Conditions: Colitis, Ulcerative
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 51
Healthy volunteers: no

Brief summary:
IBD98-M-2002 is a phase 2a , Randomized, Double blind, Placebo-controlled of IBD98-M Delayed Release capsules in subjects with Mild to Moderately Ulcerative Colitis to investigate the clinical efficacy of IBD98-M delayed release capsules (in a fixed combination) over a 6-week treatment period and 2 weeks follow up.

Detailed description:
Study IBD98-M-2002 is a Phase 2a, multicenter, randomized, double-blind, parallel-group, placebo-controlled study in patients with active, mild to moderate UC. It is being conducted as an exploratory proof of concept study to investigate the clinical efficacy of IBD98-M delayed-release capsules (in a fixed combination) over a 6-week treatment period and a 2-week follow-up period.

Patients will be screened for study enrollment up to 4 weeks prior to randomization (Visit 3). During the screening period, patients will be evaluated by conducting laboratory tests, physical examination, and sigmoidoscopy. To be eligible, patients are to have a score of ≥4 and ≤10 on the UCDAI, and a score of ≥1 on the UCDAI endoscopy subscore. In addition, the diagnosis of UC must be confirmed by endoscopic and histologic evidence in the past; if prior confirmation is not available, this must be done at the time of screening endoscopy. After the screening visits, eligible patients will be randomized to 1 of 3 study groups: (1) IBD98 M 0.8 g/day (mesalamine 0.8 g with sodium hyaluronate 92 mg), (2) IBD98 M 1.2 g/day (mesalamine 1.2 g with sodium hyaluronate 138 mg), or (3) placebo. Up to 51 patients will be enrolled in this study (including drop-out patients), with 17 patients randomized to each treatment group. Patients will be encouraged to take their medication at the same time every day.

During the study, patients will visit the clinic on 7 occasions: 2 visits during the screening period (the second screening visit is the baseline visit); 4 visits during the treatment period, Visits 3, 4, 5, and 6/early termination at Weeks 0, 2, 4, and 6; and 1 visit at the end of the follow-up period, Visit 7 at Week 8. Patients will record the dates/times of dosing (after randomization), concomitant medication, and symptoms and adverse events (AEs) in a daily diary starting at Visit 1 and continuing until the end of treatment (Visit 6/early termination). Rescue medication will not be permitted during the 6 weeks of the treatment period, and patients who are considered to not be benefiting from the therapy can be withdrawn and assigned an appropriate alternative UC treatment by the Investigator. Compliance will be assessed throughout the study by determining the amount of unused medication. Records will be kept of all medication dispensed, used, and returned by each patient. At the end of the study, all unused trial medication and used packaging will be returned to the Sponsor. All study medication will be accounted for and any discrepancies documented.

Arms:
arm 1: High dose, twice a day for 6 weeks. arm 2: Placebo, twice a day arm 3: Low dose, twice a day for 6 weeks

Interventions: intervention 1: High dose intervention 2: Low dose intervention 3: Placebo
Intervention descriptions: intervention 1: 6 capsules of IBD98-M, twice a day intervention 2: 4 capsules of IBD98-M intervention 3: Placebo

Protocol document:
Prot_000.pdf: 
Holy Stone Healthcare Co., Ltd. 
 
 
 
 
Protocol IBD98-M-2002 
IBD98-M Delayed-release Capsules 
Final Protocol 
  
 
 
  
24 March 2015 
 
Page 1 of 85 
 
 
CLINICAL STUDY PROTOCOL 
Protocol Number:  IBD98-M-2002 
Protocol Title:  A Phase 2a, Multicenter, Randomized, Double-blind, 
Parallel-group, Placebo-controlled Trial of IBD98-M Delayed-release Capsules 
to Induce Remission in Patients with Active, Mild to Moderate Ulcerative Colitis 
 
 
EudraCT Number: 
2015-001022-42 
Name of Product: 
IBD98-M Delayed-release Capsules 
(Mesalamine and Sodium Hyaluronate) 
Phase of Development: 
Phase 2a 
Indication: 
Mild to Moderate Ulcerative Colitis 
Sponsor: 
Albert Wu, Chief Executive Officer 
Holy Stone Healthcare Co., Ltd. 
4F, No. 88, Sec. 1, NeiHu Road 
Nei Hu District 
Taipei City, 11493 
Taiwan 
Republic of China 
Tel:  +886 2 8797 5966 
Fax: +886 2 2627 9729 
Protocol Version: 
Final 
Protocol Final Draft Date: 
24 March 2015 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Holy 
Stone Healthcare Co., Ltd.  Any unauthorized copying or use of this document 
is prohibited. 


Holy Stone Healthcare Co., Ltd. 
 
 
 
 
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Final Protocol 
  
 
 
  
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Page 2 of 85 
 
HOLY STONE HEALTHCARE CO., LTD., APPROVAL PAGE 
 
 
 
Date: 
 
Ivy Chen, MSc 
Deputy Director, Clinical Development and 
Regulatory Affairs 
 
 
 
 
 
 
 
 
Date: 
 
Albert Wu, MBA 
Chief Executive Officer 
 
 
 


Holy Stone Healthcare Co., Ltd. 
 
 
 
 
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Final Protocol 
  
 
 
  
24 March 2015 
 
Page 3 of 85 
 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree: 
 
To assume responsibility for the proper conduct of the study at this site. 
 
To conduct the study in compliance with this protocol, any future amendments, and 
with any other study conduct procedures provided by Holy Stone Healthcare Co., Ltd. 
 
Not to implement any changes to the protocol without written agreement from Holy 
Stone Healthcare Co., Ltd., and prior review and written approval from the 
Independent Ethics Committee except where necessary to eliminate an immediate 
hazard to patients. 
 
That I am thoroughly familiar with the appropriate use of the study drug, as described 
in this protocol and any other information provided by Holy Stone Healthcare Co., 
Ltd., including, but not limited to, the current Investigator’s Brochure.   
 
That I am aware of, and will comply with, good clinical practices and all applicable 
regulatory requirements. 
 
To ensure that all persons assisting me with the study are adequately informed about 
the Holy Stone Healthcare Co., Ltd., study drug and of their study-related duties and 
functions as described in the protocol. 
 
 
 
Signature: 
 
 
Date:
 
 
Name 
(print): 
 
 
 
Site 
Number: 
Investigator 
 
___________ 
 
 


Holy Stone Healthcare Co., Ltd. 
 
 
 
 
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Final Protocol 
  
 
 
  
24 March 2015 
 
Page 4 of 85 
 
CONTACT LIST 
Sponsor: 
Holy Stone Healthcare Co., Ltd. 
4F, No. 88, Sec. 1, NeiHu Rd., 
Nei Hu District 
Taipei City, 11493 
Taiwan 
Republic of China 
Sponsor’s Responsible Medical 
Director: 
 
Ivy Chen, MSc 
4F, No. 88, Sec. 1, NeiHu Rd., 
Nei Hu District 
Taipei City, 11493 
Taiwan 
Republic of China 
Telephone: +886287975966 
Sponsor’s Responsible Study Manager: 
Ivy Chen; MSc 
4F, No. 88, Sec. 1, NeiHu Rd., 
Nei Hu District 
Taipei City, 11493 
Taiwan 
Republic of China 
Telephone: +886287975966 
Contract Research Organization (CRO) 
Study Manager: 
 
Irina Medvedeva  
inVentiv Health Clinical  
2B Alexander Nevsky square,  
MOSKVA Business Center, 
Saint-Petersburg, 191317 
Russia  
Telephone: +7-812-676-7240 
CRO Medical Monitor: 
Maria Marta Harrington, MD 
inVentiv Health Clinical Spain SL 
Plaza de la Independencia 2, 1st floor 
Madrid 28001, Spain 
Telephone: +34915489840 
CRO Safety (Pharmacovigilance) 
Reporting: 
inVentiv Health Clinical 
Global Safety and Pharmacovigilance 
17-19 Marlow Road 
Maidenhead 
Berkshire 
SL6 7AA, UK  
Telephone: +441628408408 
Clinical Laboratory: 
 
Local laboratories will be used 
 


Holy Stone Healthcare Co., Ltd. 
 
 
 
 
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1 
SYNOPSIS 
Title of Study: 
A Phase 2a, Multicenter, Randomized, Double-blind, 
Parallel-group, Placebo-controlled Trial of IBD98-M Delayed-
release Capsules to Induce Remission in Patients with Active, 
Mild to Moderate Ulcerative Colitis 
Protocol Number: 
IBD98-M-2002 
Investigators/Study 
Sites: 
This study is to be conducted at 16 sites in Italy 
Phase of Development: 
2a 
Objectives: 
Primary Objective 
 
To compare the percentage of patients in ulcerative colitis 
(UC) remission at Week 6 for each of the 2 IBD98-M dose 
groups versus placebo (remission defined as the 
Ulcerative Colitis Disease Activity Index [UCDAI] score of 
≤1, with a score of 0 for rectal bleeding and stool 
frequency, no mucosal friability, and ≥1 point reduction 
from baseline in the sigmoidoscopy score) 
Secondary Objectives 
 
To compare clinical improvement rates at Week 6 among 
treatment groups (defined as a ≥3 point reduction from 
baseline in the UCDAI score) 
 
To compare endoscopic improvement at Week 6 among 
treatment groups (defined as a ≥1 point decrease in 
UCDAI mucosal appearance subscore) 
 
To determine the change in symptoms (rectal bleeding and 
stool frequency) from baseline to each study visit among 
treatment groups 
 
To evaluate the safety and tolerability profile of IBD98-M 
Exploratory Objectives 
 
To examine the effect of IBD98-M treatment on fecal 
calprotectin 
 
To examine any correlation between therapeutic response 
to IBD98-M and baseline characteristics 
Study Design and 
Methods: 
Study IBD98-M-2002 is a Phase 2a, multicenter, randomized, 
double-blind, parallel-group, placebo-controlled study in 
patients with active, mild to moderately active UC. It is being 
conducted as an exploratory proof of concept study to 
investigate the clinical efficacy of IBD98-M delayed-release 
capsules (in a fixed combination) over a 6-week treatment 
period and a 2-week follow-up period.   
Patients will be screened for study enrollment up to 4 weeks 
prior to baseline.  During the screening period, patients will be 
evaluated with laboratory tests, physical examination, and 
sigmoidoscopy.  To be eligible, patients are to have a score of 
≥4 and ≤10 on the UCDAI, and a score of ≥2 on the UCDAI 


Holy Stone Healthcare Co., Ltd. 
 
