. Has no signs or symptoms suggestive of active TB upon medical history 
and/or physical examination 
c. Has had no recent contact with a person with active TB or, if there has 
been such contact, will be referred to a physician specialising in TB to 
undergo additional evaluation and, if warranted, complete appropriate 
course of treatment for latent TB prior to the first administration of study 
drug 
d. Within 42 days prior to first administration of study medication, either has 
negative diagnostic TB test results defined as either a negative tuberculin 
skin test or a negative QuantiFERON-TB Gold test 
e. A subject who has a positive intradermal skin or positive 
QuantiFERON-TB Gold test, or who has had recent close contact with a 
person with active TB, or has signs or symptoms suggestive of active TB 
upon medical history and/or physical examination, or if required by local 
guidelines or regulations as part of routine TB screening, must have a 
negative chest radiograph (both posterioranterior and lateral views) or 
chest computed tomography scan, taken within 3 months prior to the first 
dose of study drug and read by a qualified radiologist, with no evidence of 
current active TB or old inactive TB. 
Note: If either the tuberculin skin test or QuantiFERON-TB gold test is positive AND the 
chest x-ray (or computed tomography scan) is negative, the subject is considered to have 
latent TB infection (LTBI). Subjects with LTBI may be included only if they have 
previously completed an adequate course of prophylactic treatment (per local guidelines 
or regulations) without subsequent new exposure to active TB. The need for repeat of 
prophylactic therapy if there is a history of new exposure to active TB subsequent to 
completion of prior LTBI treatment, or if prior LTBI treatment was completed 
> 3 months prior to screening, should be determined by the Investigator in consultation 
with a TB specialist. 


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APPENDIX D - PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY 
(PML) ASSESSMENT 26,27 
A subjective PML checklist (see table below) is to be administered by appropriately 
qualified site personnel (Investigator or Study Coordinator) to all subjects at Screening, at 
the designated time points as noted in Table 6-1, and whenever new neurologic 
symptoms manifest.  For each symptom in the subjective checklist that had positive 
findings, results of an objective evaluation (see below), administered by the Investigator 
to assess corresponding neurologic function, are to be recorded on the objective checklist 
and an AE recorded. 
 
 
 


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Subjective PML Checklist 
 
 
 


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Objective PML Checklist 
 
 
If the objective test corroborates the reported symptom, the subject will be referred to a 
neurologist. Otherwise, the subject will receive a follow-up call 1 week after 
administration of the objective checklist to ensure that symptoms are not recurring. 
 


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APPENDIX E - BLOOD SAMPLING SUMMARY 
Purpose 
Maximum Blood Volume 
per Sample (mL) 
Maximum Number of 
Blood Samples 
Maximum Total 
Volume (mL) 
Hepatitis screen 
3.5 
1 
3.5 
Pregnancy tests 
3 
3 
9 
Pharmacokinetic sampling 
4 
12 
48 
Pharmacodynamic sampling 
2 
7 
14 
Haematology 
4 
7 
28 
Clinical laboratory tests 
3.5 
7 
24.5 
Coagulation 
1.8 
7 
12.6 
Anti-drug antibody test 
3 
5 
15 
Immunologic analysis 
3 
1 
3 
Total 
 
 
157.6 
 


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APPENDIX F - ADVERSE EVENTS 
ADVERSE EVENTS 
Definition of Adverse Events 
An adverse event (AE; or adverse experience) is defined as any untoward medical 
occurrence experienced by a patient or healthy subject, whether or not considered drug 
related by the Investigator (or designee). A treatment-emergent AE is an AE that is reported 
after a dose of study drug. 
 
The following are all AEs: 
• 
unfavourable changes in general condition; 
• 
subjective or objective signs/symptoms; 
• 
concomitant diseases or accidents; 
• 
clinically relevant adverse changes in laboratory parameters 
observed in a subject during a clinical study. 
 
Adverse events comprise all disturbances of general health status, subjective and 
objective disease symptoms (including laboratory abnormalities), and accidents observed 
in the context of a clinical trial, irrespective of a possible causal relationship with the 
administration of the trial substance. Events occurring in the framework of a clinical trial 
during drug-free and post-treatment periods, under placebo, or in a reference group 
receiving drug or nondrug therapy are also to be designated as AEs. 
Categorization of Adverse Events 
The severity of AEs will be categorized as follows: 
• 
MILD = of little concern to the subject and/or of no clinical 
significance, is not expected to affect the subject’s health or 
well-being; 
• 
MODERATE = discomforting enough to cause interference with 
or change in usual activities, is likely to require medical 
intervention or close follow-up; 
• 
SEVERE = incapacitating or causing inability to work or 
participate in many or all usual activities, is of concern to the 
subject or poses substantial risk to the subject’s health or 
well-being, is likely to require medical intervention or close 
follow-up. 


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The Investigator (or designee) will make a determination of the relationship of the AE to 
the study drug using a 4-category system according to the following guidelines: 
• 
NOT RELATED = an AE that does not follow a reasonable 
temporal sequence from administration of the drug and can be 
reasonably explained by other factors, including underlying 
disease, complications, concomitant drugs, or concurrent 
treatment; 
• 
UNLIKELY RELATED = an AE that follows a reasonable 
temporal sequence from the administration of the drug (including 
after withdrawal of the drug) and cannot be excluded as being 
possibly caused by the drug (eg, existence of similar reports 
attributed to the suspected drug and/or its analogues, reactions 
attributable to the pharmacological effect of the drug), although 
other factors such as underlying disease, complications, 
concomitant drugs, or concurrent treatment are presumable; 
• 
POSSIBLY RELATED = an AE that follows a reasonable 
temporal sequence from administration of the drug (including after 
withdrawal of the drug) and can be excluded as being possibly 
caused by other factors, such as underlying disease, complications, 
concomitant drugs, or concurrent treatment; 
• 
RELATED = an AE that follows a reasonable temporal sequence 
from administration of the drug (including after withdrawal of the 
drug), follows a known or hypothesized cause-effect relationship, 
and (if appropriate) satisfies the following: 
• 
positive results obtained in drug sensitivity tests; 
• 
toxic level of the drug present in blood or other body fluids. 
 
An AE is associated with the use of the drug if there is a reasonable possibility that the 
experience may have been caused by the drug. 
 
The following categories will be used for the action taken with the study drug for the AE: 
drug withdrawn, dose not changed, drug interrupted, unknown, and not applicable. 
 
The following categories will be used for the outcome of the AE: resolved, resolved with 
sequelae, ongoing, fatal, and unknown. 
 


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Notification of the Independent Ethics Committees/Institutional Review Boards  
Notification of the Independent Ethics Committees/Institutional Review Boards 
(IECs/IRBs) about all relevant events (eg, serious AEs [SAEs], Suspected Unexpected 
Serious Adverse Reactions) will be performed by the Sponsor and/or by the Investigator 
according to all applicable regulations. 
Pregnancy 
The Investigator must report to the Sponsor any pregnancy occurring in a study subject 
(or subject’s partner) during the subject’s participation. The report should be submitted 
within the same timelines as an SAE, although a pregnancy per se is not considered an 
SAE. A pregnancy should be followed-up until reporting of the pregnancy’s outcome and 
the birth date. 
 
As information is available, a pregnancy diagnosed during the study will be reported 
immediately to the Investigator (or designee) or Sponsor, including pregnancy in female 
partners of male subjects. The pregnancy will be followed to term or outcome and this 
outcome will be reported to the Sponsor. Pregnancy, in and of itself, is not regarded as an 
AE or SAE unless the birth results in a congenital anomaly/birth defect or there is 
suspicion that the study medication may have interfered with the effectiveness of a 
contraceptive medication or method. 
Definition of Serious Adverse Events 
An SAE (by Food and Drug Administration [FDA] definition) is any adverse drug 
experience occurring at any dose that results in any of the following outcomes: 
• 
death; 
• 
a life-threatening adverse drug experience (ie, places the subject, in 
the view of the Investigator [or designee], at immediate risk of 
death); 
• 
inpatient hospitalization or prolongation of existing hospitalization; 
• 
a persistent or significant disability/incapacity; 
• 
a congenital anomaly/birth defect; 
• 
important medical event that may require medical or surgical 
intervention to prevent one of the above outcomes. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, 


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they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. All SAEs must be 
collected that occur after the subject signs the Informed Consent Form. 
Unexpected Adverse Drug Experience 
An unexpected adverse drug experience is any adverse drug experience, the specificity or 
severity of which is not consistent with the current Investigator’s Brochure (IB) or, if an 
IB is not required or available, the specificity or severity of which is not consistent with 
the risk information described in the general investigational plan or elsewhere in the 
current application, as amended. 
Reporting 
Food and Drug Administration-reportable AEs are AEs that are associated with the use of 
the drug and are serious and unexpected. Food and Drug Administration-reportable AEs 
will be reported by the clinical site to the Sponsor, Medical Monitor assigned by the 
Sponsor, and the responsible IRB/IEC. 
 
The Sponsor and Medical Monitor will be notified in writing (eg, facsimile) within 
24 hours of when an AE that is potentially FDA-reportable is first recognized or reported. 
 
Subsequently, a written confirmation or summary of the AE (using FDA Form 3500A, or 
equivalent) will be sent to the Sponsor within 3 working days of the original notification. 
(Instructions for completion of FDA Form 3500A may be obtained from the FDA 
website at www.fda.gov/medwatch/how.htm.) 
 
The IRB/IEC will be notified of any FDA-reportable AE within the timeframe required 
by the IRB/IEC. The IRB/IEC Serious and Unexpected Adverse Experience Submission 
Form will be completed and submitted with the copy of the written confirmation or 
summary of the AE. 
 
 
 
 


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APPENDIX G - INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE 
(IBDQ) 
INSTRUCTIONS FOR SELF-ADMINISTERED INFLAMMATORY BOWEL 
DISEASE QUESTIONNAIRE (IBDQ)  
 
This questionnaire is designed to measure the effects of your inflammatory bowel 
disease on your daily function and quality of life. You will be asked about symptoms you 
have been having as a result of your bowel disease, the way you have been feeling in 
general, and how your mood has been. 
 
There are two versions of this questionnaire, the IBDQ and IBDQ-Stoma. If you 
have a colostomy or ileostomy, you should complete the IBDQ-Stoma. Questions 1, 5, 
17, 22, 24 and 26 are slightly different in each version. Be sure you have the correct 
questionnaire. 
 
On this questionnaire there are 32 questions. Each question has graded response 
choices numbered from 1 to 7. Please read each question carefully and answer the 
number which best describes how you have been feeling in the past 2 weeks. 
 
EXAMPLE 
 
How often have you felt unwell as a result of your bowel problem in the past 2 
weeks? 
 
1 
ALL OF THE TIME 
 2 
MOST OF THE TIME 
 3 
A GOOD BIT OF THE TIME 
 4 
SOME OF THE TIME 
 5 
A LITTLE OF THE TIME 
 6 
HARDLY ANY OF THE TIME 
 7 
NONE OF THE TIME 
 
If you are having trouble understanding a question, STOP for a moment! Think 
about what the question means to you. How is it affected by your bowel problem? Then 
answer the question as best you can. You will have the chance to ask the research 
assistant questions after completing the questionnaire. This takes only a few minutes to 
complete.  
 