 
 
 
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Final Protocol 
  
 
 
  
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Page 6 of 85 
 
endoscopy subscore.  In addition, the diagnosis of UC must 
be confirmed by endoscopic and histologic evidence in the 
past; if prior confirmation is not available, this must be done at 
the time of screening endoscopy.  After the screening visits, 
eligible patients will be randomized to 1 of 3 study groups:  
(1) IBD98-M 0.8 g/day (mesalamine 0.8 g with sodium 
hyaluronate 92 mg), (2) IBD98-M 1.2 g/day (mesalamine 1.2 g 
with sodium hyaluronate 138 mg), or (3) placebo.  Up to 
51 patients will be enrolled in this study (including drop-out 
patients), with 17 patients randomized to each treatment 
group.  Patients will be encouraged to take their medication at 
the same time every day.   
During the study, patients will visit the clinic on 7 occasions:  
2 visits during the screening period (the second screening visit 
is the baseline visit); 4 visits during the treatment period at 
Weeks 0, 2, 4, and 6; and 1 visit at the end of the follow-up 
period at Week 8 (end of study/withdrawal visit).  Patients will 
record the dates/times of dosing (after randomization), 
concomitant medication, and AEs in a daily diary starting 
7 days before treatment and continuing until the end of 
study/withdrawal visit. 
Rescue medication will not be permitted during the 6 weeks of 
the treatment period, and patients who are considered to not 
be benefiting from the therapy can be withdrawn and assigned 
an appropriate alternative UC treatment by the Investigator.  
Compliance will be assessed throughout the study by 
determining the amount of unused medication.  Records will 
be kept of all medication dispensed, used, and returned by 
each patient.  At the end of the study, all unused trial 
medication and used packaging will be returned to the 
Sponsor.  All study medication will be accounted for and any 
discrepancies documented. 
Selection of Patients: 
Inclusion Criteria 
A patient must meet all of the following criteria to be eligible for 
this study.   
1. Male or female, age ≥18 and <75 years, suffering from 
UC for at least 6 months prior to Screening 
2. Female patients must be postmenopausal, sterile, or 
have a negative urine pregnancy test prior to entering 
the study and use adequate contraception during the 
study if of childbearing potential. 
3. Diagnosis of active UC with UCDAI ≥4 and ≤10, with 
endoscopy score of ≥2 in the UCDAI mucosal 
appearance subscore 
4. Patients with either newly diagnosed or relapsed UC 


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(onset of current episode of relapse must be within 6 
weeks of screening).  Diagnosis of UC must be 
confirmed by endoscopic and histologic evidence in the 
past; if prior confirmation is not available, this must be 
done at the time of screening endoscopy. 
5. Patients must have up-to-date surveillance 
colonoscopy for malignancy, per treatment guideline. 
6. Willing and able to provide signed informed consent 
Exclusion Criteria  
A patient who meets any of the following criteria is ineligible to 
participate in this study. 
1. Patients diagnosed with Crohn’s disease,  
indeterminate colitis, or ischemic colitis  
2. Female patients who are pregnant or breastfeeding  
3. Ulcerative proctitis with <15 cm of disease 
4. Patients with infectious colitis as determined by 
assessment for Clostridium difficile (C. difficile) and 
fecal pathogens at screening or treatment for C.  
difficile within 30 days prior to screening 
5. History of or current evidence of toxic megacolon, 
fulminant colitis (eg, Lichtiger score of ≥10), colonic 
perforation 
6. Any previous colonic surgery (except appendectomy) 
or short bowel syndrome 
7. Patients who required doses of mesalamine higher 
than 2.4 g/day for previous flares 
8. Hypersensitivity to salicylates/aspirin 
9. Use of the following medications:  
a) Use of oral or rectal 5-aminosalicylic (5-ASA) 4 
weeks prior to randomization 
b) Use of systemic or rectal corticosteroid 4 weeks 
prior to or during screening 
c) Use of anti-tumor necrosis factor-alpha 
(anti-TNF-α) agents or other biologics such as 
vedolizumab within 90 days prior to or during 
screening  
d) Use of immunosuppressants (eg, azathioprine, 
mercaptopurine) within 6 weeks prior to or 
during screening  
e) Use of antibiotics for UC within the 7 days prior 


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to or during screening
10. Clinically significantly abnormal electrocardiogram 
(ECG) at screening   
11. Liver cirrhosis or alanine aminotransferase (ALT) 
and/or aspartate aminotransferase (AST) levels >2 
times the upper limit of normal (ULN)   
12. Serum creatinine >2X ULN 
13. Positive pre-study drug/alcohol screen 
14. Participation in another clinical study involving an 
investigational agent within the 3 months prior to 
screening (Visit 1).  Patients cannot participate in any 
other investigational medication or medical device 
study (participation in a registry or observational study 
without an additional therapeutic intervention is 
allowed). 
15. Any unstable or uncontrolled cardiovascular, 
pulmonary, hepatic, renal, gastrointestinal, 
genitourinary, hematological, coagulation, 
immunological, endocrine/metabolic, or other medical 
disorder that, in the opinion of the investigator, would 
confound the study results or compromise patient 
safety 
16. Had any surgical procedure requiring general 
anesthesia within 30 days prior to screening or is 
planning to undergo major surgery during the study 
period  
17. Any active malignancy within the last 5 years, except 
for basal cell carcinoma of the skin, or if female, in situ 
cervical carcinoma that has been surgically excised 
18. Patient has a history of hepatitis (B or C) or human 
immunodeficiency virus (HIV). 
19. In the opinion of the Investigator, the patient is unable 
to adhere to the requirements of the study. 
 
Planned Sample Size: 
Approximately 51 patients are to be enrolled, with 17 patients 
randomized to each group. 
Sample size justification 
Simon’s randomized Phase 2 design was used.  The average 
remission rate of placebo is approximately 0.2.  With a Type I 
error of 0.05, power of 0.8, and the difference in remission 
rates between the best treatment and the other treatments 
≥0.18, each arm requires 17 patients, giving the total number 
of patients to be enrolled as 51. 
Investigational Therapy: 
IBD98-M (mesalamine and sodium hyaluronate) delayed-
release capsules, administered orally twice a day (BID). 
Reference Therapy: 
Placebo capsule, administered orally BID. 
Treatment Duration: 
For each patient, up to 4 weeks of screening, 6 weeks of 


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treatment and 2 weeks of follow-up 
Criteria for Evaluation: 
Efficacy:  Efficacy is evaluated by assessing clinical and 
endoscopic changes over time.  Patient-reported symptoms 
include stool frequency and rectal bleeding, and Investigator 
assessments include mucosal appearance (from 
sigmoidoscopy) and ratings of disease activity.  The UCDAI 
combines these patient-reported and Investigator-reported 
scores. 
Remission as defined by UCDAI score of ≤1, with a score of 0 
for rectal bleeding and stool frequency, no mucosal friability, 
and ≥1-point reduction from baseline in the sigmoidoscopy 
score.   
Clinical improvement is defined as a ≥3-point reduction from 
baseline in the UCDAI score.  Endoscopic improvement was 
defined as a ≥1-point reduction from baseline in the UCDAI 
mucosal appearance subscore. 
 
Safety: Safety will be evaluated in terms of treatment-
emergent adverse events (TEAEs), serious adverse events 
(SAEs), physical examination findings, vital signs, clinical 
laboratory parameters (including chemistry, hematology, 
coagulation, and urinalysis), and periodic ECGs. 
Study Endpoints: 
Primary Endpoint 
 
Percentage of subjects in remission at Week 6.   
Remission is defined as a UCDAI score of ≤1, with a score 
of 0 for rectal bleeding and stool frequency, no mucosal 
friability, and ≥1 point reduction from baseline in the 
sigmoidoscopy score).   
Secondary Endpoints 
The secondary efficacy endpoints are as follows: 
 
Proportion of subjects with clinical improvement at Week 6 
(defined as a ≥3 point reduction from baseline in the 
UCDAI score) 
 
Proportion of subjects with endoscopic improvement at 
Week 6 (defined as a ≥1 point decrease in UCDAI 
mucosal appearance subscore) 
 
Change in symptoms (rectal bleeding and stool frequency) 
from baseline to each study visit  
The safety endpoints of this study are as follows:  
 
Incidence and severity of all TEAEs 
 
Incidence and severity of SAEs  
 
Systemic tolerance (physical examination, vital signs, 
ECGs, and laboratory assessments of safety parameters)  
Exploratory endpoints 


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 
Reduction in fecal calprotectin 
Statistical Methods and 
Planned Analyses: 
Analyses will be done on the intent-to-treat (ITT) population 
and the per-protocol population.  The primary outcome, the 
percentage of patients in remission at Week 6, will be 
calculated for each treatment group.  An analysis of variance 
(ANOVA) approach will be used. 
 


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2 
TABLE OF CONTENTS 
1 
SYNOPSIS ............................................................................................................ 5 
2 
TABLE OF CONTENTS ................................................................................... 11 
IN-TEXT TABLES .............................................................................................. 14 
3 
LIST OF ABBREVIATIONS ............................................................................ 15 
4 
INTRODUCTION ............................................................................................... 18 
4.1 
Background on Ulcerative Colitis .....................................................................18 
4.2 
Background on Investigational Products .........................................................19 
4.3 
Nonclinical Studies .............................................................................................20 
4.4 
Clinical Studies ....................................................................................................24 
4.5 
Rationale for Conducting the Study .................................................................26 
5 
STUDY OBJECTIVES AND ENDPOINTS .................................................... 30 
5.1 
Study Objectives .................................................................................................30 
5.2 
Study Endpoints ..................................................................................................31 
5.2.1 
Primary Endpoint .............................................................................31 
5.2.2 
Secondary Endpoints ......................................................................31 
5.2.3 
Exploratory Endpoints ....................................................................31 
6 
INVESTIGATIONAL PLAN .............................................................................. 31 
6.1 
Description of Overall Study Design and Plan ...............................................31 
6.2 
Discussion of Study Design ..............................................................................33 
7 
SELECTION AND WITHDRAWAL OF PATIENTS ..................................... 33 
7.1 
Inclusion Criteria .................................................................................................33 
7.2 
Exclusion Criteria ................................................................................................34 
7.3 
Withdrawal, Removal, and Replacement of Patients ....................................36 
8 
TREATMENTS ................................................................................................... 37 
8.1 
Details of Study Treatments ..............................................................................37 
8.2 
Dosage Schedule ...............................................................................................38 
8.3 
Study Treatment Assignment ...........................................................................38 
8.4 
Blinding .................................................................................................................39 
8.5 
Treatment Accountability and Compliance .....................................................39 
8.6 
Prior and Concomitant Illnesses, Procedures, and Medications .................40 
8.6.1 
Prior and Concomitant Illnesses ...................................................40 