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QUALITY OF LIFE IN INFLAMMATORY BOWEL DISEASE 
QUESTIONNAIRE (IBDQ) 
 
This questionnaire is designed to find out how you have been feeling during 
the last 2 weeks. You will be asked about symptoms you have been having as a result 
of your inflammatory bowel disease, the way you have been feeling in general, and 
how your mood has been. 
 
1. 
How frequent have your bowel movements been during the last two weeks? 
Please indicate how frequent your bowel movements have been during the last 
two weeks by picking one of the options from 
 
1 BOWEL MOVEMENTS THE MOST FREQUENT YOU HAVE EVER 
EXPERIENCED 
2 EXTREMELY FREQUENT 
3 VERY FREQUENT 
4 MODERATE INCREASE IN FREQUENCY OF BOWEL MOVEMENTS 
5 SOME INCREASE IN FREQUENCY OF BOWEL MOVEMENTS 
6 SLIGHT INCREASE IN FREQUENCY OF BOWEL MOVEMENTS 
7 NORMAL, NO INCREASE IN FREQUENCY OF BOWEL MOVEMENTS 
 
2. 
How often has the feeling of fatigue or of being tired and worn out been a 
problem for you during the last 2 weeks?  Please indicate how often the feeling of 
fatigue or tiredness has been a problem for you during the last 2 weeks by picking 
one of the options from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
3. 
How often during the last 2 weeks have you felt frustrated, impatient or restless?  
Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 


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3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
 
4. 
How often during the last 2 weeks have you been unable to attend school or do 
your work because of your bowel problem?  Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
 
 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
5. 
How much of the time during the last 2 weeks have your bowel movements been 
loose?  Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
6. 
How much energy have you had during the last 2 weeks?  Please choose an option 
from 
 
1 NO ENERGY AT ALL 
2 VERY LITTLE ENERGY 
3 A LITTLE ENERGY 
4 SOME ENERGY 
5 A MODERATE AMOUNT OF ENERGY 
6 A LOT OF ENERGY 
7 FULL OF ENERGY 
 


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7. 
How often during the last 2 weeks did you feel worried about the possibility of 
needing to have surgery because of your bowel problem?  Please choose an option 
from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
8. 
How often during the last 2 weeks have you had to delay or cancel a social 
engagement because of your bowel problem?  Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
9. 
How often during the last 2 weeks have you been troubled by cramps in your 
abdomen?  Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
10. 
How often during the last 2 weeks have you felt generally unwell?  Please choose 
an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 


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Final Protocol Amendment 3: 16 November 2017 
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3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
11. 
How often during the last 2 weeks have you been troubled because of fear of not 
finding a toilet?  Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
12. 
How much difficulty have you had, as a result of your bowel problems, doing 
leisure or sports activities you would have liked to have done during the last 2 
weeks?  Please choose an option from 
 
1 A GREAT DEAL OF DIFFICULTY; ACTIVITIES MADE IMPOSSIBLE 
2 A LOT OF DIFFICULTY 
3 A FAIR BIT OF DIFFICULTY 
4 SOME DIFFICULTY 
5 A LITTLE DIFFICULTY 
6 HARDLY ANY DIFFICULTY 
7 NO DIFFICULTY; THE BOWEL PROBLEMS DID NOT LIMIT SPORTS OR 
LEISURE ACTIVITIES 
 
13. 
How often during the last 2 weeks have you been troubled by pain in the 
abdomen?  Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 


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7 NONE OF THE TIME 
 
14. 
How often during the last 2 weeks have you had problems getting a good night’s 
sleep or been troubled by waking up during the night?  Please choose an option 
from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
15. 
How often during the last 2 weeks have you felt depressed or discouraged? Please 
choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
16. 
How often during the last 2 weeks have you had to avoid attending events where 
there was no toilet close at hand?  Please choose an option from  
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
17. 
Overall, in the last 2 weeks, how much of a problem have you had with passing 
large amounts of wind?  Please choose an option from 
 


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Final Protocol Amendment 3: 16 November 2017 
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1 A MAJOR PROBLEM 
2 A BIG PROBLEM 
3 A SIGNIFICANT PROBLEM 
4 SOME TROUBLE 
5  A LITTLE TROUBLE 
6 HARDLY ANY TROUBLE 
7 NO TROUBLE 
 
18. 
Overall, in the last 2 weeks, how much of a problem have you had maintaining or 
getting to the weight you would like to be at?  Please choose an option from 
 
1 A MAJOR PROBLEM 
2 A BIG PROBLEM 
3 A SIGNIFICANT PROBLEM 
4 SOME TROUBLE 
5  A LITTLE TROUBLE 
6 HARDLY ANY TROUBLE 
7 NO TROUBLE 
 
19. 
Many patients with bowel problems often have worries and anxieties related to 
their illness. These include worries about getting cancer, worries about never 
feeling any better, and worries about having a relapse.  In general, how often 
during the last 2 weeks have you felt worried or anxious?  Please choose an option 
from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
20. 
How much of the time during the last 2 weeks have you been troubled by a 
feeling of abdominal bloating?  Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 


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Final Protocol Amendment 3: 16 November 2017 
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4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
21. 
How often during the last 2 weeks have you felt relaxed and free of tension?  
Please choose an option from 
 
1 NONE OF THE TIME 
2 A LITTLE OF THE TIME 
3 SOME OF THE TIME 
4 A GOOD BIT OF THE TIME 
5 MOST OF THE TIME 
6 ALMOST ALL OF THE TIME 
7 ALL OF THE TIME 
 
22. 
How much of the time during the last 2 weeks have you had a problem with rectal 
bleeding with your bowel movements?  Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
23. 
How much of the time during the last 2 weeks have you felt embarrassed as a 
result of your bowel problem?  Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
24. 
How much of the time during the last 2 weeks have you been troubled by a 


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CONFIDENTIAL 
Protocol PTG-100-02 
 
 
Final Protocol Amendment 3: 16 November 2017 
Page 99 of 101 
 
feeling of having to go to the toilet even though your bowels were empty?  Please 
choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
25. 
How much of the time during the last 2 weeks have you felt tearful or upset?  
Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
26. 
How much of the time during the last 2 weeks have you been troubled by 
accidental soiling of your underpants?  Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
27. 
How much of the time during the last 2 weeks have you felt angry as a result of 
your bowel problem?  Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 


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Final Protocol Amendment 3: 16 November 2017 
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4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
28. 
To what extent has your bowel problem limited sexual activity during the last 2 
weeks?  Please choose an option from 
 
1 NO SEX AS A RESULT OF BOWEL DISEASE 
2 MAJOR LIMITATION AS A RESULT OF BOWEL DISEASE 
3 MODERATE LIMITATION AS A RESULT OF BOWEL DISEASE 
4 SOME LIMITATION AS A RESULT OF BOWEL DISEASE 
5 A LITTLE LIMITATION AS A RESULT OF BOWEL DISEASE 
6 HARDLY ANY LIMITATION AS A RESULT OF BOWEL DISEASE 
7 NO LIMITATION AS A RESULT OF BOWEL DISEASE 
 
29. 
How much of the time during the last 2 weeks have you been troubled by nausea 
or an upset stomach?  Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
30. 
How much of the time during the last 2 weeks have you felt irritable?  Please 
choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
31. 
How often during the past 2 weeks have you felt a lack of understanding from 


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Protocol PTG-100-02 
 
 
Final Protocol Amendment 3: 16 November 2017 
Page 101 of 101 
 
others?   Please choose an option from 
 
1 ALL OF THE TIME 
2 MOST OF THE TIME 
3 A GOOD BIT OF THE TIME 
4 SOME OF THE TIME 
5 A LITTLE OF THE TIME 
6 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME 
 
32. 
How satisfied, happy, or pleased have you been with your personal life during the 
past 2 weeks?  Please choose one of the following options from 
 
1 VERY DISSATISFIED, UNHAPPY MOST OF THE TIME 
2 GENERALLY DISSATISFIED, UNHAPPY 
3 SOMEWHAT DISSATISFIED, UNHAPPY 
4 GENERALLY SATISFIED, PLEASED 
5 SATISFIED MOST OF THE TIME, HAPPY 
6 VERY SATISFIED MOST OF THE TIME, HAPPY 
7 EXTREMELY SATISFIED, COULD NOT HAVE BEEN MORE HAPPY OR 
PLEASED 

SAP_001.pdf: 
 
Protagonist Therapeutics 
Protocol PTG-100-02 
Version 1.0 
 
Confidentiality 
This document is confidential and proprietary property of Protagonist and to be used only as authorized by 
Protagonist.  No part is to be reproduced, disclosed to others, or quoted without prior written authorization from 
Protagonist. 
STATISTICAL ANALYSIS PLAN 
Protocol PTG-100-02 
A PHASE 2B RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PARALLEL ADAPTIVE 2-STAGE, MULTI-CENTRE 
STUDY TO EVALUATE THE SAFETY AND EFFICACY OF ORAL PTG-
100 INDUCTION IN SUBJECTS WITH MODERATE TO SEVERE 
ACTIVE ULCERATIVE COLITIS 
 
Protocol Number: 
(Version Date) 
PTG-100-02 
08 SEPT 2016 
Name of Test Drug: 
PTG-100 
Phase: 
2b 
Methodology: 
Randomized, Double-Blind, Placebo-Controlled, Parallel 
Adaptive 2-Stage Multi-Center Trial 
Sponsor: 
Protagonist Therapeutics, Inc. 
521 Cottonwood Drive, Suite 100 
Milpitas, CA 95035 
 
Sponsor Representative: 
Richard S Shames 
Chief Medical Officer 
Document Date: 
08 SEPT 2016 
Document Version: 
1.0 
 
 




Protagonist Therapeutics, Inc. 
Protocol PTG-100-02 
08 SEPT 2016 
 
CONFIDENTIAL 
3
TABLE OF CONTENTS 
Section 
Page
1.
INTRODUCTION AND OBJECTIVES OF ANALYSIS......................6
1.1. 
Introduction .................................................................................... 6 
1.2. 
Objectives of Statistical Analysis .................................................. 6 
2. 
STUDY DESIGN ........................................................................................ 7 
2.1. 
Synopsis of Study Design ............................................................... 7 
2.2. 
Randomization Methodology ........................................................ 7 
2.3. 
Stopping Rules and Unblinding .................................................... 8 
2.4. 
Study Procedures ........................................................................... 8 
2.5. 
Efficacy, Pharmacokinetic, and Safety Variables ..................... 12 
2.5.1. 
Efficacy Variables ........................................................... 12 
2.5.2. 
Pharmacokinetic Variables ............................................. 13 
2.5.3. 
Pharmacodynamic and Immunogenicity Variables ........ 13 
2.5.4. 
Safety Variables .............................................................. 13 
3. 
SUBJECT POPULATIONS .................................................................... 14 
3.1. 
Population Definitions ................................................................. 14 
3.2. 
Protocol Violations ....................................................................... 14 
4. 
STATISTICAL METHODS ................................................................... 15 
4.1. 
Sample Size Justification ............................................................. 15 
4.2. 
General Statistical Methods and Data Handling ...................... 15 
4.2.1. 
General Methods ............................................................. 15 
4.2.2. 
Computing Environment ................................................. 16 
4.2.3. 
Methods of Pooling Data ................................................ 16 
4.2.4. 
Adjustments for Covariates ............................................. 16 
4.2.5. 
Multiple Comparisons/Multiplicity ................................ 16 
4.2.6. 
Subpopulations ................................................................ 16 
4.2.7. 
Withdrawals, Dropouts, Loss to Follow-up .................... 16 
4.2.8. 
Missing, Unused, and Spurious Data .............................. 17 
4.2.9. 
Visit Windows ................................................................ 18 
4.3. 
Interim Analyses .......................................................................... 20 
4.4. 
Subject Disposition ....................................................................... 21 


Protagonist Therapeutics, Inc. 
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08 SEPT 2016 
 
CONFIDENTIAL 
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Section 
Page
4.5.
Demographic and Baseline Characteristics...............................22
4.6. 
Efficacy Evaluations .................................................................... 22 
4.6.1. 
Primary Efficacy Analysis .............................................. 22 
4.6.2. 
Secondary Efficacy Analyses.......................................... 24 
4.6.3. 
Exploratory Analyses ...................................................... 25 
4.7. 
Pharmacokinetic and Pharmacodynamic Evaluations ............. 25 
4.7.1. 
Pharmacokinetic Evaluations .......................................... 25 
4.7.2. 
Pharmacodynamic Evaluations ....................................... 26 
4.8. 
Safety Analyses ............................................................................. 27 
4.8.1. 
Adverse Events ............................................................... 27 
4.8.2. 
Laboratory Data .............................................................. 28 
4.8.3. 
Vital Signs and Physical Examinations .......................... 28 
4.8.4. 
Electrocardiogram ........................................................... 28 
4.8.5. 
Concomitant Medications ............................................... 29 
5. 
CHANGES TO PLANNED ANALYSES .............................................. 30 
6. 
References ................................................................................................. 31 
7. 
CLINICAL STUDY REPORT APPENDICES ..................................... 32 
7.1. 
Statistical Tables to be Generated .............................................. 32 
7.2. 
Data Listings to be Generated ..................................................... 37 
 


Protagonist Therapeutics, Inc. 
Protocol PTG-100-02 
08 SEPT 2016 
 
CONFIDENTIAL 
5
ABBREVIATIONS 
Abbreviation 
Definition 
ADRC 
Adaptive design review committee 
AE 
Adverse events 
AESI 
Adverse events of special interest 
AUC 
Area under the concentration versus time curve 
AUC0-t 
Area under the concentration-time curve from time 0 to the time of the 
last sample collection 
Cmax 
Maximum plasma concentration 
Ctrough 
trough (predose) concentration  
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
IA  
Interim Analysis 
ICH 
International Conference on Harmonisation 
IXRS 
Interactive web/voice response system 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing Not at Random 
PK 
Pharmacokinetic 
RE 
Receptor expression 
%RO 
Receptor occupancy 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
Tmax 
Time to maximum plasma concentration 
TNF-α 
Tumor necrosis factor - alpha 


Protagonist Therapeutics, Inc. 
Protocol PTG-100-02 
08 SEPT 2016 
 
CONFIDENTIAL 
6
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
This Statistical Analysis Plan (SAP) has been developed for the final analysis for protocol PTG-
100-02, a Phase 2b Randomized, Double-Blind, Placebo-Controlled, Parallel Adaptive 2-
Stage, Multi-Centre Study To Evaluate The Safety And Efficacy Of Oral PTG-100 
Induction In Subjects With Moderate To Severe Active Ulcerative Colitis. 
This SAP outlines the safety and efficacy analyses, including tables, listings and graphical 
presentations to be included in the Clinical Study Report (CSR). Additional analyses may be 
requested by the Sponsor after review of the pre-planned analyses. 
1.2. 
Objectives of Statistical Analysis 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objective(s).  Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided.  The statistical 
analyses and summary tabulations described in this SAP will provide the basis for the results 
sections of the clinical study report (CSR) for this trial. 
This SAP also will outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 


Protagonist Therapeutics, Inc. 
Protocol PTG-100-02 
08 SEPT 2016 
 
CONFIDENTIAL 
7
2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This will be a randomized, double-blind, placebo-controlled, multi-center, parallel adaptive 2-
stage design study. It is anticipated that approximately 240 male and non-gravid female subjects 
aged 18 to 80 years with moderate to severe active ulcerative colitis will be randomized. (If only 
two arms are selected for continuation following the interim analysis, then up to approximately 
210 subjects will be randomized). Randomization will be stratified by prior treatment with 
Tumor necrosis factor-alpha (TNF-α) antagonist use.  
 
Stage 1 is a four-arm randomized evaluation of three dose regimens of PTG-100 (150 mg, 300 
mg, and 900 mg) compared with placebo. After approximately 60-80 subjects have completed 
the full 12 weeks of dosing, an interim analysis will be performed leading to selection of dose(s) 
that will be discontinued in Stage 2. Subjects will continue to be randomized across the 4 arms 
during the interim analysis until dose(s) are selected for Stage 2 of the trial. 
 
Stage 2 is a randomized evaluation of the dose(s) of PTG-100 selected based on the interim 
analysis data compared with placebo. Since the trial provides for a 12-week treatment period, it 
is expected that an additional approximately 60 subjects would be randomized in equal 
proportions to the 4 treatment groups while the first approximately 60-80 subjects' 12-week data 
are accumulated and analyzed. These Stage 2 subjects will be referred to as the “overrun”, and 
will be included in all final analyses, but not in the interim analysis. Subjects in the continuing 
arms who are randomized after Stage 1 and before the end of the interim analysis period will be 
included in all analyses as Stage 2 subjects. Hence, in Stage 2 the remaining subjects would be 
randomized in equal proportions to the selected dose(s) and placebo. This would yield 
approximately 70-80 subjects per treatment group for the selected doses. Final analysis will 
combine all observed data from both Stages 1 and 2.  
 
Stage 2 Modification Post-Interim Analysis: It is possible that a new treatment arm (600 mg) 
not tested in Stage 1 could be added to the trial in Stage 2. It is to be considered as exploratory 
only, and the data collected on subjects randomized to this arm will not be included in any 
hypothesis testing for overall trial results. The data from this arm will be compared only to the 
data of subjects randomized to the placebo arm, for all trial endpoints. 
 
2.2. 
Randomization Methodology 
Subjects are randomized 1:1:1:1 by interactive web/voice response system (IXRS) in Stage 1. 
Subjects will be stratified by prior treatment with TNF-α antagonist use (Yes/ No). Subject 
enrollment will occur in 2 stages relative to the interim analysis. An independent Data 
Monitoring Committee (DMC) will monitor safety throughout the study period and may be 
unblinded as necessary. Limited personnel required for conducting the analyses may also be 
unblinded to allow necessary safety oversight.  The DMC will also be involved in the interim 
analysis. The purpose of the interim analysis will be to conduct a futility analysis and to identify 
which treatment arms provide optimal data in order to select those (one or two) PTG-100 dose 
levels for continual enrollment as the most informative and effective dose arms. Dose selection 


Protagonist Therapeutics, Inc. 
Protocol PTG-100-02 
08 SEPT 2016 
 
CONFIDENTIAL 
8
will further be made in consideration of safety data and sound clinical judgment, and will be 
made by the Adaptive Design Review Committee (ADRC), which will be comprised of the 
DMC and a representative of the Sponsor (not involved in the direct conduct of the study).  
After the unblinded interim analysis by the ADRC, additional subjects will be randomized 
equally (1:1 or 1:1:1 as appropriate) to the selected doses of PTG-100 and placebo with 
stratification maintained in Stage 2.  
2.3. 
Stopping Rules and Unblinding 
Conditional power will also be computed at the interim analysis. It is the probability that the 
trial will yield a statistically significant difference for clinical remission at the higher chosen 
dose for Stage 2 if the observed difference at the Interim Analysis (IA) is the TRUE underlying 
difference and the trial is continued to completion. If this probability is less than 10%, the 
decision could be made by the ADRC to stop the trial for futility after review of safety data and 
other efficacy and/or exploratory endpoints. 
This will be a double-blind, placebo-controlled study. As such, the sponsor (other than the 
designated representative of the ADRC), CRO, medical monitors, investigator, site pharmacist 
(or designee), site personnel involved in study conduct, and subjects will remain blinded to 
study medication assignment.   
An independent Data Monitoring Committee (DMC) will monitor safety throughout the study 
period and may be unblinded as necessary. Limited personnel required for conducting the 
analyses may also be unblinded to allow necessary safety oversight.  The DMC will also be 
involved in the interim analysis. Limited personnel required for conducting the interim analysis 
will also be unblinded. Unblinded personnel required for the interim analysis will be defined in 
the DMC charter. The sponsor representative serving on the ADRC will not be involved in the 
periodic safety monitoring performed by the DMC. 
Unblinding of individual subject treatment assignments may be permitted in the event of an 
emergency situation requiring knowledge of treatment assignment; however, subject assignment 
should not be routinely unblinded. Unblinding will be performed via the IXRS system from 
Almac (Craigavon, Northern Ireland). This randomization information may be opened and the 
randomization for each individual subject made available to the Investigator (or designee) only 
in the event of a medical emergency or an adverse event (AE) that necessitates identification of 
the clinical trial material for the welfare of that subject. Except in a medical emergency, the 
Investigator (or designee) and blinded clinical site staff will remain blinded during the conduct 
of the study and until such time that all discrepancies in the clinical database are resolved (i.e., 
at the database lock). The date/initials and reason for the Investigator (or designee) removing the 
study blind will be documented. Unblinding for any other reason will be considered a protocol 
violation. 
2.4. 
Study Procedures 
 
 
 


Protagonist Therapeutics, Inc. 
Protocol PTG-100-02 
08 SEPT 2016 
 
CONFIDENTIAL 
9
The schedule of assessments, as outlined in the study protocol, is provided in Table 1. 
Table 1 
Schedule of Assessments 
 
Screening
Random-
ization 
Period 
Treatment 
Follow 
up 
 
 
Days -35 
to -7 
Day -7 to 
Day -1 
Day 0 
(pre-
dose)1 
Day 0 
(dosing, 
post-dose)
Day 14 
±3 days 
Day 28 
±3 days 
Day 42 
±3 days 
Day 56 
±3 days 
Day 702 
±3 days 
Day 84  
±3 days 
Day 112 
±7 days
Early 
Termi-
nation3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medications4 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
Physical Examination5 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Vital Signs6 
X 
 
X 
X7 
X 
X 
X 
X 
 
X 
X 
X 
12-lead ECG6 
X 
 
X8 
 
X 
 
 
X 
 
X 
X9 
X 
Laboratory: 
Haematology, 
Coagulation, Serum 
Chemistry10 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Stool C.diff, Culture, 
and Ova and Parasites 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (dipstick and 
microscopy if 
abnormal) 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
PML Neurological 
Assessment11 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 


Protagonist Therapeutics, Inc. 
Protocol PTG-100-02 
08 SEPT 2016 
 
CONFIDENTIAL 
10
 
Screening
Random-
ization 
Period 
Treatment 
Follow 
up 
 
 
Days -35 
to -7 
Day -7 to 
Day -1 
Day 0 
(pre-
dose)1 
Day 0 
(dosing, 
post-dose)
Day 14 
±3 days 
Day 28 
±3 days 
Day 42 
±3 days 
Day 56 
±3 days 
Day 702 
±3 days 
Day 84  
±3 days 
Day 112 
±7 days
Early 
Termi-
nation3 
Hepatitis B & C; TB 
Test 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
(WOCBP) 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Sigmoidoscopy 
X12 
 