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8.6.2 
Concomitant Procedures ................................................................40 
8.6.3 
Prior and Concomitant Medications .............................................40 
9 
STUDY PROCEDURES ................................................................................... 41 
9.1 
Patient Informed Consent ..................................................................................44 
9.2 
Procedures by Study Visit .................................................................................44 
9.2.1 
Screening Period:  Visit 1 (Days -28 to -7) and Visit 2 (Days -14 
to -1, Baseline) .................................................................................44 
The second screening (baseline) visit will occur within -14 to -1 days 
prior to Day 0.  The following procedures will be performed: ...44 
9.2.2 
Treatment Period:  Visit 3 (Day 0 [± 1 day]; Randomization) ...45 
9.2.3 
Treatment Period:  Visits 4, 5, and 6 or End-of-Study Visit, or 
Early Termination Visit (Days 14, 28, and 42) (± 3 days) .........45 
9.2.4 
Follow-up Period:  Visit 7 (Day 56 [± 3 days]) ............................46 
10 
EFFICACY ASSESSMENTS ........................................................................... 47 
10.1  Ulcerative Colitis Disease Activity Index (UCDAI) Score ........................47 
10.2  Inflammatory Bowel Disease Questionnaire (IBDQ) ................................48 
10.3  Short Form-36 ....................................................................................................48 
11 
SAFETY ASSESSMENTS ............................................................................... 49 
11.1  Vital Signs ............................................................................................................49 
11.2  Physical Examination .........................................................................................49 
11.3  Electrocardiogram ...............................................................................................50 
11.4  Laboratory Assessments ...................................................................................50 
11.5  Stool Sample for Cultures .................................................................................52 
11.6  Fecal Calprotectin Sample Collection .............................................................52 
11.7  Diary Completion and Review ..........................................................................52 
11.8  Adverse Events ...................................................................................................53 
11.8.1  Adverse Events ................................................................................53 
11.8.2  Serious Adverse Events .................................................................55 
11.8.3  Pregnancy ........................................................................................56 
11.8.4  Overdose ..........................................................................................57 
12 
STATISTICAL ANALYSIS ............................................................................... 57 
12.1  Determination of Sample size ...........................................................................58 
12.2  Analysis Populations ..........................................................................................58 
12.3  Demographic and Baseline Characteristics ...................................................59 


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12.4  Efficacy Analysis .................................................................................................59 
12.4.1  Analysis of Efficacy Endpoints ......................................................59 
12.5  Safety Analysis ....................................................................................................60 
12.6  Interim Analysis ...................................................................................................60 
13 
STUDY MANAGEMENT .................................................................................. 61 
13.1  Approval and Consent .......................................................................................61 
13.1.1  Regulatory Guidelines ....................................................................61 
13.1.2  Independent Ethics Committee .....................................................61 
13.1.3  Informed Consent ............................................................................61 
13.2  Data Handling ......................................................................................................62 
13.3  Source Documents .............................................................................................63 
13.4  Record Retention ................................................................................................63 
13.5  Monitoring ............................................................................................................63 
13.6  Quality Control and Quality Assurance ...........................................................64 
13.7  Protocol Amendment and Protocol Deviation ................................................64 
13.7.1  Protocol Amendment ......................................................................64 
13.7.2  Protocol Deviations .........................................................................64 
13.8  Ethical Considerations .......................................................................................65 
13.9  Financing and Insurance ...................................................................................65 
13.10 Publication Policy / Disclosure of Data ............................................................65 
14 
REFERENCES ................................................................................................... 67 
15 
APPENDICES .................................................................................................... 69 


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IN-TEXT TABLES 
Table 1:  Details of Study Treatments ...................................................................... 38 
Table 2:  Schedule of Events ................................................................................... 42 
Table 3:  Laboratory Assessments .......................................................................... 51 
Table 4:  Classification of Adverse Events by Intensity ............................................ 54 
Table 5:  Classification of Adverse Events by Relationship to Study Drug .............. 54 


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3 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
5-ASA 
5-aminosalicylic agent 
6-MP 
6 mercaptopurine 
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic 
transaminase) 
ANOVA 
Analysis of variance 
Anti-TNF-α 
Anti- tumour necrosis factor alpha 
aPTT 
Activated partial thromboplastin time 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase) 
AZA 
Azathioprine 
BID 
Twice daily 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
C.  difficile 
Clostridium Difficile 
CPK 
Creatine phosphokinase 
CRP 
C-reactive protein 
CFR 
Code of Federal Regulations 
DCF 
Data clarification form 
DNBS 
Dinitrobenzene sulfonic acid 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
GAG 
Glycosaminoglycan 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
HA 
Hyaluronic acid 
Hb 
Hemoglobin 


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HCG 
Human chorionic gonadotropin 
Hct 
Hematocrit 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HHA 
High molecular weight hyaluronic acid 
HRQoL 
Health-related quality of life 
IB 
Investigator’s Brochure 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
IBS 
Irritable bowel syndrome 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IND 
Investigational New Drug  
INR 
International normalized ratio 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IV 
Intravenous 
IVRS 
Interactive voice response system 
LDH 
Lactate dehydrogenase 
LHA 
Low molecular weight HA 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCS 
Mental component summary 
MCV 
Mean corpuscular volume 
MPO 
Myeloperoxidase 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NOAEL 
No-observed-adverse-effect-level 
PCS 
Physical component summary 
PT 
Prothrombin time 
 
 
QoL 
Quality of life 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SF-12 
12 item Short-form questionnaire 


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SAP 
Statistical analysis plan 
TEAE 
Treatment emergent adverse events 
Tlag 
Time from administration to first quantifiable concentration
Tmax 
Time of Maximum Drug Concentration 
TNBS 
2,4,6-trinitrobenzenesulonic acid 
UC 
Ulcerative colitis 
UCDAI 
Ulcerative Colitis Disease Activity Index 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
WBC 
White blood cell 
 


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4 
INTRODUCTION 
4.1 Background on Ulcerative Colitis 
Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease affecting 
the colon.  The prevalence is estimated as 70 to 150 cases per 100,000 with peak 
age of onset between 15 and 25 years.  Ulcerative colitis affects 15% of children, 
and may present before school-age.  The disease usually involves the rectum but 
may extend proximally to involve a portion of or the entire colon.  About 40% to 50% 
of patients have disease that is limited to the rectum and the rectosigmoid colon, 
30% to 40% have disease extending beyond the sigmoid flexure but not involving 
the whole colon, and 20% have pancolitis.1 
The mainstay of therapy for mild to moderate UC is sulfasalazine and 
5-aminosalicylic (5-ASA) agents.  These agents are effective at inducing remission 
in UC and in maintaining remission in UC.  The majority of patients with moderate to 
severe active UC benefit from topical, oral, or parenteral glucocorticosteroids.  
Remission, however, cannot be maintained with steroids.  Azathioprine (AZA) or 
6-mercaptopurine (6-MP) have been employed as glucocorticoid-sparing agents in 
patients unable to be weaned from glucocorticoids.  In early 2006, the first anti-tumor 
necrosis factor-alpha (anti-TNF-α) agent was approved for the treatment of UC 
refractory to both corticosteroids and AZA/6-MP.  Surgery with colectomy is curative 
but can be associated with significant morbidity and is thus reserved for acute 
severe (fulminant) colitis or resistant cases, and in some cases, as cancer 
prevention.  Intestinal continuity can be restored by construction of an ileal pouch-
anal pouch anastomosis.  Pouchitis is an inflammation of the ileal pouch, occurring 
in up to 20% to 30% of patients with an ileal pouch-anal anastomosis.  The risk of 
colorectal cancer is increased in patients with extensive disease, and surveillance is 
usually introduced after 8-10 years of disease duration with regular colonoscopies.  
Mortality is not increased in UC patients in general, but the disease may present as 
life-threatening acute severe colitis.  Extra-intestinal manifestations of UC include 
primary sclerosing cholangitis, as well as eye, joint, and skin manifestations.1 


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4.2 Background on Investigational Products 
Holy Stone Healthcare Co., Ltd., (Holy Stone Healthcare) has developed a new 
combination therapy IBD98-M, containing mesalamine and sodium hyaluronate, for 
the treatment of mild to moderate UC.   
Mesalamine is an amino-salicylate non-steroidal anti-inflammatory drug.  Although 
its mechanism of action is not fully understood, mesalamine appears to act topically 
rather than systemically.  Mucosal production of arachidonic acid metabolites, 
through the cyclooxygenase and lipoxygenase pathways, is increased in patients 
with chronic UC, and it is possible that mesalamine diminishes inflammation by 
blocking cyclooxygenase and inhibiting prostaglandin production in the colon.2  
Mesalamine has been approved in the US under different brand names.  Currently, 
oral, modified-release mesalamine formulations approved for marketing in the US 
market include Apriso®, Asacol®, Lialda®, Pentasa®, and Delzicol®.  The different 
formulations of mesalamine available on the market differ mainly in the location 
where the drug is released in the gastrointestinal tract to accomplish its therapeutic 
effect; thus, the indications of each product are directly related to the site of drug 
release.3  
Sodium hyaluronate, the sodium salt of hyaluronic acid (HA), is a natural 
polysaccharide found in high concentrations in several soft connective tissues, 
including skin, umbilical cord, synovial fluid, and vitreous humor.  Significant 
amounts of sodium hyaluronate are also found in lung, kidney, brain, and muscle 
tissues.  Solutions of sodium hyaluronate manifest very unusual rheological 
properties and are exceedingly lubricious and very hydrophilic.  Sodium hyaluronate 
may enhance the mucosal repair and restoration of the mucosal protective layer.  
Based on these properties, it is expected that supplementation of sodium 
hyaluronate may provide a protective barrier to the lining of the colon affected by UC. 
IBD98-M is a delayed-release formulation, in the form of a capsule filled with enteric-
coated pellets designed to allow the release of both mesalamine and sodium 
hyaluronate at pH 6.8 or above at the terminal ileum (ascending colon).  It is 


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intended to be used for the treatment of mild to moderate UC.  Each capsule is filled 
with multiple-layer pellets containing 200 mg of mesalamine and 23 mg of sodium 
hyaluronate.  Each pellet consists of a microcrystalline cellulose inner core, which is 
coated first with mesalamine, then with sodium hyaluronate, and finished with an 
enteric coating film.  The combination of mesalamine with sodium hyaluronate may 
allow a reduction in dose of mesalamine, to minimize side effects and enhance 
therapeutic efficacy. 
4.3 Nonclinical Studies 
IBD98E (Sodium Hyaluronate) Studies 
As part of the development program for IBD98-M, nonclinical efficacy studies were 
performed in rat models.  The concentration of HA for efficacy of 0.5% HA solution 
was evaluated on 2,4,6-trinitrobenzenesulonic acid (TNBS)-induced UC rat model.  
Thirty-six Sprague Dawley rats were divided into 2 groups (treatment group and 
control group, n=18 for each group).  All rats were fasting at least 24 hours, then 
treated with 1 mL TNBS (50 mg/mL) and observed for 3 consecutive days for stool 
consistency.  During the observation period (Day 1 to Day 3), 2 rats died.  In order to 
confirm the colonic lesion after TNBS treatment, 5 rats with soft stools were 
sacrificed on Day 4.  Results showed that the 2 dead rats and the 5 rats with soft 
stool had suffered obvious colonic injury with TNBS treatment.  The remainder of the 
rats with soft/watery stools were treated with 0.5% HA solution (treatment group, 
10 rats) or phosphate-buffered solution (control group, 7 rats) via anus for 
7 consecutive days (Day 4 to Day 10).  Rats with normal stool were excluded from 
the study on Day 4.  Rats that died during the experimental period (Day 4 to Day 10) 
were excluded from further analyses.  On Day 11, all remaining rats (treatment 
group, 9 rats; control group, 4 rats) were sacrificed and processed for colitis 
examination.  The mean lengths of colitis wound in control and treatment groups 
were 1.875 cm and 1.25 cm, respectively.  The overall results showed that the mean 
recovery rate of the treatment group compared to the control group was 33% (See 
Investigator’s Brochure)4.   