 
 
 
 
 
 
 
X 
 
X 
Colonic Biopsy 
X12 
 
 
 
 
 
 
 
 
X 
 
X 
Mayo Score13 
X12 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
JCV Antibody Testing14 
X14 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
Eligibility 
 
 
X 
 
 
 
 
 
 
 
 
 
Randomisation15 
 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IBDQ 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Faecal Calprotectin 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
Urine Pregnancy 
(WOCBP) 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
PK Blood Collection16 
 
 
X 
X17 
X 
X 
X 
X 
 
X17 
 
X17 
PD Blood Collection16 
 
 
X 
X17 
X 
X 
X 
X 
 
X17 
 
X17 
ADA Testing 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Exploratory 
Immunologic 
Assessment Blood 
Sample18 
 
 
X 
 
 
 
 
 
 
 
 
 
IP Administration19 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 


Protagonist Therapeutics, Inc. 
Protocol PTG-100-02 
08 SEPT 2016 
 
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ADA = anti-drug antibodies; AE = adverse event; ECG = electrocardiogram; IBDQ = Inflammatory Bowel Disease Questionnaire; IP = investigational product; JCV= John 
Cunningham virus; PD = pharmacodynamics; PK = pharmacokinetics; PML = progressive multifocal leukoencephalopathy; TB = tuberculosis; WOCBP = women of childbearing 
potential. 
1 All predose procedures should be completed prior to dosing. 
2 Day 70 AE monitoring will be obtained via phone call and data to calculate rectal bleeding and stool frequency subscores will be obtained. 
3 Procedures to be performed within 10 days of Early Termination.  
4 All prior medications taken within 3 months before screening should be recorded. 
5 Complete physical examinations should be conducted at Screening, Day 84, Day 112, and/or Early Termination. Directed physical examinations should be conducted at other 
time points. The Day 0 postdose examination will occur 4 hours postdose. 
6 Participants should be rested in a supine or semi-recumbent position for ≥ 3 minutes prior to recording of ECGs and vital signs. The ECGs and vital signs should be assessed prior 
to blood draws. Temperature by oral, axillary, or tympanic route may be permitted provided the same route is used for the participant throughout the study. 
7 Vital signs will be done at 1, 2, and 4 hours ± 20 minutes postdose following the first dose of study drug. 
8 Predose (baseline) ECGs should be repeated 3 times with 1- to 2-minute intervals between ECG readings, all within 2 hours prior to dosing.  
9 ECG only to be performed if previously abnormal. 
10 Laboratory samples collected at Screening and on Day 0 (predose), Day 28, Day 84 (or Early Termination), and Day 112 MUST be after the participant has FASTED from all 
food and drink except water for ≥ 8 hours (except for any dietary requirements that are part of sigmoidoscopy prep). Chemistry Panel at these fasting visits will include cholesterol 
and glucose analytes. All other non-fasting visits will have Chemistry Panel completed without cholesterol and glucose analytes. See Appendix B for list of analytes assessed. 
11 PML Assessment Questionnaire (see Appendix D). If the Screening PML assessment was performed within 14 days of Day 0, it will not need to be repeated on Day 0. 
12 Sigmoidoscopy, biopsy, and a baseline complete Mayo Score are to be completed within 14 days of randomisation (as close to randomisation as possible) after confirmation of 
eligibility from other screening tests. Eligibility/ baseline complete Mayo Score should be done before the day of sigmoidoscopy. Sigmoidoscopy should be the last procedure 
before randomisation. Subjects must meet eligibility criteria of Mayo Score 6 to 12 and endoscopy subscore of ≥ 2 in order to be randomised. 
13 Complete Mayo Score (including all 4 subscores) to be assessed at Screening, Day 84, and Early Termination (if possible); partial Mayo Score (without endoscopy subscore) to 
be assessed at all other time points except Day 70 where only rectal bleeding and stool frequency subscores will be reported via phone. 
14 JCV antibody testing must be performed within 90 days prior to dosing. Testing will be performed at the time of the pretreatment sigmoidoscopy if no prior results (within the 
90-day timeframe) are available, and if the subject is eligible for study enrolment. Results will not determine eligibility for the trial. 
15Randomisation will occur after all subject eligibility has been confirmed in the screening period. Randomisation in the interactive web/voice response system must be completed 
in advance of Day 0. Dosing should occur within 7 days of randomisation. 
16 Baseline (Day 0 predose) PK and PD blood samples will be taken within 2 hours prior to dosing. PD samples to be taken at selected sites only. 
17 PK samples are to be collected at 1, 2, and 4 hours ± 20 minutes postdose on Day 0 and Day 84 or Early Termination (if possible) only. PD samples to be collected 4 hours ± 
20 minutes postdose on Day 0 and Day 84 or Early Termination (if possible) only. For every visit other than Day 0, a single PK and PD sample will be obtained within 1 hour prior 
to taking the regularly scheduled dose. 
18 A separate blood sample will be collected at selected sites (Day 0 predose only) for immunologic assessment. 
19 IP will be administered once daily for 84 days. The first drug will be administered at the study centre and subjects will be observed for at least 4 hours. On visits to study site, 
subjects should take the daily dose of study medication after completion of all blood collections. 
 


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2.5. 
Efficacy, Pharmacokinetic, and Safety Variables 
2.5.1. 
Efficacy Variables 
The primary efficacy endpoint for this study is the proportion of subjects receiving PTG-100 
with clinical remission at Week 12 compared with placebo.  
Clinical remission is defined as follows using the Mayo subscores of stool frequency, rectal 
bleeding, and endoscopy: 
1. Stool frequency subscore of 0 or 1 with a pre-specified change of 1 or more from 
baseline 
2. Rectal bleeding subscore of 0 
3. Endoscopy subscore of 0 or 1 (modified so that a score of 1 does not include friability) 
Secondary endpoints, all based on comparison of individual PTG-100 dose levels with placebo, 
include: 
1. Proportion of subjects with clinical response at Week 12 (Day 84) (defined as at least 1 
point and 30% reduction from baseline in rectal bleeding and stool frequency subscores) 
2. Proportion of subjects with endoscopic response at Week 12 (Day 84) (defined as an 
endoscopic subscore of 0 or 1) 
3. Mean change in endoscopy subscore from baseline to Week 12 (Day 84) 
4. Mean change in rectal bleeding subscore from baseline to Weeks 2, 4, 6, 8, 10, 12, and 
16 (Days 14, 28, 42, 56, 70, 84, and 112) 
5. Mean change in stool frequency subscore from baseline to Weeks 2, 4, 6, 8, 10, 12, and 
16 (Days 14, 28, 42, 56, 70, 84, and 112) 
6. Proportion of subjects with endoscopic remission at Week 12 (defined as an endoscopic 
subscore of 0) 
7. Mean change in Complete Mayo Score (including all four subscores) from baseline to 
Week 12 (Day 84) 
8. Mean change in Partial Mayo Score (excluding endoscopy subscore) from baseline to 
Weeks 2, 4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 70, 84, and 112) 
9. Mean change in fecal calprotectin levels from baseline to Weeks 6 (Day 42) and 12 (Day 
84)  
10. Mean change in IBDQ score from baseline to Week 12 (Day 84) 
Exploratory endpoints include: 
1. Mean change in histological score from baseline to Week 12 
2. Effects of ADA on PK, safety, and efficacy in subjects with positive ADA 
 


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2.5.2. 
Pharmacokinetic Variables 
Blood samples for determination of PTG-100 pharmacokinetics were to be collected as outlined 
in Table 1. Maximum concentration (Cmax), trough (predose) concentration (Ctrough) and the time 
of Cmax (Tmax) will be taken directly from the observed data.  The area under the concentration-
time curve (AUC0-t) from time 0 to the time of the last sample collection will be calculated 
using the linear trapezoidal rule. 
2.5.3. 
Pharmacodynamic and Immunogenicity Variables 
Quantitation of percent α4β7 receptor occupancy (%RO) and α4β7 receptor expression (RE) on 
peripheral blood T cells will be evaluated as secondary endpoints.  
ADA will be categorized as screening, confirmatory, or neutralizing. The proportion of subjects 
developing neutralizing anti-drug antibodies (ADA) by Week 12 (Day 84) and Week 16 (Day 
112) will be evaluated.  
Exploratory endpoints will include: 
1. Analysis of peripheral blood lymphocytes in subjects on individual PTG-100 dose levels 
compared to placebo   
2. Number of β7 positive cells in colonic biopsies as assessed by immunohistochemistry 
(IHC) in subjects on individual PTG-100 dose levels compared to placebo 
3. Changes in immunologic/PD biomarkers in the target population  
 
2.5.4. 
Safety Variables 
Safety assessments performed during the study included physical examinations, measurement of 
vital signs, 12-lead electrocardiograms (ECGs), clinical laboratory evaluations including 
hematology, serum chemistry, and urinalysis, concomitant medications, and monitoring of AEs. 


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3. 
SUBJECT POPULATIONS 
3.1. 
Population Definitions 
The following subject populations will be evaluated and used for presentation and analysis of 
the data: 
Safety Population: all randomized subjects who received any amount of study drug. 
Full Analysis Set (FAS): all randomized subjects who received any amount of study drug and 
who have results from baseline and from ≥1 post-baseline assessment will be included in the 
PD and efficacy analysis.  
Per Protocol (PP) Population: all subjects in the FAS without any major protocol violations 
Pharmacokinetic (PK) Population: all randomized subjects who receive a Day 0 dose of study 
drug and who have sufficient PK data for analysis (meeting the required minimum blood 
volume collected along with the sampling schedule, and sampling time, and without 
vomiting) 
Subjects in the all populations will be included in the respective treatment groups on an as-
treated basis.  
 
 
The safety population will be used for safety analyses, demographic and other baseline subject 
characteristics, and the FAS and PP populations will be used for the primary, secondary, 
exploratory, PD, and immunogenicity endpoints. The FAS population will also be used for the 
Disposition by Study Visit tabulation. The PK population will be used for PK summaries. 
 
If it is determined that a significant number of subjects were not treated as randomized, 
additional analyses on the subjects analyzed as randomized may be performed.  
  