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Treatment with 0.5% HA and 0.25% HA solutions in the TNBS-induced UC rat model 
was further investigated in 60 rats.  Before testing, the TNF-α concentration in each 
rat was evaluated.  Rats with TNF-α concentrations higher than the predetermined 
criterion of exclusion (130 pg/mL) were excluded.  The remaining rats were given 
TNBS to induce inflammatory bowel disease (IBD) and then divided into 4 groups of 
6 rats.  Each group was given different test samples:  (A) 0.25% HA plus 0.42% 
Carbomer 971, (B) 0.5% HA plus 0.08% Carbomer 971, (C) 0.25% HA, and (D) 
0.5% HA.  The rats were fasted for more than 24 hours before administering 1 mL of 
glycerol to clean out intestinal feces.  The rats were then given 1 mL of TNBS via a 
catheter to induce IBD and observed for 4 days.  On Day 1, after induction, rats were 
allowed normal consumption of food; feces of all rats were normal.  However on 
Day 1, 8 rats had normal feces, 20 rats had soft stools, and 14 rats had watery 
stools.  On Day 4, only 5 rats had watery stools continuously, 14 rats had normal 
stools, and 22 rats continued to have soft stools.  On Day 4, rats with normal stools 
were excluded, and the remaining rats were divided into 4 groups and continuously 
given one of A, B, C, or D test samples for a period of 14 days (Day 4 to Day 17).  
On both Day 11 and Day 18, half of the remaining rats were sacrificed to determine 
the degree of lesions.  The average length of colon with of inflammation colitis for 
Groups A and B had a range of 0-1.5 cm; Group C showed no lesions on the colon; 
and Group D had an average colitis length of 0-0.5 cm.  On Day 4, serum TNF-α 
concentration was significantly higher than that on Day 0.  The concentration level of 
TNF-α then gradually decreased, reaching its lowest point on Day 18.  However, on 
the same day, the serum concentrations of TNF-α were not significantly different 
between groups.  In terms of the distribution of lesion size from Day 11 to Day 18, 
rats in Group C had recovered, Group D showed a gradual recovery trend, but rats 
in Groups A and B were not significantly different.  From a clinical perspective, the 
Group C treatment (0.25% HA) provided the greatest effect, followed by the Group D 
treatment (0.5% HA).  However, the TNF-α concentration level of each group 
showed no significant difference; therefore, TNF-α could not be an evaluation 
indicator. 


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In a third efficacy study, 32 TNBS-induced UC rats were randomized to 4 groups, 
each with 8 rats, and were treated rectally with solutions of different molecular 
weights of HA:  0.25% HA with a ratio of high molecular weight HA (HHA) to low 
molecular weight HA (LHA) of 1:1, 0.25% HA with a ratio of 4:1, 0.125% HA with a 
ratio of 1:1, and 0.0625% HA with a ratio of 1:1.  On Day 11 and Day 18, the rats 
were sacrificed, and tissue was collected for macroscopic observations and scoring.  
The results showed that the recovery rate was over 90% in the treatment groups of 
0.25% HA with a HHA:LHA ratio of 4:1 and 0.0625% HA with a ratio of 1:1.  The 
other groups had recovery rates of 70-80%.  However, there were no statistically 
significant differences in wound healing between groups on Day 11 or Day 18. 
IBD98-M (Mesalamine and Sodium Hyaluronate) Studies 
 
In a nonclinical efficacy study, 2 combinations of mesalamine and HA were 
compared with the marketed product Colasa™ (mesalamine) and a phosphate 
buffer.  Forty TNBS-induced UC rats randomized to 4 groups, each with 10 rats, 
were treated rectally with one of the following solutions:  0.0625% HA (2000 kDa 
HA/1000 kDa HA) plus 25% Colasa (5 mg/mL mesalamine), 0.0625% HA (2000 kDa 
HA/350 kDa HA) plus 25% Colasa (5 mg/mL mesalamine), Colasa (20 mg/mL 
mesalamine), or phosphate buffer.  On Day 9 and Day 14, rats were sacrificed, and 
tissue was collected for macroscopic observations and scoring.  Results showed that 
the recovery rates of rats treated with the solutions of HA plus Colasa (5 mg/mL) and 
Colasa alone(20 mg/mL) were superior to the phosphate buffer solution alone; and 
that there were no differences in recovery rates between the preparations with the 
2 different molecular weights of HA. 
Another efficacy study investigated the adhesion efficacy of HA on ulcer colon tissue 
in rats induced with colitis.  The wound-healing ability of colitis rat models was also 
investigated.  A total of 64 rats with TNBS-induced colitis were randomly divided into 
4 groups to receive daily intracolonic treatment for 4 days with one of the following 
solutions:  phosphate buffer, HA, mesalamine, and a mixture of HA and mesalamine.  
An additional group of 10 rats was a non-induced control group treated with 


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phosphate buffer.  At the end of the treatment period, macroscopic and microscopic 
colonic injuries were scored, and myeloperoxidase (MPO) activity and cytokine gene 
expression were measured in colonic tissues.   
The results showed that treatment of TNBS-induced colitis with HA or HA with 
mesalamine was superior to treatment with phosphate buffer solution and 
mesalamine alone in reducing inflammation and promoting colonic mucosa healing.  
The treatments containing HA exhibited a similar trend of reduction in MPO activity 
and inflammatory cytokine gene expression.  The results in the rat model of 
inflammatory colitis support the hypothesis that HA may play an accelerating role in 
treating inflammatory bowel disease.   
A nonclinical efficacy study evaluating the therapeutic effects and efficacy of 
IBD98-M was also performed in dinitrobenzene sulfonic acid (DNBS) colitis-induced 
pigs.  Four groups, each with 3 pigs, were treated orally with capsules of IBD98-M 
200 mg (2 different formulations) BID, placebo, or Pentasa® 500 mg capsules BID 
for 28 days.  To evaluate the healing effect of test articles, endoscopy and biopsy 
procedures were performed.  An endoscopy examination was performed on Day 0 
(pre-induction) and on Days 7, 14, 35, and 49 after treatment.  A biopsy was 
performed on Day 35 and 49 after treatment.   
The results showed that IBD98-M significantly reduced erythema of the colonic 
epithelium induced by DNBS and enhanced healing substantially.  After 28 
consecutive days of oral administration, more than 80% of the IBD98-M group had 
colitis wound healing, compared with 62% and 50% in the Pentasa® group and 
placebo group, respectively. 
In addition, a 28-day repeated-dose toxicity study (Study PSD14030002) and a 
13-week repeated-dose toxicity study (Study PSA14030025) were conducted to 
evaluate the possible health hazards likely to arise from repeated exposure to the 
test articles mesalamine and sodium hyaluronate formulated as delayed-release 
pellets (same pellets used to fill the capsules in IBD98-M product), given to Sprague 
Dawley rats via oral gavage.  As oral mesalamine formulations have been used as 


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treatment for the induction and maintenance of remission of UC for many years, the 
purpose of this toxicology study was not to define a maximum tolerated dose of 
mesalamine in rats.  Instead, the purpose was to evaluate the safety profile of the 
combination of mesalamine and sodium hyaluronate in rats.  Accordingly, the results 
show that the IBD98-M pellet formulation was well tolerated when administered 
either once daily for 28 days or once daily for 13 weeks at the designated dose 
levels of 30, 120 and 480 mg/kg of mesalamine and 4.31, 17.25,  and 69 mg/kg of 
sodium hyaluronate.  No compound-related deaths, clinical signs, or ocular 
abnormalities were observed.  Administration of IBD98-M pellet formulation for 
4 weeks had no significant effects on body weight, hematology, and clinical 
chemistry or urinalysis parameters.  In the 28-day study, high-dose male rats 
displayed increased food consumption during Week 3, but no significant effects were 
observed at other times or in female rats.  No treatment-related effects on organ 
weights, gross pathology, or histopathology were observed.  Based on these study 
results, the NOAEL (no-observed-adverse-effect-level) was 480 mg/kg/day of 
mesalamine and 69 mg/kg/day* of sodium hyaluronate when given from the test 
article, IBD98-M pellet formulation. 
*The NOAEL of sodium hyaluronate should be 55.2 mg/kg/day.  The decrease of the 
amount of HA was recalculated due to the fact that the loss in the manufacturing 
processes should be excluded.   
4.4 Clinical Studies 
IBD98E (Sodium Hyaluronate) Study 
In a prospective, uncontrolled, open-label 28-day Phase I pilot trial, 21 patients with 
active distal UC (Ulcerative Colitis Disease Activity Index [UCDAI] ≥4 and 
sigmoidoscopy score ≥1) received an IBD98E 50 mg/60 mL(0.083%) enema once a 
day.  A paired student’s t-test was performed to assess statistically significant 
differences in patients between baseline and Day 28.   


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No SAEs were recorded.  At Day 28, 9 (42.9%) patients were clinical responders; 10 
(47.6%) patients had an endoscopic response; 8 (38.1%) patients achieved clinical 
remission; and 10 (47.6%) achieved endoscopic remission.  The mean UCDAI score 
decreased from 6.10 at baseline to 3.81 at Day 28 (p=0.001), and the average 
endoscopic score decreased from 1.57 to 1.10 (p=0.004). 
In this study, IBD98E was found to be safe and has some effect in the induction of 
clinical and endoscopic remission.   
IBD98-M (Mesalamine and Sodium Hyaluronate) Study 
A Phase 1 trial (Study 110200), a single-dose, 3-way crossover study in healthy 
subjects, was conducted to compare IBD98-M with the US reference Delzicol® 
(mesalamine delayed-release capsules) and with the same IBD98-M formulation 
without sodium hyaluronate (mesalamine delayed-release capsules).  The primary 
objective of this Phase 1 study was to compare the rate and extent of absorption of 
IBD98-M 200 mg-28.75 g* delayed-release capsule versus Delzicol 400 mg 
delayed-release capsule, administered as a single oral dose of 2 capsules of IBD98-
M 200 mg-28.75 mg* (total dose of 400 mg-57.50* mg), or 1 capsule of Delzicol 400 
mg under fasting conditions.  The secondary objectives of the study evaluated 
whether sodium hyaluronate had an impact on the bioavailability of mesalamine from 
the IBD98-M delayed-release capsule, with and without sodium hyaluronate, and the 
safety and tolerability of IBD98-M following the administration of a single dose of 
2 capsules of IBD98-M 200 mg-28.75 mg* in healthy subjects.  The study also 
included the exploratory objective to characterize the pharmacokinetic profile of HA 
following administration of a single dose of 2 capsules of IBD98-M 
200 mg-28.75 mg*. 
The results showed an overall bioavailability of mesalamine of approximately 40% 
higher following IBD98-M administration under fasting conditions compared with 
Delzicol.  The most important difference in mesalamine absorption was observed 
within the first 12 hours after the product administration.  The lag time (Tlag), time 
from administration to first quantifiable concentration) and time of maximum drug 