Of note, per the adaptive study design, the overrun subjects randomized in Stage 2 will be 
included in all analyses where data is available.  
As noted in Section 2.1, subjects randomized during Stage 2 to a dose not studied in Stage 1 will 
be included in final analyses. 
3.2. 
Protocol Violations 
At the discretion of the sponsor, major protocol violations as determined by a review of the data 
prior to unblinding of the study results and the conduct of statistical analyses may result in the 
removal of a subject’s data from the Per Protocol Population.  The sponsor, or designee, will be 
responsible for producing the final protocol violation file (formatted as a Microsoft Excel file), 
in collaboration with Cytel and the data monitoring group as applicable; this file will include a 
description of the protocol violation, and clearly identify whether or not this violation warrants 
exclusion from the Per Protocol Population.  This file will be finalized prior to hard database 
lock. 
All protocol violations will be presented in the data listings. 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
Approximately 240 male and non-gravid female subjects aged 18-80 with moderate to severe 
active UC will be randomized.  
Prior studies1-7 suggest treatment effects of ~21 percentage point differences from placebo 
clinical remission rate of ~10%.  Those values were assumed for purposes of design of this 12-
week treatment trial. 
Table 2 below shows power for representative scenarios of potential TRUE underlying dose-
response relationships, as well as that for no drug effect to assess type 1 error (calculations via 
Cytel's EAST COMPASS adaptive dose-finding software based on 1000 simulations of each 
design, with each simulated trial analyzed as described in Section 4.6).  
Table 2 Power and Type 1 Error for Various Response Rates 
 
TRUE underlying response rates 
power (alpha=0.025, 1-sided) 
placebo 
150 
mg 
300 mg 
900 
mg 
N=260 
N=240 
N=220 
N=200 
0.1 
0.2 
0.31 
0.31 
93% 
91% 
90%
84%
0.1 
0.17 
0.24 
0.31 
83% 
82% 
78%
75%
0.1 
0.1 
0.1 
0.1 
3.4% 
2.2% 
1.7%
2.1%
 
4.2. 
General Statistical Methods and Data Handling 
4.2.1. 
General Methods 
All output will be incorporated into Microsoft Excel or Word files, sorted and labeled according 
to The International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) recommendations, and formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, pharmacokinetic, 
pharmacodynamic and safety parameters.  For categorical variables, summary tabulations of the 
number and percentage within each category (with a category for missing data) of the parameter 
will be presented.  For continuous variables, the mean, median, standard deviation, minimum 
and maximum values will be presented.     
Formal statistical hypothesis testing will be performed on the primary efficacy endpoint with all 
tests conducted at the 1-sided, 0.025 level of significance.  Summary statistics will be presented, 
as well as confidence intervals on selected parameters, as described in the sections below. 


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4.2.2. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software 
(Version 9.2), unless otherwise noted.  Medical History and adverse events will be coding using 
the most current MedDRA version available.  Concomitant medications will be coded using the 
most current World Health Organization (WHO) Drug version available and WHODRUG DD B 
Format.  
4.2.3. 
Methods of Pooling Data 
Data will be pooled across all study sites for analyses. Homogeneity of the treatment effect 
across sites will be evaluated using a logistic regression model with response rate as the 
dependent variable and terms for treatment, site, and treatment by site interaction as fixed 
effects. Sites with small enrollment numbers will be pooled with the closest geographical site, as 
necessary, to ensure model convergence.  
4.2.4. 
Adjustments for Covariates 
The analyses may be adjusted for the randomization stratification factor, prior treatment with 
TNF- α antagonist. It will be used in the stratified primary efficacy analysis, and as a covariate 
in models used for continuous endpoints. 
4.2.5. 
Multiple Comparisons/Multiplicity 
Multiplicity will be addressed via a closed testing procedure with combined p-values computed 
for each of the two stages of the trial (interim analysis and post-interim analysis). Each stage p-
value will be adjusted as appropriate by a closed testing multiple comparison approach that 
controls the overall type 1 error at alpha equal to 0.025, one-sided. Further details will be 
provided in Section 4.6. 
Testing of secondary endpoints will only be performed if the primary efficacy null hypothesis is 
rejected. A hierarchical testing procedure will be used for the multiple secondary endpoints at 
the 0.025 (one-sided) alpha level. The first ten secondary endpoints will be tested in the order 
that they are presented in Section 2.5.1. For secondary endpoints compared at multiple time 
points, only the comparison at Week 12 will be used for hierarchical testing purposes.  
4.2.6. 
Subpopulations 
Summaries on the primary and secondary efficacy endpoints will be presented by the 
randomization stratum, prior treatment with TNF-α antagonist. 
4.2.7. 
Withdrawals, Dropouts, Loss to Follow-up 
For subjects who are withdrawn by the Investigator (or designee) or who voluntarily withdraw 
prematurely from the study, replacement subjects will be enrolled only if deemed necessary by 
the sponsor. Replacement subjects will be assigned a subject number by adding 300 to the 
number of the subject they are replacing (e.g., Subject No. 305 replaces Subject No. 005) and 
will be enrolled into the same randomization arm as the subject whom they are replacing. 
Analyses will utilize all available data obtained from such subjects (withdrawn and replacement 
subjects), in accordance with the study population definitions. 


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4.2.8. 
Missing, Unused, and Spurious Data 
All data recorded on the CRF will be included in data listings that will accompany the clinical 
study report. 
For the primary efficacy endpoint and other success/failure secondary endpoints, subjects who 
discontinue prior to Week 12 will be considered treatment failures, a worst-case scenario.   
These endpoints include  
 Clinical Remission (primary endpoint) 
 Clinical Response 
 Endoscopic Response 
 Endoscopic Remission 
A single sensitivity analysis on each of these endpoints will utilize the per protocol population 
(complete-case) in order to examine the robustness of the results. 
 
For all continuous secondary endpoints, data will be analyzed using a mixed model repeated 
measures approach described in Section 4.6.2. The MMRM method assume that missing data 
arose from a missing at random (MAR) mechanism, i.e. the missing data is independent of 
unobserved data given the non-missing data. The MAR assumption is reasonable in clinical 
trials as the observed data explain much of the missingness in many scenarios, particularly in 
well controlled studies such as clinical trials, in which an extensive effort is made to observe all 
the outcomes and the factors that influence them. In MMRM, the information from the observed 
data is used via the within-patient correlation structure to provide information about unobserved 
data.  The data from all visits are simultaneously analyzed using restricted maximum likelihood 
methods and no explicit imputation for missing values is performed. This method will be used 
in the testing of the secondary endpoints.  
In addition, sensitivity analyses may be performed on complete datasets where missing data is 
imputed using the following methodology: 
 LOCF (last observation carried forward) 
 WOCF (missing data imputed using the worst observation observed prior to that time 
point) 
 Per Protocol population (complete-case scenario- no imputation required) 
 Multiple Imputation 
 
For multiple imputation, two approaches may be used. In the first approach, for missing 
response data at various time points, the following steps are taken: 
 Draw a random sample from the normal distribution with a mean and variance calculated 
from the non-missing responses at that time point 
 Repeat this process five times to form five imputed complete datasets 
  Fit the MMRM model to each imputed dataset to estimate the treatment effect on the 
response variable and the variance 


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 Combine the results from the five imputed dataset using SAS Proc MIANALYZE to 
derive the multiple imputation estimates of treatment effect and variance. 
 
The second multiple imputation approach will be used to impute data in the event that missing 
data are missing not at random (MNAR) but rather depend on the observed and unobserved 
data. This imputation approach would use the same steps as above, but the random sample 
would be drawn from a distribution pre-defined and related to the responses that are observed.  
 
Exploratory endpoints will not be imputed. 
 
Adverse event (AE) dates that are missing or incomplete will be handled in the following 
manner to determine whether an AE is treatment-emergent:  
If the start date/time of an AE is partially or completely missing, the date/time will be compared 
as far as possible with the date/time of the start of administration of study drug. The AE will be 
assumed to be treatment emergent if it cannot be definitively shown that the AE did not occur or 
worsen during the treatment-emergent period (worst case approach).  
 
The following general rules will be used:  
 
 If the start time of an AE is missing but the start date is complete, an AE will only be 
excluded as being treatment emergent if the start date is before the date of study drug 
administration or if the stop date/time is before study drug administration.  
 If the start time and day are missing but the start month and year are complete, an AE 
will only be excluded as being treatment emergent if the start month/year is before the 
month/year of study drug administration or if the stop date/time is before study drug 
administration.  
 If the start day and month are missing but the start year is complete, an AE will only be 
excluded as being treatment emergent if start year is before the year of study drug 
administration or if the stop date/time is before study drug administration.  
 If the start date is completely missing, an AE will be considered treatment-emergent 
unless the stop date/time is before study drug administration.  
 
4.2.9. 
Visit Windows 
Table 3 below presents the allowable visit windows and intervals for analysis of efficacy 
variables. For the purposes of statistical analysis, the visit days will be recalculated in terms of 
study days since the first day of dosing as illustrated below. 
Baseline will be defined as the last non-missing pre-treatment assessment. For post-baseline 
visits, if a subject has more than one assessment occurring in the same visit window, the data 
from the visit closest to the scheduled study day will be used. If two visits have the same 
distance from the scheduled study day, the data of the visit after the scheduled study day will be 
used. 


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Table 1 
Evaluation Intervals for Efficacy Analysis 
Evaluation 
Protocol-Specified Interval 
Interval for Analysis 
Baseline (Screening and Pre-Dose) 
Day –35 to Day 0 
Day –35 to Day 0 (Pre-Dose) 
Day 0 (Post-Dose) 
Day 0 (Post-Dose) 
Day 0 (Post-Dose) 
Day 14 
Day 11 post to Day 17 post 
Day 1 post to Day 24 post 
Day 28 
Day 25 post to Day 31 post 
Day 25 post to Day 38 post 
Day 42 
Day 39 post to Day 45 post 
Day 39 post to Day 52 post 
Day 56 
Day 53 post to Day 59 post 
Day 53 post to Day 66 post 
Day 70 
Day 67 post to Day 73 post 
Day 67 post to Day 80 post 
Day 84 
Day 81 post to Day 87 post 
Day 81 post to Day 104 post 
Day 112 (Follow-Up) 
Day 105 post to Day 119 post 
Day 105 post to Day 119 post 
Actual dates and times will be used for pharmacokinetic and pharmacodynamic analyses rather 
than nominal days and times. 
4.3. 
Interim Analyses 
An unblinded interim analysis (IA) will be performed by the ADRC after approximately 60-80 
subjects have completed the full 12 weeks dosing. A futility analysis will be performed; if the 
trial does not meet criteria for futility, further analysis will be conducted in order to drop one (or 
two) of the PTG-100 dose arms. Following the IA, randomization will continue to the remaining 
dose arms (Stage 2).  
Conditional power will also be computed at the IA. It is the probability that the trial will yield a 
statistically significant difference for clinical remission at the higher chosen dose for Stage 2 if 
the observed difference at the IA is the TRUE underlying difference and the trial is continued to 
completion. If this probability is less than 10%, the ADRC could suggest that the trial be 
stopped for futility after review of safety and other efficacy and exploratory endpoints.  
Conditional power for an active dose versus placebo is derived as follows. 
 Let ߜመଶ be the observed difference of proportions between the active dose and placebo group 
based on data from the second stage. Then ݌ଶ= ߔ൬
ఋ෡మ
ௌா൫ä෠మ൯൰. Therefore  
 
ߔቆ
ߜመଶ
ܵܧ൫ߜመଶ൯ቇ≤ߔቊߔିଵ(ߙ) −ݓଵߔିଵ(݌෤ଵ )
ݓଶ
ቋ 
 
or equivalently 
 
ߜመଶ
ܵܧ൫ߜመଶ൯≤ߔିଵ(ߙ) −ݓଵߔିଵ(݌෤ଵ )
ݓଶ
 


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Denote the true difference of response rates between the selected active dose and placebo group 
by ߜ. Then we have 
 
ߜመଶ−ߜ
ܵܧ൫ߜመଶ൯≤ߔିଵ(ߙ) −ݓଵߔିଵ(݌෤ଵ )
ݓଶ
−
ߜ
ܵܧ൫ߜመଶ൯ 
 
Note that 
ఋ෡మିఋ
ௌா൫ఋ෡మ൯ follows an approximately standard normal distribution. Hence the conditional 
power is given by 
 
ܲቊߜመଶ−ߜ
ܵܧ൫ߜመଶ൯≤ߔିଵ(ߙ) −ݓଵߔିଵ(݌෤ଵ )
ݓଶ
−
ߜ
ܵܧ൫ߜመଶ൯ቋ 
 
= ߔቊߔିଵ(ߙ) −ݓଵߔିଵ(݌෤ଵ )
ݓଶ
−
ߜ
ܵܧ൫ߜመଶ൯ቋ 
 
 where ܵܧ൫ߜመଶ൯= ට
గ೟ (ଵିగ೟)
௡మ೟
+
గ೎ (ଵିగ೎)
௡మ೎
    and ݊ଶ௧, ݊ଶ௖  are the number of subjects for the active 
dose and placebo group at the second stage respectively. Since we don't know ߜ, ߨ௧, ߨ௖, we will 
replace them by those observed from the first stage data in the conditional power calculation. 
PD, efficacy, and safety data will be analyzed to model dose- and exposure-response from Stage 
1 of the trial to allow dropping of an ineffective or redundant arm(s). It is also possible that a 
new dose arm (not tested in Stage 1 of the trial) could be added in Stage 2 for exploratory 
purposes. Since the trial provides for a 12-week treatment period, it is expected that an 
additional approximately 60 subjects would be randomized in equal proportions to the 4 
treatment groups while the first approximately 60-80 subjects' 12-week data are accumulated 
and analyzed. Hence, in Stage 2 the remaining subjects would be randomized in equal 
proportions to the selected dose(s) and placebo. This would yield approximately 70-80 subjects 
per treatment group for the selected doses. The final analysis will combine all observed data 
from both Stages 1 and 2.    
Dose selection will further be made in consideration of safety data and sound clinical judgment, 
and will be made by the ADRC), which will be comprised of the DMC and a representative of 
the Sponsor (not involved in the direct conduct of the study). No pre-specified algorithm will be 
defined for the IA. Only the ADRC, which will make the dose selection for Stage 2, and the 
Independent Statistical Center, which will perform the IA, will be unblinded. 
4.4. 
Subject Disposition 
Subject disposition will be tabulated, including the number screened, the number randomized by 
treatment group, the number with major protocol violations, the number in each subject 
population for analysis, the number that withdrew prior to completing the study, and reasons for 
withdrawal.   


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The disposition by study visit tabulation will be based on the FAS population in order to report 
specifically on the disposition of dosed subjects with endpoint data.  
Disposition will also be presented graphically in the study report using a CONSORT diagram, 
utilizing frequencies from validated tabular outputs. 
A by-subject listing of study completion information, including the reason for premature study 
withdrawal, if applicable, will be presented. 
4.5. 
Demographic and Baseline Characteristics 
Baseline, demographic, medical history, and physical examination at screening information will 
be summarized for the safety population using descriptive statistics.  No formal statistical 
comparisons will be performed. These variables will also be summarized by analysis stage (1 
vs. 2), both overall and restricted to the placebo group. Baseline disease characteristics from the 
sigmoidoscopy, biopsy, and a baseline Complete Mayo Score will also be summarized by 
analysis stage, both overall and restricted to the placebo group. 
Demographic and Baseline data will be provided in data listings. 
A by-subject listing of all medical history conditions and physical examination documented at 
screening for the randomized population will be provided.  
Exposure to study drug will be summarized by treatment group for the safety population. 
Exposure will be summarized by total amount of time in the study and total number of days on 
study drug. A by-subject listing of exposure to study drug for all randomized subjects will also 
be provided. 
4.6. 
Efficacy Evaluations 
4.6.1. 
Primary Efficacy Analysis  
The primary efficacy endpoint for this study is the proportion of subjects receiving PTG-100 
with clinical remission at Week 12 compared with placebo, as defined in Section 2.5.1. 
Efficacy analysis for the primary endpoint will be conducted using the FAS population and will 
be repeated on the PP population as a sensitivity analysis. 
The proportion of subjects with clinical remission at Week 12 will be calculated and reported 
with a two-sided 95% exact confidence interval as an estimate of the true proportion of subjects 
with clinical remission in the target patient population. Two approaches will be used to report 
the percentages: 
Approach 1: The naïve percentage and associated 95% CI for each dose group, based on data 
combined across both stages of the trial. 
Approach 2: For doses that are selected for Stage 2, the Stage 2-only proportion of subjects with 
clinical remission and 95% CI will be reported. For doses not selected for Stage 2, the 
proportions and associated 95% CI based on Stage 1 data only will be reported. 
Analysis to examine treatment effect (i.e. odds ratio for clinical remission among subjects with 
each active dose vs. placebo and 95% CI) will be carried out at the Week 12 time point, 
employing a Cochran-Mantel-Haenszel test stratified for prior TNF-α use (yes/no). Raw p-
values, unadjusted for multiple comparisons, associated with each odds ratio will also be 
presented. 


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To obtain the primary endpoint study p-values, Simes-adjusted p-values8 for each dose regimen 
vs. placebo that are produced for the primary endpoint from the first and second stages of the 
study will be combined by using the inverse normal combination function to obtain the final p-
value.  
The components contributing to the Stage 1 portion of the p-value will include data of subjects 
from all 4 original dose groups (placebo, low, medium, high dose) who were enrolled during 
Stage 1, defined as on or before the data snapshot date for the interim look at efficacy.  
 
The components contributing to the Stage 2 portion of the p-value will be data from subjects 
from the dose groups that were not discontinued who were enrolled after the date of the data 
snapshot for the interim look at efficacy.  
The final p-value for the trial primary endpoint will be a weighted combination of the two 
components, as described below. 
The null hypothesis to be tested is  
 
ܪ଴: ߨ஼= ߨ௅= ߨெ= ߨு  
 
against the alternative hypothesis 
 
ܪଵ: at least one of ߨ௅, ߨெ, ߨு  is different from ߨ஼ 
 
where ߨ஼  is the response rate for placebo arm, and ߨ௅, ߨெ, ߨு  are the response rates for the 
three active dose groups. Let ݓଵ= √ݐଵ  and ݓଶ= ඥ1 −ݐଵ   be the prespecified weights where 
ݐଵ  is the statistical information time for interim analysis. Let ݌ଵ௅, ݌ଵெ, ݌ଵு be the marginal p-
values for the three comparisons based on the test statistics of difference of proportions between 
active dose and placebo group. The test is left tailed. Let ݌ଵ(ଵ) ≤݌ଵ(ଶ) ≤݌ଵ(ଷ)  be the ordered p-
values. Let ݌෤ଵ   be the Simes adjusted p-value based on the first stage data. Then 
 
݌෤ଵ = min {3݌ଵ(ଵ),
ଷ
ଶ݌ଵ(ଶ), ݌ଵ(ଷ)} . 
 
Let ݌ଶ  be the p-value for the comparison for the selected dose versus placebo group. The final 
combined Simes p-value is given by 
 
ߔ(ݓଵߔିଵ(݌෤ଵ ) + ݓଶߔିଵ(݌ଶ ))  
 
where ߔ(. ) is the cumulative distribution function of standard normal variable and ߔିଵ(. ) is 
the inverse cumulative distribution function of standard normal variable.  
 
The final analysis is significant if  
 
ߔ൫ݓଵߔିଵ(݌෤ଵ ) + ݓଶߔିଵ(݌ଶ )൯≤ߙ  
 
which is the same as  


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݌ଶ≤ߔቄ
ఃషభ(ఈ)ି௪భఃషభ(௣෤భ )
௪మ
ቅ  
  
Analyses of the primary endpoint will be conducted separately for the subjects with prior TNF-alpha 
use and those without prior TNF-alpha use. Treatment effect estimates will be reported using the 
naïve odds ratio estimator and its associated 95% CI. P-values will be derived from unstratified 
Cochran-Mantel-Haenszel tests. 
 
4.6.2. 
Secondary Efficacy Analyses 
Analyses for the secondary endpoints will be conducted using the FAS and PP populations.  
Where applicable, baseline is defined as the last non-missing pre-treatment assessment prior to 
initiation of study treatment.   
All secondary endpoints that reflect a dichotomous response will be analyzed in the same 
manner as the primary efficacy endpoint. These secondary endpoints include  
 
 Proportion of subjects with endoscopic response at Week 12 (Day 84) (defined as an 
endoscopic subscore of 0 or 1) 
 Proportion of subjects with clinical response at Week 12 (Day 84) (defined as at least 1 
point and 30% reduction from baseline in rectal bleeding and stool frequency subscores) 
 Proportion of subjects developing neutralizing antidrug antibodies (ADA) 
o Methods for detection of ADA in clinical samples are presented in Section 7.8 of 
the protocol 
 Proportion of subjects with endoscopic remission at Week 12 (defined as an endoscopic 
subscore of 0) 
Hypothesis testing for all continuous secondary endpoints will be conducted using repeated 
measures mixed analysis of covariance model adjusted for treatment, time point, treatment-by-
time point interaction, stratification factor (TNF-alpha prior use) and baseline values. For 
subjects who withdraw prematurely, the last observation will be carried forward. These analyses 
will be based on the Stage 1 and Stage 2 combined data for exploratory purposes. Pairwise 
comparisons of active drug versus placebo for the change from baseline endpoints will be 
conducted and p-values derived as described in the analysis of the primary efficacy endpoint.  In 
addition, a summary of observed values and change from baseline values will be presented for 
each endpoint. Graphical summaries by treatment group of mean change from baseline over 
time up to Week 12 will also be presented. 
Continuous secondary endpoints include 
 


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 Mean change in complete Mayo Score (including all four subscores) from baseline to 
Week 12 
 Mean change in Partial Mayo Score (excluding endoscopy subscore) from baseline to 
Weeks 2, 4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 70, 84, and 112) 
 Mean change in endoscopy subscore from baseline to Week 12 (Day 84) 
 Mean change in rectal bleeding and stool frequency subscores from baseline to Weeks 2, 
4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 70, 84, and 112) 
 Mean change in fecal calprotectin levels from baseline to Weeks 6 and 12  
 Mean change in IBDQ score from baseline to week 12 
4.6.3. 
Exploratory Analyses 
Analyses for the exploratory endpoints will be conducted using the FAS and PP populations.   
Exploratory endpoints include: 
 
 Mean change in histological score from baseline to Week 12 (Day 84) 
 Effects of ADA on PK, safety, and efficacy in subjects with positive ADA 
 
For the first two exploratory endpoints, these will be analyzed in the same fashion as their 
primary and secondary counterparts. The effects of ADA on PK, safety, and efficacy may be 
evaluated by performing subgroup analyses (ADA + vs. ADA -) if ADA is detected in clinical 
samples.  
 