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concentration (Tmax) of mesalamine were 2 hours and 6 hours, respectively, for 
IBD98-M (with and without sodium hyaluronate), whereas they were 7.5 hours and 
14 hours, respectively, for Dezicol.  These values reflect the delayed release nature 
of the formulations.  Following administration of mesalamine-sodium hyaluronate 
400 mg-57.8 mg*, exogenous concentrations of HA could be differentiated from 
endogenous concentrations for most of the subjects.  The time to reach the 
maximum concentration was approximately 6 hours.  The elimination half-life was 
approximately 2.5 hours. 
The overall incidence of subjects reporting treatment-emergent adverse events 
(TEAEs) was similar after the intake of IBD98-M versus mesalamine-only products 
(IBD98-M without sodium hyaluronate and Delzicol).  IBD98-M was well tolerated, 
with no major unexpected side effects.  No safety concerns with respect to the 
clinical biochemistry, hematology, or urinalysis tests were observed.  There were no 
clinically relevant changes from baseline observed, and no TEAEs were laboratory 
abnormalities. 
* The amount of HA within a capsule should be 23 mg.  The total daily dose used in the 
Phase 1 study should be 400 mg of mesalamine with 46 mg of HA.  The decrease of the 
amount of HA was recalculated due to the fact that the loss in the manufacturing processes 
should be excluded. 
4.5 Rationale for Conducting the Study  
Holy Stone Healthcare is developing the IBD98-M delayed-release capsule that 
combines mesalamine and sodium hyaluronate for the treatment of mild to moderate 
UC.   
In UC, a damaged mucosal barrier is thought to be an initiating factor of the 
inflammation of the mucosa secondary to the insult by colonic bacterial flora.  It has 
been postulated that the damaged mucosal barrier of the colon lining with insufficient 
essential components such as lipids and glycosaminoglycan (GAG) may be one of 
the potential causes of ulcerative colitis.  It is therefore expected that the 
supplementation of some of these components might help in restoring the damaged 


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mucosa.  This is borne out to some extent by the fact that the addition of butyrate, a 
short chain fatty acid, has been reported to improve the efficacy of mesalamine in 
refractory distal UC.  The data show that the topical administration of butyrate in 
addition to 4 g of topical mesalamine is significantly more effective in refractory distal 
UC than administration of mesalamine alone in inducing remission or improvement.  
Further, there are also some indications that sodium hyaluronate can contribute to 
the hydration and maintenance of the integrity of the intestinal mucosa, thus 
facilitating the induction of remission of active UC.5,6,7,8 
Based on these results, the IBD98-M delayed-release capsule may have the 
potential to be used for the treatment of mild to moderate UC.  This combination of 
sodium hyaluronate and mesalamine may have additional therapeutic benefit by 
providing protective barriers to the lining of the colon affected by UC, in addition to 
the anti-inflammatory activity of mesalamine.  This combination may also allow a 
reduction in the mesalamine daily dose, thus reducing possible mesalamine side 
effects. 
The safety and efficacy of mesalamine is well known, and mesalamine is generally 
well tolerated.   
The safety and efficacy of sodium hyaluronate for the proposed indication (treatment 
of mild to moderate UC) has not yet been fully proven in humans.  However, there 
are some indications that it might have some therapeutic effect with acceptable 
safety in individual sufferers. 
Mesalamine 
Mesalamine is an amino-salicylate non-steroidal anti-inflammatory drug.  Its oral 
form has been used for over 70 years to treat UC, proctitis, and proctosigmoiditis; 
and mesalazine enema is indicated for the treatment of UC of the distal colon and 
rectum.  The usual dose for the delayed-release oral formulation is up to 4 g of 
mesalazine once daily, or in 2 or 3 divided doses.   


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Sodium Hyaluronate 
Sodium hyaluronate functions as a tissue lubricant and is thought to play an 
important role in modulating the interactions between adjacent tissues.  It is a 
polysaccharide which is distributed widely in the extracellular matrix of connective 
tissue and in epithelial and neural tissues, contributing significantly to cell 
proliferation and migration.  Mechanical protection for tissues and cell layers 
(corneal, endothelium, and epithelium) are provided by the high viscosity of the 
solution.  In facilitating wound healing, it is thought that sodium hyaluronate acts as a 
protective transport vehicle, taking peptide growth factors and other structural 
proteins to a site of action.  It is then enzymatically degraded and active proteins are 
released to promote tissue repair.  Among its other medical uses sodium 
hyaluronate is also used to coat the bladder lining in treating interstitial cystitis. 
Proposed Dose for Phase 2 Clinical Studies 
From the studies outlined above (Sections 4.3 and 4.4), results show that:  
 In colitis rat models, the wound-healing ability of HA, with and without 
mesalamine, was superior to treatment with phosphate buffer solution and 
mesalamine alone in reducing inflammatory bowel and promoting colonic 
mucosa healing.  This result supports the hypothesis that HA may play a 
beneficial role in IBD treatment.   
 IBD98-M significantly reduced the erythema of colonic epithelium of pig colitis 
induced by DNBS and enhanced healing substantially; the healing rate 
following IBD98-M treatment was approximately 80%, compared to 62% and 
50% following treatments with Pentasa and placebo, respectively. 
 In Sprague Dawley rats, IBD98-M was well tolerated when administered once 
daily for 28 days to a maximum of 1075.2 mg/kg/day based on pellet weight.  
This is equivalent to 480 mg/kg/day of mesalamine and 69 mg*/kg/day of 
sodium hyaluronate. 


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 In a Phase I clinical trial performed in healthy males and females, the overall 
bioavailability of mesalamine was approximately 40% higher following 
IBD98-M administration compared with that of Delzicol.  Further, the overall 
bioavailability of mesalamine was approximately 20% lower following 
administration of IBD98-M without the sodium hyaluronate component.  The 
overall incidence of subjects reporting TEAEs was similar following the intake 
of IBD98-M and mesalamine-only products (IBD98-M without sodium 
hyaluronate, and Delzicol). 
 Finally, in a clinical trial of safety and efficacy of an IBD98E (hyaluronate) 
50 mg/60 mL enema, the clinical response was 42.9% with an endoscopic 
response of 47.6%.  Although this was an uncontrolled, open study, this result 
suggests that hyaluronate may have some effect in the treatment of UC. 
* The amount of HA should be 55.2 mg.  The decrease in the amount of HA was 
recalculated due to the fact that the loss in the manufacturing processes (20% loss) should 
be excluded. 
Overall, as shown by the nonclinical and clinical studies, mesalamine and sodium 
hyaluronate as a combination therapy may provide additional therapeutic benefits, 
compared to each individual component, such as enhanced efficacy and a reduction 
in mesalamine dose by up to 40%, along with lower incidence of side effects.  This is 
further supported by the nonclinical study conducted in the TNBS-induced IBD pig 
model, in which the results showed that the combination formulation IBD98-M 
provided better efficacy on mucosal healing even though the treatment dose of 
mesalamine was 40% of the dose in the marketed mesalamine product. 
Regarding the proposed dose of hyaluronate, the clinical trial with the hyaluronate 
enema offers some useful data.  In this study, the dose used was 50 mg of 
hyaluronate.  It is generally accepted that mesalamine enema is recommended for 
the treatment of UC of the distal colon including proctosigmoiditis, which is roughly 
just over one third of the large bowel.  It is therefore reasonable to assume that for 


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the oral treatment of diffuse colitis, it may be advisable to test a daily dose of about 
3 times the dose in the enema shown to have some effect in the distal colon only.   
In conclusion, based on the clinical and nonclinical findings, and for the purposes of 
evaluating the proof-of-concept, the proposed mesalamine daily doses for this 
Phase 2a clinical study are 800 mg and 1.2 g, with the sodium hyaluronate daily 
doses of 92 mg and 138 mg per day, respectively. 
5 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 Study Objectives 
Primary Objective 
 To compare the percentage of patients in UC remission at Week 6 for each of 
the 2 IBD98-M dose groups versus placebo (remission defined as the 
Ulcerative Colitis Disease Activity Index [UCDAI] score of ≤1, with a score of 
0 for rectal bleeding and stool frequency, no mucosal friability, and ≥1 point 
reduction from baseline in the sigmoidoscopy score) 
Secondary Objectives 
 To compare clinical improvement rates at Week 6 among treatment groups 
(defined as a ≥3 point reduction from baseline in the UCDAI score) 
 To compare endoscopic improvement at Week 6 among treatment groups 
(defined as a ≥1 point decrease in UCDAI mucosal appearance subscore) 
 To determine the change in symptoms (rectal bleeding and stool frequency) 
from baseline to each study visit among treatment groups 
 To evaluate the safety and tolerability profile of IBD98-M 
Exploratory Objectives 
 To examine the effect of IBD98-M treatment on fecal calprotectin 
 To examine any correlation between therapeutic response to IBD98-M and 
baseline characteristics 


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5.2 Study Endpoints 
5.2.1 Primary Endpoint  
 Percentage of patients in remission at Week 6 
Remission as defined by UCDAI] score of ≤1, with a score of 0 for rectal bleeding 
and stool frequency, no mucosal friability, and ≥1 point reduction from baseline in 
the sigmoidoscopy score. 
5.2.2 Secondary Endpoints 
The secondary efficacy endpoints are as follows: 
 Proportion of subjects with clinical improvement at Week 6 (defined as a ≥3 
point reduction from baseline in the UCDAI score) 
 Proportion of subjects with endoscopic improvement at Week 6 (defined as a 
≥1 point decrease in UCDAI mucosal appearance subscore) 
 Change in symptoms (rectal bleeding and stool frequency) from baseline to 
each study visit 
The safety endpoints are as follows: 
 Incidence and severity of all TEAEs 
 Incidence and severity of SAEs 
 Systemic tolerance (physical examination, vital signs, electrocardiograms 
(ECG)s, and laboratory assessments of safety parameters) 
5.2.3 
Exploratory Endpoints 
 Reduction in fecal calprotectin 
6 
INVESTIGATIONAL PLAN 
6.1 Description of Overall Study Design and Plan 
Study IBD98-M-2002 is a Phase 2a, multicenter, randomized, double-blind, parallel-
group, placebo-controlled trial in patients with active, mild to moderate UC.  It is 
being conducted as an exploratory proof-of-concept study to investigate the clinical 
efficacy of IBD98-M delayed-release capsules (in a fixed combination) over a 
6-week treatment period and a 2-week follow-up period. 