4.7. 
Pharmacokinetic and Pharmacodynamic Evaluations 
Pharmacokinetic analyses will be conducted using the Pharmacokinetic Population. 
Pharmacodynamic analyses will be conducted using the FAS and PP populations. 
4.7.1. 
Pharmacokinetic Evaluations 
Pharmacokinetic variables will be calculated from the individual PTG-100 plasma concentration 
data using standard non-compartmental methods.  Maximum concentration (Cmax), trough 
(predose) concentration (Ctrough) and the time of Cmax (Tmax) will be taken directly from the 
observed data.  The area under the concentration-time curve (AUC0-t) from time 0 to the time of 
the last sample collection will be calculated using the linear trapezoidal rule.   
PK analyses will be performed using commercial software such as Phoenix™ WinNonlin® 
Version 6.4 or higher (Certara USA Inc.). All pharmacokinetic calculations will be performed 
using published non-compartmental relationships. Actual dose administration times and sample 
collection times will be used for the analyses as recorded on the CRF. Plasma concentrations 
below the lower limit of quantification will be set to zero for the analysis.  


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Individual PTG-100 concentration data will be listed and summarized by treatment group with 
descriptive statistics (sample size [N], arithmetic mean, standard deviation [SD], median, 
minimum, maximum, geometric mean, and geometric coefficient of variation [CV]). Mean and 
individual PTG-100 concentration-time profiles will be presented graphically on both linear and 
semi-logarithmic scales. All statistical analyses will use non-rounded parameter estimates. 
Plasma concentration data and the pharmacokinetic parameter estimates will be presented by 
study group. Pharmacokinetic parameter estimates will be three or four significant figures for 
presentation. No attempt will made to estimate missing data. Other parameters and data 
handling procedures may be added as appropriate. Missing values will not be imputed, and if 
sufficient data are missing for a given subject, that subject may be considered non-evaluable for 
pharmacokinetic analysis and would not be included in the PK Population.  
All plasma concentration data and the per-subject pharmacokinetic parameters will be displayed 
in listings. 
4.7.2. 
Pharmacodynamic Evaluations 
Quantitation of α4β7 %RO and α4β7 RE on peripheral blood T cells will be evaluated as 
secondary endpoints.  
Exploratory endpoints will include: 
1. Analysis of peripheral blood lymphocytes in subjects on individual PTG-100 dose levels 
to placebo   
2. Average number of β7 positive cells in colonic biopsies as assessed by 
immunohistochemistry (IHC) in subjects by PTG-100 dose levels and compared to 
placebo 
3. Characterization of immunologic biomarkers in the target population (selected sites 
only) 
Individual data will be listed for each individual and summarized by nominal sampling time 
point and treatment group with descriptive statistics (arithmetic mean, SD, median, minimum, 
and maximum). A summary of change-from-baseline at each protocol specified time-point by 
treatment group will also be presented. The change of PD indicators over time will be 
demonstrated graphically and will be compared among the dose levels using the same mixed 
model as the other continuous secondary and exploratory endpoints. 
Further summaries may use pre-clinical and clinical data from previous studies to explore the 
PK/PD relationship to correlate with clinical endpoints. 
Receptor occupancy and α4β7 expression in peripheral blood will be listed for each individual 
and summarized by treatment group using frequency/count data. 
 


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4.8. 
Safety Analyses 
Safety analyses will be conducted using the Safety Population.  The safety analyses generated 
will be a presentation of AEs, SAEs, clinical labs, vital signs, ECGs, and physical examinations 
as described below. 
4.8.1. 
Adverse Events 
The primary safety endpoint is the proportion of subjects with at least 1 AE comparing 
individual PTG-100 dose groups with placebo.  
Secondary endpoints (all based on comparison of individual PTG-100 dose levels to placebo) 
will include: 
 Frequency and type of AEs (affecting ≥ 5% of subjects)  
 Proportion of subjects with at least 1 SAE  
 Number and type of SAEs  
 Frequency of adverse events of special interest (AESI) including serious or opportunistic 
infection (viral, bacterial, fungal including systemic/ gut localization), allergic/ drug 
reactions, immune system disorders, and PML or new onset neurologic symptoms 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and displayed in tables and listings using System Organ Class (SOC) and Preferred 
Term. 
Analyses of adverse events will be performed for those events that are considered treatment 
emergent, where treatment emergent is defined as any adverse event with onset after the 
administration of study medication through the end of the study visit or any event that was 
present at baseline but worsened in intensity or was subsequently considered drug-related by the 
investigator through the end of the study.   
Adverse events are summarized by subject incidence rates, therefore, in any tabulation, a subject 
contributes only once to the count for a given adverse event (SOC or preferred term). 
The number and percentage of subjects  
 with any treatment-emergent adverse event 
 with any treatment-emergent adverse events assessed by the Investigator as related to 
treatment (definite, probable, or possible relationship) 
 with any treatment-emergent serious adverse event  
 with treatment-emergent adverse events by severity 
 with adverse events affecting ≥ 5% of subjects within any treatment group across both 
stages of the study 
 with AESI 
will be summarized by treatment group and overall.  In addition, all active groups will be pooled 
in the summaries for comparison to placebo. In these tabulations, each subject will contribute 


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only once (i.e., the most related occurrence or the most intense occurrence) to each of the 
incidence rates in the descriptive analysis, regardless of the number of episodes. 
Three additional tables will present the incidence of treatment-emergent adverse events by PT, 
treatment-emergent events leading to study withdrawal and treatment-emergent events with a 
fatal outcome, sorted in the order of frequency for the entire safety population. 
All adverse events occurring on study (pre-treatment, treatment, follow-up) will be listed in 
subject data listings. 
By-subject listings also will be provided for the following: subject deaths; serious adverse 
events; and adverse events leading to withdrawal.  
4.8.2. 
Laboratory Data 
Clinical laboratory values will be expressed using SI units. 
A tabulation (n, %) by treatment group and overall of whether a subject had a clinical 
abnormality at any time, and a listing of clinical abnormalities, for all identified laboratory 
abnormalities, will be generated. 
Tabulation of actual value and change from baseline to each on study evaluation will be 
presented for each clinical laboratory parameter, including hematology and clinical chemistry.  
In the event of repeat values, the last non-missing value per study day/time will be used. 
Continuous lab parameters will be categorized as low, medium, or high based on the value of 
the parameter. Shift tables for lab parameters from baseline to all applicable visits will be 
presented. 
All laboratory data will be provided in data listings. 
4.8.3. 
Vital Signs and Physical Examinations 
Tabulation of actual value and change from baseline to each on study evaluation will be 
presented for all vital signs.  No hypothesis testing will be conducted for vital sign data. 
By-subject listings of vital sign measurements will be presented in data listings. 
Physical examination results at each time point will be summarized; shifts from baseline in 
physical examination findings to each on study visit will also be presented.  Clinically 
significant changes in physical examinations will be listed for each participant and described in 
the text of the final report.  
A tabulation (n, %) of subjects with a physical examination abnormality will be presented by 
visit and dose group. The tabulation will be presented by body system. Subjects with no 
examination for a particular body system will not be included in the summary statistics for that 
body system. No formal statistical comparisons will be performed. 
All physical examination findings will be presented in a data listing. 
4.8.4. 
Electrocardiogram 
Tabulation of actual value and change from baseline to each on study evaluation will be 
presented for all continuous ECG measurements (heart rate, PR interval, QRS interval, QT 
interval).  No hypothesis testing will be conducted for vital sign data. 


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ECG results will also be summarized by the number and percent of subjects with overall 
normal, abnormal and clinically significant abnormal results at baseline and each study visit. 
All ECG data for each subject will be provided in data listings. 
4.8.5. 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug dictionary. Results will be 
tabulated by Anatomic Therapeutic Class (ATC) and preferred term. 
The use of concomitant medications will be included in by-subject data listing. 


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5. 
CHANGES TO PLANNED ANALYSES 
As of this date, there have been no changes between the protocol-defined statistical analyses and 
those presented in this statistical plan. 


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6. 
REFERENCES 
 
1. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J et al. (2005). 
Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 
353(23):2462-2476 & [Correction, 2006, 354(20):2200]. 
 
2. Sandborn WJ, Van Assche G, Reinisch W, Colombel J-F, D'Haens G, Wolf DC et al. 
(2012). Adalimumab induces and maintains clinical remission in patients with moderate-
to-severe ulcerative colitis. Gastroenterology 142(2):257-265.e3. 
 
3. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel J-F, Sandborn WJ et al. 
(2013). Vedolizumab as induction and maintenance therapy for ulcerative colitis 
GEMINI 1 Study Group. N Engl J Med 369(8):699-710. 
 
4. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel J-F, Sands BE et al. 
(2013). Vedolizumab as induction and maintenance therapy for Crohn's disease GEMINI 
2 Study Group. N Engl J Med 369(8):711-721. 
 
5. Takeda Pharmaceuticals America, Inc. (2014). Prescribing Information: ENTYVIO 
(Vedolizumab) for Injection, for Intravenous Use. [Label Package]. Deerfield (IL): 
Takeda Pharmaceuticals America, Inc. Available at: 
http://general.takedapharm.com/content/file.aspx?FileTypeCode=ENTYVIOPI&cacheR
andomizer=1b94c181-3ea4-4aa4-8ac5-3a0592873792 [May, 2014]. 
 
6. Gibaldi M, Perrier D. Pharmacokinetics. 2nd edition. New York, NY: Marcel Dekker 
Inc.; 1982. 
 
7. Department of Health and Human Services, Food and Drug Administration. 
International Conference on Harmonisation; Guidelines on Structure and Content of 
Clinical Study Reports; Availability. Federal Register. 1996;61(138):37320-37343. 
 
8. Simes RJ.  An improved Bonferroni procedure for multiple tests of 
significance. Biometrika. 1986;73:751-754


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7. 
CLINICAL STUDY REPORT APPENDICES 
7.1. 
Statistical Tables to be Generated 
Disposition/Demographics/Baseline/Exposure (CSR Table Section 14.1) 
Table 14.1.1.1 
Subject Enrollment and Disposition (All Subjects) 
Table 14.1.1.2 
Subject Disposition by Visit (FAS) 
Table 14.1.2 
Demographic and Baseline Characteristics (Safety Population) 
Table 14.1.3 
Baseline Disease Characteristics (Safety Population) 
Table 14.1.4 
Medical History (Safety Population) 
Table 14.1.5 
Physical Examination at Screening (Safety Population) 
Table 14.1.6 
Exposure to Study Treatment (Safety Population) 
Efficacy/Pharmacokinetic Results (CSR Table Section 14.2) 
Table 14.2.1.1A 
Proportion of Subjects with Clinical Remission at Week 12 (FAS) 
Table 14.2.1.1B 
Proportion of Subjects with Clinical Remission at Week 12 (PP) 
Table 14.2.1.2A 
Proportion of Subjects with Clinical Remission at Week 12 by Prior 
TNF-alpha Use (FAS) 
Table 14.2.1.2B 
Proportion of Subjects with Clinical Remission at Week 12 by Prior 
TNF-Alpha Use (PP) 
Table 14.2.1.3A 
Proportion of Subjects with Endoscopic Response at Week 12 (FAS) 
Table 14.2.1.3B 
Proportion of Subjects with Endoscopic Response at Week 12 (PP) 
Table 14.2.1.4A 
Proportion of Subjects with Clinical Response at Week 12 (FAS) 
Table 14.2.1.4B 
Proportion of Subjects with Clinical Response at Week 12 (PP) 
Table 14.2.1.5A 
Proportion of Subjects with Endoscopic Remission at Week 12 (FAS) 
Table 14.2.1.5B 
Proportion of Subjects with Endoscopic Remission at Week 12 (PP) 
Table 14.2.2.1A 
Change in complete Mayo Score from Baseline to Week 12 (FAS) 