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Patients will be screened for study enrollment up to 4 weeks prior to baseline.  
During the screening period, patients will be evaluated with laboratory tests, physical 
examinations, and sigmoidoscopy.  To be eligible, patients are to have a score of ≥4 
and ≤10 on the UCDAI, and a score of >2 on the endoscopy subscore would be 
included.  In addition, the diagnosis of UC must be confirmed visually by endoscopy 
images.  After the screening visits, eligible patients will be randomized to 1 of 3 
study groups:  (1) IBD98-M 0.8 g/day (mesalamine 0.8 mg with sodium hyaluronate 
92 mg), (2) IBD98 M 1.2 g/day (mesalamine 1.2 g with sodium hyaluronate 138 mg), 
or (3) placebo.  Up to 51 patients will be enrolled in this study (including drop-out 
patients), with 17 patients randomized to each treatment group.   
Study blind will be maintained using a double-dummy technique.  Eligible patients 
will be randomized centrally via an interactive voice response system (IVRS), and 
each patient will receive 3 capsules twice a day for a period of 6 weeks, 
administered orally in 1 of the following regimens: 
 Patients in the 0.8 g/day group will receive 2 capsules of IBD98-M (200 mg of 
mesalamine/23 mg of sodium hyaluronate) and 1 placebo BID. 
 Patients in the 1.2 g/day group will receive 3 capsules of IBD98-M (200 mg of 
mesalamine/23 mg of sodium hyaluronate) BID. 
 Patients in the placebo will receive 3 placebo tablets BID.   
Patients should be encouraged to take their medication at the same time every day. 
During the study, patients will visit the clinic on 7 occasions:  2 visits during the 
screening period (the second screening visit is the baseline visit); 4 visits during the 
treatment period at Weeks 0, 2, 4, and 6; and an end-of-study/withdrawal visit at 
Week 8, concluding the follow-up period.  Patients will record symptoms in a daily 
diary starting 7 days before treatment and continuing until the end-of study visit.  For 
the baseline scoring of rectal bleeding and stool frequency items, the worst score 
from the previous 7 days of diary data before the randomization visit will be used, 


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excluding the day of and the day after endoscopy, as well bowel preparation for 
endoscopy where applicable. 
6.2 Discussion of Study Design 
This Phase 2a study is being conducted as an exploratory proof of concept study to 
examine efficacy and tolerability of the combination of mesalamine with sodium 
hyaluronate.  The primary objective is to determine the efficacy of IBD98-M, 
assessed by the ability to induce clinical and endoscopic remission after 6 weeks of 
treatment compared with placebo, in patients with active mild to moderate UC.  The 
study examines 2 delayed-release doses of IBD98-M (mesalamine 0.8 g with 
sodium hyaluronate 92 mg, and mesalamine 1.2 g with sodium hyaluronate 138 mg) 
compared with placebo following 6 weeks of treatment.  In addition, the study will 
also evaluate the safety of IBD98-M.  The study design and primary/secondary 
objectives reflect those recommended for evaluating the efficacy, safety, and 
tolerability of an investigational product in patients with active mild to moderate UC.1 
Simon’s randomized Phase 2 design was used.9  The average remission rate of 
placebo is approximately 0.2  With a Type I error of 0.05, power of 0.8, and the 
difference in remission rates between the best treatment and the other treatments 
≥0.18, each arm requires 17 patients, giving the total number of patients to be 
enrolled as 51. 
7 
SELECTION AND WITHDRAWAL OF PATIENTS 
7.1 Inclusion Criteria 
Patients must meet all of the following criteria in order to be eligible for the study: 
1. Male or female, age ≥18 and <75 years, suffering from UC for at least 
6 months 
2. Female patients must be postmenopausal, sterile, or have a negative urine 
pregnancy test prior to entering the study and use adequate contraception 
during the study if of childbearing potential. 
3. Diagnosis of active UC with UCDAI ≥4 and ≤10, with endoscopy score of ≥2 
in the UCDAI mucosal appearance subscore. 


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4. Patients with either newly diagnosed or relapsed UC (onset of current 
episode of relapse must be within 6 weeks of screening).  Diagnosis of UC 
must be confirmed by endoscopic and histologic evidence in the past; if prior 
confirmation is not available, this must be done at the time of screening 
endoscopy. 
5. Patients must have up-to-date surveillance colonoscopy for malignancy, per 
treatment guideline. 
6. Willing and able to provide signed informed consent 
7.2 Exclusion Criteria  
Patients meeting any of the following criteria are ineligible to participate in this study: 
1. Patients diagnosed with Crohn’s disease,  indeterminate colitis, or ischaemic 
colitis  
2. Female patients who are pregnant or breastfeeding  
3. Ulcerative proctitis with <15 cm of disease 
4. Patients with infectious colitis, as determined by assessment for C.  difficile 
and fecal pathogens at screening, or treatment for C.  difficile within 30 days 
prior to screening 
5. History of or current evidence of toxic megacolon, fulminant colitis (eg 
Lichtiger score of ≥10), colonic perforation 
6. Any previous colonic surgery (except appendectomy) or short bowel 
syndrome 
7. Patients who required doses of mesalamine higher than 2.4 g/day for 
previous flares 
8. Hypersensitivity to salicylates / aspirin 
9. Use of the following medications:  
a. Use of oral or rectal 5-ASA 4 weeks prior to randomization 


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b. Use of systemic or rectal corticosteroid 4 weeks prior to or during 
screening 
c. Use of anti-TNFα agents or other biologics such as vedolizumab within 
90 days prior to or during screening 
d. Use of immunosuppressants (eg, azathioprine, mercaptopurine) within 
6 weeks prior to or during screening 
e. Use of antibiotics for UC within the 7 days prior to or during screening 
10. Clinically significantly abnormal ECG at screening   
11. Liver cirrhosis or alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) levels >2 times the upper limit of normal (ULN) 
12. Serum creatinine >2X ULN 
13. Positive pre-study drug/alcohol screen 
14. Participation in another clinical trial involving an investigational agent within 
3 months prior to screening (Visit 1).  Patients cannot participate in any other 
investigational medication or medical device trial while participating in this 
study (participation in a registry or observational study without an additional 
therapeutic intervention is allowed) 
15. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, 
gastrointestinal, genitourinary, hematological, coagulation, immunological, 
endocrine/metabolic, or other medical disorder that, in the opinion of the 
Investigator, would confound the study results or compromise patient safety 
16. Had any surgical procedure requiring general anesthesia within 30 days prior 
to screening or is planning to undergo major surgery during the study period  
17. Any active malignancy within the last 5 years, except for basal cell carcinoma 
of the skin, or if female, in situ cervical carcinoma that has been surgically 
excised 


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18. Patient has a history of hepatitis (B or C) or human immunodeficiency virus 
(HIV) 
19. In the opinion of the Investigator, the patient is unable to adhere to the 
requirements of the study  
7.3 Withdrawal, Removal, and Replacement of Patients 
At any time, a patient's participation in the study may be terminated at his/her 
request or on the basis of the Investigator’s clinical judgment.  The reason for patient 
withdrawal will be noted on the electronic case report form (eCRF).   
A patient may be discontinued from the study for the following medical or 
administrative reasons: 
 Occurrence of an AE that in the judgment of the Investigator suggests an 
unacceptable risk to the patient  
 Development of any condition on-study that, in the opinion of the Investigator 
or the Sponsor, places the patient at an unacceptable medical risk if he/she 
continues 
 Pregnancy 
 Patient request 
 Institution of additional medical (rescue) therapy for UC.  Rescue medication 
will not be permitted during the 6-week double-blind treatment period, and 
patients considered as treatment failures will be withdrawn and assigned an 
appropriate alternative UC treatment by the Investigator. 
The Investigator may discontinue individual patients from the study at any time.   
Patients will be encouraged to complete the study; however, they may voluntarily 
withdraw at any time.  The date of and reason for study discontinuation must be 
recorded on the eCRF regardless of the reason for withdrawal; all patients will be 
asked to undergo an end-of-study/early termination evaluation.  Every attempt will 
be made to obtain all of the end-of-study assessments, including all of the subscales 


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of the UCDAI (i.e., stool frequency, bleeding, physician's assessment, and 
sigmoidoscopy score). 
This study may be terminated at the discretion of the Sponsor or any regulatory 
agency.  An Investigator may elect to discontinue or stop the study at his or her site 
for any reason, including safety or low enrollment. 
In the event that a patient discontinues prematurely from the study due to a TEAE or 
serious TEAE, the TEAE or serious TEAE will be followed until it resolves (returns to 
normal or baseline values) or stabilizes, or until it is judged by the Investigator to be 
no longer clinically significant. 
Patients who withdraw or are withdrawn may not re-enter the study and will not be 
replaced under this protocol. 
8 
TREATMENTS 
8.1 Details of Study Treatments 
IBD98-M (mesalamine, United States Pharmacopeia [USP], and sodium hyaluronate) 
drug product is a delayed-release capsule.  Each capsule is filled with multiple-layer 
pellets containing 200 mg of mesalamine and 23 mg of sodium hyaluronate.  Each 
pellet consists of a microcrystalline cellulose inner core, which is coated first with 
mesalamine, USP, then with sodium hyaluronate, and finished with an enteric 
coating film.  The enteric-coated pellets are designed to allow the release of 
mesalamine and sodium hyaluronate from the pellets at or above pH 6.8 at the 
terminal ileum (ascending colon).  The matching placebo capsule will be 
indistinguishable from the drug capsule. 
The capsules (placebo or drug) are packaged into 200-cc white, wide-mouth, round 
HDPE bottles sealed with an aluminum foil pad and covered with a polypropylene 
plastic cap.  The product stability is for 12 months when the product is stored in a 
stability chamber of 25° C +/- 2° C. The product should be stored at 15° to 25° C 
[59° to 77° F]. 
Study treatments are described in 錯誤! 找不到參照來源。. 


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Table 1: Details of Study Treatments 
 
Preparations to be Administered 
 
Placebo 
Test Product (New Drug)- 
0.8 g/day dose group 
Test Product (New Drug)-
1.2 g/day dose group 
Investigational 
Name 
Not 
applicable 
IBD98-M 
IBD98-M 
Manufacturer 
Holy Stone 
Healthcare 
Holy Stone Healthcare 
Holy Stone Healthcare 
Total Daily Dose  
Not 
applicable 
Mesalamine 0.8 g; sodium 
hyaluronate 92 mg (total 4 
capsules) 
Mesalamine 1.2 g; sodium 
hyaluronate 138 mg (total 6 
capsules) 
Dosage 
Not 
applicable 
2 test product capsules and 
1 placebo capsule, BID 
3 test product capsules BID 
Route 
Oral 
Oral 
Oral 
Formulation 
Capsule 
Capsule 
Capsule 
Capsule Strength 
Not 
applicable 
Mesalamine 200 mg; sodium 
hyaluronate 23 mg 
Mesalamine 200 mg; sodium 
hyaluronate 23 mg 
 
8.2 Dosage Schedule 
Patients will be randomized to 1 of 3 treatment groups:  IBD98-M 0.8 g/day 
(mesalamine 0.8 g with hyaluronate 92 mg), IBD98-M 1.2 g/day (mesalamine1.2 g 
with hyaluronate 138 mg), or placebo.  Three blinded capsules of study medication 
(1 capsule from each of the 3 bottles in the medication kit) will be taken by each 
patient orally with water twice a day (See section 8.4).  Patients will be instructed to 
swallow the study medication whole without breaking or chewing.  Patients will be 
required to take the medication twice a day and will be encouraged to take their 
medication at the same times every day (in the morning and evening).  All doses 
taken during the study must be recorded in the patient’s diary.   
8.3 Study Treatment Assignment 
Patients will be assigned treatment according to a 1:1:1 randomization schedule 
produced by inVentiv.  The randomization code will not be available to the 
Bioanalytical Division of inVentiv until the clinical and analytical phases of the study 
have been completed.   