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Table 14.2.2.1B 
Change in complete Mayo Score from Baseline to Week 12 (PP) 
Table 14.2.2.1C 
Change in complete Mayo Score from Baseline to Week 12 (Sensitivity 
Analyses - if Needed) 
Table 14.2.2.2A 
Change in Partial Mayo Score from Baseline Over Time (FAS) 
Table 14.2.2.2B 
Change in Partial Mayo Score from Baseline Over Time (PP) 
Table 14.2.2.2C 
Change in Partial Mayo Score from Baseline Over Time (Sensitivity 
Analyses - if Needed) 
Table 14.2.2.3A 
Change in Endoscopy Subscore from Baseline to Week 12 (FAS) 
Table 14.2.2.3B 
Change in Endoscopy Subscore from Baseline to Week 12 (PP) 
Table 14.2.2.3C 
Change in Endoscopy Subscore from Baseline to Week 12 (Sensitivity 
Analyses – if Needed) 
Table 14.2.2.4A 
Change in Rectal Bleeding Subscore from Baseline Over Time (FAS) 
Table 14.2.2.4B 
Change in Rectal Bleeding Subscore from Baseline Over Time (PP) 
Table 14.2.2.4C 
Change in Stool Frequency Subscore from Baseline Over Time 
(Sensitivity Analyses – if Needed) 
Table 14.2.2.5A 
Change in Stool Frequency Subscore from Baseline Over Time (FAS) 
Table 14.2.2.5B 
Change in Stool Frequency Subscore from Baseline Over Time (PP) 
Table 14.2.2.5C 
Change in Stool Frequency Subscore from Baseline Over Time 
(Sensitivity Analyses – if Needed) 
Table 14.2.2.6A 
Change in Fecal Calprotectin Levels from Baseline Over Time (FAS) 
Table 14.2.2.6B 
Change in Fecal Calprotectin Levels from Baseline Over Time (PP) 
Table 14.2.2.6C 
Change in Fecal Calprotectin Levels from Baseline Over Time 
(Sensitivity Analyses – if Needed) 
Table 14.2.2.7A 
Change in IBDQ score from Baseline Over Time (FAS) 
Table 14.2.2.7B 
Change in IBDQ score from Baseline Over Time (PP) 


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Table 14.2.2.7C 
Change in IBDQ score from Baseline Over Time (Sensitivity Analyses 
– if Needed) 
Table 14.2.2.7A 
Change in Histological score from Baseline Over Time (FAS) 
Table 14.2.2.7B 
Change in Histological score from Baseline Over Time (PP) 
Table 14.2.3 
Summary of Pharmacokinetic Parameters (PK Population) 
Table 14.2.4.1A 
Change in α4β7 Receptor Occupancy on Peripheral Blood T cells Over 
Time (FAS) 
Table 14.2.4.1B 
Change in α4β7 Receptor Occupancy on Peripheral Blood T cells Over 
Time (PP) 
Table 14.2.4.2A 
Summary of α4β7 Receptor Expression on Peripheral Blood T cells 
Over Time (FAS) 
Table 14.2.4.2B 
Summary of α4β7 Receptor Expression on Peripheral Blood T cells 
Over Time (PP) 
Table 14.2.4.3A 
Change in Peripheral Blood Lymphocytes Over Time (FAS) 
Table 14.2.4.3B 
Change in Peripheral Blood Lymphocytes Over Time (PP) 
Table 14.2.4.4A 
Change in β7 Positive Cells in Colonic Biopsies Over Time (FAS) 
Table 14.2.4.4B 
Change in β7 Positive Cells in Colonic Biopsies Over Time (PP) 
Table 14.2.5.1A 
Proportion of Subjects with Positive Neutralizing ADA by Week 12 and 
Week 16 (FAS) 
Table 14.2.5.1B 
Proportion of Subjects with Positive Neutralizing ADA by Week 12 and 
Week 16 (PP) 
Displays of Adverse Events (CSR Section 14.3.1) 
Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events by Treatment 
Group (Safety) 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term and Treatment Group, Sorted in Descending 
Frequency according to the Total Column (Safety) 


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Table 14.3.1.3 
Summary of Related/Possibly, Probably and Definitely Related 
Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term and Treatment Group (Safety) 
Table 14.3.1.4 
Summary of Treatment-Emergent Adverse Events by Severity, System 
Organ Class, Preferred Term and Treatment Group (Safety) 
Table 14.3.1.5 
Summary of Treatment-Emergent Serious Adverse Events by System 
Organ Class, Preferred Term and Treatment Group (Safety) 
Table 14.3.1.6 
Summary of Most Common (>=5% within any treatment group) 
Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term and Treatment Group (Safety) 
Table 14.3.1.7 
Summary of Treatment-Emergent Adverse Events by Preferred Term 
and Treatment Group (Safety) 
Table 14.3.1.8 
Summary of Adverse Events Leading to Study Withdrawal by System 
Organ Class, Preferred Term and Treatment Group (Safety) 
Table 14.3.1.9 
Summary of Treatment-Emergent Adverse Events with a Fatal Outcome 
by System Organ Class, Preferred Term and Treatment Group (Safety) 
Listings of Deaths, Serious Adverse Events and Other Significant Events (CSR Section 
14.3.2) 
Table 14.3.2.1 
Listing of Subject Deaths 
Table 14.3.2.2 
Listing of Serious Adverse Events 
Table 14.3.2.3 
Listing of Adverse Events Leading to Withdrawal or Death 
Abnormal Laboratory Value Tables and Listings (CSR Section 14.3.4) 
Table 14.3.4.1.1 
Summary of Clinical Laboratory Abnormalities: Hematology (Safety) 
Table 14.3.4.1.2 
Summary of Clinical Laboratory Abnormalities: Chemistry (Safety) 
Table 14.3.4.1.3 
Summary of Clinical Laboratory Abnormalities: Urinalysis (Safety) 
Table 14.3.4.1.4 
Summary of Clinical Laboratory Abnormalities: Coagulation (Safety) 
Table 14.3.4.2.1 
Listing of Clinical Laboratory Abnormalities: Hematology (Safety) 


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Table 14.3.4.2.2 
Listing of Clinical Laboratory Abnormalities: Chemistry (Safety) 
Table 14.3.4.2.3 
Listing of Clinical Laboratory Abnormalities: Urinalysis (Safety) 
Table 14.3.4.2.4 
Listing of Clinical Laboratory Abnormalities: Coagulation (Safety) 
Other Safety Information (CSR Section 14.4) 
Table 14.4.1.1 
Clinical Laboratories: Hematology Actual Values and Changes Over 
Time on Study (Safety Population) 
Table 14.4.1.2 
Clinical Laboratories: Chemistry Actual Values and Changes Over 
Time on Study (Safety Population) 
Table 14.4.1.3 
Clinical Laboratories: Urinalysis Actual Values and Changes Over Time 
on Study (Safety Population) 
Table 14.4.1.4 
Clinical Laboratories: Coagulation Actual Values and Changes Over 
Time on Study (Safety Population) 
Table 14.4.2.1 
Clinical Laboratories: Shifts from Baseline Over Time on Study for 
Hematology (Safety Population) 
Table 14.4.2.2 
Clinical Laboratories: Shifts from Baseline Over Time on Study for 
Clinical Chemistry (Safety Population) 
Table 14.4.2.1 
Clinical Laboratories: Shifts from Baseline Over Time on Study for 
Urinalysis (Safety Population) 
Table 14.4.2.2 
Clinical Laboratories: Shifts from Baseline Over Time on Study for 
Coagulation (Safety Population) 
Table 14.4.3 
Vital Signs: Actual Values and Changes Over Time on Study (Safety 
Population) 
Table 14.4.4 
Shifts from Baseline Over Time on Study for Physical Examination 
Findings (Safety Population) 
Table 14.4.5 
Electrocardiogram Results: Actual Values and Changes Over Time on 
Study (Safety Population) 
Table 14.4.6 
Concomitant Medications (Safety Population) 
Table 14.4.7 
Summary of Physical Examinations 


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7.2. 
Data Listings to be Generated 
 
Discontinued Subjects (CSR Appendix 16.2.1) 
Listing 16.2.1 
Subject Disposition and Study Termination Information 
Protocol Deviations (CSR Appendix 16.2.2) 
Listing 16.2.2.1 
Inclusion Criteria 
Listing 16.2.2.2 
Exclusion Criteria 
Listing 16.2.2.3 
Admission and Discharge Dates 
Listing 16.2.2.4 
Protocol Deviations 
Subjects Excluded from Efficacy Analysis (CSR Appendix 16.2.3) 
Listing 16.2.3.1 
Subjects Excluded from Efficacy Analyses 
Demographics and Baseline Data (CSR Appendix 16.2.4) 
Listing 16.2.4.1 
Demographic and Baseline Information 
Listing 16.2.4.2 
Baseline Disease Data 
Listing 16.2.4.3 
Medical History 
Listing 16.2.4.4 
Hepatitis and TB Testing 
Compliance and/or Drug Concentration Data (CSR Appendix 16.2.5) 
Listing 16.2.5.1 
Dosing Information 
Listing 16.2.5.2 
Pharmacokinetic and Pharmacodynamic Assay Samples  
Listing 16.2.5.3 
Pharmacokinetic Data 
Individual Efficacy Response Data (CSR Appendix 16.2.6) 
Listing 16.2.6.1 
Efficacy Results: Complete Remission, Endoscopic Response and 
Remission, and Clinical Response  


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Listing 16.2.6.2 
Efficacy Results: Complete and Partial Mayo Scores (Including 
Subscores) Over Time 
Listing 16.2.6.3 
Efficacy Results: Fecal Calprotectin Levels Over Time 
Listing 16.2.6.4 
Efficacy Results: IBDQ Scores Over Time 
Listing 16.2.6.5 
Efficacy Results: Histological Scores Over Time 
Adverse Event Listings (each subject) (CSR Appendix 16.2.7) 
Listing 16.2.7.1 
Adverse Events by MedDRA SOC, Verbatim Term, Preferred Term 
and Subject 
Listing of Individual Laboratory Measurements by Subject (CSR Appendix 16.2.8) 
Listing 16.2.8.1 
Laboratory Results: Hematology 
Listing 16.2.8.2 
Laboratory Results: Chemistry 
Listing 16.2.8.3 
Laboratory Results: Urinalysis 
Listing 16.2.8.4 
Laboratory Results: Coagulation 
Other Safety Data (CSR Appendix 16.2.9) 
Listing 16.2.9.1 
Vital Signs 
Listing 16.2.9.2 
Physical Examinations 
Listing 16.2.9.3 
Electrocardiograms 
Listing 16.2.9.4 
Prior and Concomitant Medications 
Listing 16.2.10 
Pharmacodynamic Parameters 
Listing 16.2.11 
Immunogenicity (ADA Status) 
Listing 16.2.12 
Serum Pregnancy Testing 
Listing 16.2.13 
Sigmoidoscopy and Colonic Biopsy