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8.4 Blinding 
Blinding of study treatments to the patient, site staff, and Sponsor will be maintained 
during the study using a double-dummy technique.  Each patient will be dispensed 
with an IVRS-assigned kit, labeled with a unique kit ID at Visit 2, Week 0.  Each kit 
will contain 3 bottles labeled with A, B, and C.  Each patient should take 1 capsule 
from each bottle twice a day.  Each kit shall contain sufficient supply for 6 weeks.   
The study will be double-blind.  Subjects will receive 1 of 3 different treatment kits, 
identical in appearance, as outlined in table below. 
Treatment Group 
Bottle A 
Bottle B 
Bottle C 
IBD98-M 0.8 g/day 200 mg IBD98-M 
200 mg IBD98-M 
Matching Placebo 
IBD98-M 1.2 g/day 200 mg IBD98-M 
200 mg IBD98-M 
200 mg IBD98-M 
Placebo 
Matching Placebo 
Matching Placebo 
Matching Placebo 
   
8.5 Treatment Accountability and Compliance 
It is the responsibility of the Sponsor to ensure that study medications provided for 
this study are manufactured under Good Manufacturing Practices and are suitable 
for human use.  It is the responsibility of the Sponsor to ship a sufficient amount of 
dosage units to allow inVentiv to maintain an appropriate sampling for the study, and 
for drug retention, according to Food and Drug Administration (FDA) regulation (21 
CFR 320.38, 320.63).  Study medication will be stored by inVentiv as per applicable 
requirements.     
The medications will be stored in a locked, environmentally controlled medication 
room with restricted access.  Container(s) will bear a label containing at least the 
name of the study drug, lot and/or batch number, and manufacturing and/or 
expiry/retest date and a unique kit number.  Individual patient doses will be 


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dispensed according to the kit number as assigned by IVRS, at Visit 3.  All study 
drug received at the site will be inventoried and accounted for throughout the study 
and the result recorded in the drug accountability/retention record according to the 
appropriate inVentiv Standard Operating Procedure. 
Compliance will be assessed by determining the amount of unused medication.  
Records will be kept of all medication dispensed, used, and returned by each patient.  
All doses taken during the study must be recorded in the patient’s diary.  The 
medication bottles (partial and empty) must be checked at the end of the study and 
compliance recorded on the Dosage Administration Record of the eCRF.  At the end 
of the study, all unused trial medication and used packaging will be returned to the 
Sponsor.  All study medication will be accounted for and any discrepancies 
documented. 
8.6 Prior and Concomitant Illnesses, Procedures, and Medications 
8.6.1 Prior and Concomitant Illnesses 
Investigators should document all prior significant illnesses that the patient has 
experienced within 3 months prior to screening and in line with entry criteria.  
Additional illnesses present at the time when informed consent is given and up to the 
time of first dose are to be regarded as concomitant illnesses.  Illnesses first 
occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as adverse events (AEs) on the eCRF. 
8.6.2 Concomitant Procedures 
All procedures that are performed during the study must be recorded in the patient’s 
source documents and in the eCRF.  The following should be taken into account 
with regard to concomitant procedures: 
 Patients may not undergo major elective surgery while enrolled in this study.   
 Patients may not donate blood, sperm, or oocytes during the study and for 6 
months after the last dose of study drug. 
8.6.3 Prior and Concomitant Medications 


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Patients must follow the medication restrictions outlined in the inclusion and 
exclusion criteria (Sections 7.1 and 7.2) during the study.  The use of hormonal 
contraceptives will be allowed and documented.  Any concomitant medication use 
other than the occasional use of acetaminophen will be evaluated on a case-by-case 
basis by the Investigator.  All concomitant medication use will be documented. 
The use of the following medications is prohibited during the study: 
 Rectal 5-ASA, budesonide, or steroids 
 Systemic (oral or intravenous [IV]) corticosteroid 
 Oral or parenteral immunuosuppresants for treatment of UC 
 Antibiotics for treatment of UC 
9 
STUDY PROCEDURES 
Table 2  outlines the timing of procedures and assessments to be performed 
throughout the study.  See Sections 錯誤! 找不到參照來源。 to 11.8 for additional 
details of study procedures. 
 


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Table 2: Schedule of Events   
 
STUDY PROCEDURE  
Screening 
Treatment Period 
Follow-up 
Visit 1 
(Screening)
Visit 2 
(Baseline)
Visit 3 
 
Visit 4 
Visit 5 
Visit 6/Early 
termination
Visit 7 
 
DAY  
--28 to -7 
-14 to -1 
0(± 1 day)
14(± 3 days)
28(± 3 days)
42(± 3 days) 56(± 3 days) 
Informed consent  
X 
 
 
 
 
 
 
Demographics / Medical History  
X 
 
 
 
 
 
 
Confirm Study Eligibility  
X 
X 
X 
 
 
 
 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
Physical Examination  
X 
 
X 
Xa 
Xa 
X 
X 
Weight and Height  
X 
 
 
 
 
X 
 
12-Lead ECG  
X 
 
 
 
 
X 
 
Hepatitis Screening  
X 
 
 
 
 
 
 
CBC with differential  
X 
 
X 
X 
X 
X 
X 
Coagulation (aPTT, PT, INR)  
X 
 
 
X 
 
X 
 
Serum Chemistry  
X 
 
X 
X 
X 
X 
X 
Urinalysis  
X 
 
X 
X 
X 
X 
X 
Pregnancy Testb
X 
 
X
 
X
X
 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
UCDAIc 
 
X 
X 
X 
X 
X 
 
IBDQ, SF-36 
 
 
X 
 
 
X 
 
CRP  
 
 
X 
 
X 
X 
 
Flexible Sigmoidoscopy  
 
Xd 
 
 
 
X 
 
Distribution of Diary / Check  
X 
X 
X 
X 
X 
X 
 
Stool for culture, C.  difficile toxin, and ova 
& parasite 
X 
 
 
 
 
 
 
Randomization  
 
 
Xe 
 
 
 
 
Treatment Distribution / accountability  
 
 
X 
X 
X 
Xf
 
Stool calprotectin  
 
 
X 
 
 
X 
 
Abbreviations: AE=adverse event; ECG= electrocardiogram; aPTT= activated partial prothrombin time; BMI= body mass index; PT= prothrombin time; INR= 
international normalization ratio; CRP=C-reactive protein;  HRQoL= Health Related Quality of LIfe; IBDQ= Inflammatory Bowel Disease Questionnaire; C.  
difficile=Clostridium Difficile; eCRF=electronic case report form; UCDAI= Ulcerative Colitis Disease Activity Index 


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a. 
Physical examinations performed on Days 14 and 28 should be abbreviated physical exams.  New findings should be recorded as AEs 
b. 
Pregnancy test performed at screening should be serum test, after screening should be urine pregnancy tests 
c. 
UCDAI on Days 0 and 42 should be complete UCDAI score including the endoscopy subscore.  UCDAI at Screening Visit 2, and Days14 and 28 should be 
partial UCDAI score including only stool frequency, rectal bleeding and physician’s global assessment  
d. 
Screening sigmoidoscopy must be performed on day -14 to -1  
e. 
To be performed prior to dosing 
f. 
On Day 42, there will be no study drug distribution  


 
 
 
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9.1 Patient Informed Consent 
Prior to performing any study-related procedures, the Investigator (or his/her 
designated staff member) will obtain written informed consent from the patient.   
9.2 Procedures by Study Visit 
Assessments are to be performed as outlined in the following by-visit subsections.   
9.2.1 Screening Period:  Visit 1 (Days -28 to -7) and Visit 2 (Days -14 to -1, 
Baseline)  
The first screening visit will occur within -28 to -7 days prior to Day 0.  The following 
procedures will be performed:  
 
Informed consent 
 
Demographics data collection: date of birth, country, gender, and ethnicity 
 
Physical examination (including weight and height for body mass index [BMI])  
 
All current and past medical conditions and disease history 
 
Verification of inclusion and exclusion criteria 
 
Vital signs (pulse, blood pressure, and body temperature) measurements 
 
12-lead ECG 
 
Serology for HIV, and Hepatitis B and C 
 
Hematology assessments: complete blood count (CBC) with differential, 
activated partial prothrombin time (aPTT), prothrombin time (PT), and 
international normalization ratio (INR)     
 
Serum chemistry 
 
Urinalysis 
 
Serum sample for pregnancy test 
 
Recording of AEs and concomitant medications 
 
Stool sample for C.  difficile, culture, and calprotectin 
 
Distribution of diary  
 
The second screening (baseline) visit will occur within -14 to -1 days prior to Day 0.  
The following procedures will be performed:  
 
Verification of inclusion and exclusion criteria 


 
 
 
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 
Vital signs (pulse, blood pressure, and body temperature) measurements 
 
Recording of AEs and concomitant medications 
 
UCDAI 
 
Flexible sigmoidoscopy  
 
Distribution of diary  
 
9.2.2  
Treatment Period:  Visit 3 (Day 0 [± 1 day]; Randomization) 
All patients will undergo the following procedures: 
 
Physical examination (including weight and height for BMI calculation) 
 
Vital signs (pulse, blood pressure, and body temperature) measurements 
 
Verification of inclusion and exclusion criteria 
 
Hematology assessments: Complete blood count (CBC) with differential 
 
Serum chemistry, including C-reactive protein (CRP) 
 
Urinalysis 
 
Urine pregnancy test 
 
Recording of AEs and concomitant medications 
 
Randomization via IVRS  
 
Check diary 
 
UCDAI 
 
Inflammatory Bowel Disease Questionnaire (IBDQ); 36-Item Short Form 
Questionnaire (SF-36) 
 
Stool sample for calprotectin 
 
Reserve blood sample 
 
Distribution and check of diary  
 
Blinded study medication distribution 
 
9.2.3  
Treatment Period:  Visits 4, 5, and 6 or End-of-Study Visit, or Early 
Termination Visit (Days 14, 28, and 42) (± 3 days) 
All patients will undergo the following procedures: 
 
Physical examination (weight and height at Visit 6 only) 
 
Vital signs (pulse, blood pressure, and body temperature) measurements 
 
ECG (Visit 6 only) 


 
 
 
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 
Hematology assessments: CBC with differential at Visits 4, 5, and 6; and 
aPTT, PT, and INR at Visit 4 only 
 
Serum chemistry (CRP at Visit 5 and 6 only) 
 
Urinalysis 
 
Urine pregnancy test (at Visit 5 and 6 only) 
 
Recording of AEs and concomitant medications 
 
UCDAI 
 
IBDQ; SF-36 (only at Visit 6) 
 
Check diary and distribution of diary (except Visit 6) 
 
Blinded study medication distribution (except at Visit 6) 
 
Stool sample for calprotectin (only at Visit 6) 
 
Reserve blood sample 
 
Flexible sigmoidoscopy (only at Visit 6) 
 
9.2.4 Follow-up Period:  Visit 7 (Day 56 [± 3 days]) 
Patients who prematurely withdraw from the study for any reason should complete 
the Early Termination Visit requirements.  If the Early Termination Visit is not done, 
the reason(s) will be recorded in the CRF.  All patients will undergo the following 
Visit 7 procedures: 
 
Vital signs (pulse, blood pressure, and body temperature) measurements 
 
Physical examination 
 
Hematology assessments: CBC with differential 
 
Serum chemistry 
 
Urinalysis 
 
Recording of AEs and concomitant medications 


 
 
 
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10 EFFICACY ASSESSMENTS 
10.1 Ulcerative Colitis Disease Activity Index (UCDAI) Score 
The modified UCDAI score will be used for assessment of efficacy during the study.  
Subjects are strongly encouraged to complete the symptom diary on a daily basis 
throughout the study.   
Timing of diary entries for UCDAI 
 At Baseline (Day 0), the timing of the diary entries depends on when the 
endoscopy is performed 
o If the endoscopy is performed within 5 days of randomization (Day 0), 
use the diary entries from 3 consecutive days immediately prior to the 
preparation day for the endoscopy. 
o If the endoscopy is performed 6 to 14 days prior to the randomization 
day (Day 0), the diary entries from 3 consecutive days immediately 
prior to Day 0 should be used. 
o The endoscopy must be performed within 14 days of randomization 
(Day 0). 
 For visits where an endoscopy is not needed (Day 14 and 28), diary entries 
from the 3 days preceding the visit day will be used for the assessment of 
stool frequency, rectal bleeding, and physician’s global assessment. 
 For the Day 42 visit, diary entries from the 3 days preceding the visit day or 
the preparation for endoscopy, whichever comes first, will be used for the 
UCDAI assessment.  Endoscopy must be performed within 3 days of the 
target visit day.   
See Appendix 1 for further detail.   


 
 
 
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Endoscopy subscore of the UCDAI 
Sigmoidoscopy will be conducted during the second screening visit (for baseline 
UCDAI) and at Day 42 ± 3 days / early termination.  The cleansing preparation 
should be conducted per site routine.  The endoscopy performed at both visits 
should be a sigmoidoscopy, only the segment distal to the splenic flexure should be 
considered for purpose of endoscopy scoring (range from 0 to 3 points) per modified 
UCDAI (Appendix 1).  Note that the modified UCDAI designates the presence of any 
friability as score of 2.   
10.2 Inflammatory Bowel Disease Questionnaire (IBDQ) 
The Inflammatory Bowel Disease Questionnaire (IBDQ) will be used to 
measure disease specific quality of life (QoL).  The IBDQ is a self-
administered 32-item questionnaire that evaluates QoL across 4 dimensions: 
(1) Bowel – symptoms related to primary bowel disturbance, (2) Systemic 
symptoms, (3) Emotional function, and (4) Social function.  The response to 
each question can range from 1 to 7, with 1 indicating severe problem and 7 
normal health.  The total IBDQ is computed as the sum of the responses to 
the individual IBDQ questions.  The total score can range between 32 and 224, 
with higher scores indicating better QoL.  IBDQ will be completed at Days 0 
and 42.  See Appendix 3. 
10.3  Short Form-36 
The Short Form-36 (SF-36) questionnaire will be used to measure general health-
related QoL.  Individual subscale scores and two summary scores will be calculated: 
(1) physical component summary (PCS), which includes physical functioning, role-
physical, bodily pain, and general health; (2) mental component summary (MCS), 
which includes vitality, social functioning, role-emotional, and mental health.  SF-36 
form will be completed at Days 0 and 42.  See Appendix 4. 


 
 
 
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11 SAFETY ASSESSMENTS 
Safety assessments (vital signs, physical examinations, periodic ECG recordings, 
AEs, SAEs, clinical laboratory results [routine hematology and biochemistry] are to 
be performed as specified in the Schedule of Events, Table 2. 
11.1 Vital Signs 
Vital signs (body temperature, respiration rate, heart rate, and blood pressure 
measurements) will be evaluated at the visits indicated in the Schedule of Events.  
All vital signs will be measured after the patient has been resting in a sitting position 
for at least 5 minutes.  Blood pressure measurements are to be taken in the same 
arm for the duration of the study.  Body weight (without shoes) will be recorded 
whenever vital signs are recorded, and height (without shoes) will be recorded at 
baseline only. 
Vital sign measurements will be repeated if clinically significant or 
machine/equipment errors occur.  Out-of-range blood pressure, respiratory rate, or 
heart rate measurements will be repeated at the Investigator’s discretion.  Any 
confirmed, clinically significant vital sign measurements must be recorded as AEs. 
11.2 Physical Examination 
A complete physical examination (heart, eyes, ears, nose, and throat [HEENT], heart, 
lungs, abdomen, skin, cervical and axillary lymph nodes, neurological, and 
musculoskeletal systems) will be performed at Screening Visit 1, Visit 3 and Visit 6.  
Physical examinations will be performed by a physician.  In addition, medical history 
will be recorded at screening, including smoking history, if applicable. 
A limited physical examination to verify continued patient eligibility and to follow any 
change in medical history will be performed at the visits indicated in the Schedule of 
Assessments (Visit 4 and 5).  Symptom-driven limited physical examinations will be 
performed as clinically indicated at any study visit.  All changes not present at 


 
 
 
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baseline or described in the past medical history and identified as clinically 
noteworthy must be recorded as AEs. 
11.3 Electrocardiogram 
A 12-lead resting ECG will be obtained at the visits indicated in the Schedule of 
Events.   
At screening, the Investigator will examine the ECG traces for signs of cardiac 
disease that could exclude the patient from the study.  An assessment of normal or 
abnormal will be recorded, and if the ECG is considered abnormal, the abnormality 
will be documented on the eCRF.  ECGs may be repeated if clinically significant 
abnormalities are observed or artifacts are present. 
11.4 Laboratory Assessments 
Laboratory assessment samples (Table 3) are to be obtained at designated visits as 
detailed in the Schedule of Events. 


 
 
 
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Table 3: Laboratory Assessments 
Blood Tests 
Hematology 
Serum chemistry 
Coagulation 
Full and differential blood count 
Hematocrit (Hct) 
Hemoglobin (Hb) 
Mean corpuscular hemoglobin 
 
(MCH) 
Mean corpuscular hemoglobin 
 
concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count  
White blood cell (WBC) count 
 
with differential  
 
Albumin 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Blood urea nitrogen (BUN) or urea 
Creatinine 
Creatine phosphokinase (CPK) 
Electrolytes (Na, K,) 
Gamma--glutamyl transpeptidase 
(GGT) 
Glucose  
Lactate dehydrogenase (LDH) 
Total bilirubin 
Total cholesterol 
Triglyceride 
C-reactive protein (CRP) 
Prothrombin time (PT)
Activated partial 
thromboplastin time 
(PTT) 
INR (international 
normalization ratio) 
Pregnancy test: A serum pregnancy test will be performed on all female patients of childbearing 
potential at the screening visit 
Urinalysis (dipstick) 
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood and WBCs 
Specific gravity 
Urine human chorionic gonadotropin (HCG) (pre-menopausal females only)  
Urobilinogen 
Fecal calprotectin 
 
Blood and urine samples will be analyzed at a local laboratory facility.  Urine 
samples will be analyzed by dipstick, and a microscopic analysis will be performed if 
the results of dipstick indicate abnormalities to be further investigated.  Stool 


 
 
 
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samples will be collected and analyzed as described in Sections 11.5 and 11.6.  All 
laboratory reports must be reviewed, signed, and dated by the Investigator.  A 
legible copy of all reports must be filed with both the patient's eCRF and medical 
record (source document) for that visit.  Any laboratory test result considered by the 
Investigator to be clinically significant should be considered an AE (clinically 
significant AEs include those that require an intervention).  Clinically significant 
abnormal values occurring during the study will be followed until repeat test results 
return to normal, stabilize, or are no longer clinically significant.   
11.5 Stool Sample for Cultures 
A stool sample will be obtained for culture, ova and parasite evaluation, and C.  
difficile assay.  A sample will be collected and cultured during screening and at any 
point in the study when a patient becomes symptomatic, including worsening or 
return of disease activity. 
11.6 Fecal Calprotectin Sample Collection 
A stool sample will be collected on Days 0 and 42 for the analysis of fecal 
calprotectin, a biomarker of intestinal inflammatory activity. 
Serum samples will be collected for CRP on Days 0, 28, and 42 for analysis of CRP, 
a blood biomarker for inflammation.   
11.7 Diary Completion and Review 
During screening, patients will be instructed on how to appropriately complete the 
diary.  The symptoms of UC must be recorded throughout the study, including the 
screening period.  The patient diaries will be distributed at Visit 1 to record baseline 
data in the 7 days prior to Day 0.  Diaries will be distributed at Visits 2, 3, 4, and 5 to 


 
 
 
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collect patient data during the treatment period.  Diary entries will be reviewed by 
site personnel at the visits indicated in the Schedule of Events.   
11.8 Adverse Events 
11.8.1 Adverse Events 
An AE is any symptom, physical sign, syndrome, or disease that either emerges 
during the study or, if present at screening, worsens during the study, regardless of 
the suspected cause of the event.  All medical and psychiatric conditions (except 
those related to the indication under study) present at screening will be documented 
in the medical history eCRF.  Changes in these conditions and new symptoms, 
physical signs, syndromes, or diseases should be noted on the AE eCRF during the 
rest of the study.  Clinically significant laboratory abnormalities should also be 
recorded as AEs.   
AE Reporting 
Patients will be instructed to report AEs at each study visit.  All AEs are to be 
followed until resolution or until a stable clinical endpoint is reached. 
Each AE is to be documented on the CRF with reference to date of onset, duration, 
frequency, severity, relationship to study drug, action taken with study drug, 
treatment of event, and outcome.  Furthermore, each AE is to be classified as being 
serious or non-serious.  Changes in AEs and resolution dates are to be documented 
on the eCRF. 
For the purposes of this study, the period of observation for collection of AEs 
extends from the time the patient gives informed consent until the follow-up visit 
(Visit 7).  Follow-up of the AE, even after the date of therapy discontinuation, is 
required until the event resolves or stabilizes at a level acceptable to the Investigator. 
Specific guidelines for classifying AEs by intensity and relationship to study drug are 
given in Table 4 andTable 5. 


 
 
 
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Table 4: Classification of Adverse Events by Intensity 
MILD:  An event that is easily tolerated by the patient, causing minimal discomfort and not interfering 
with everyday activities 
MODERATE:  An event that is sufficiently discomforting to interfere with normal everyday activities 
SEVERE:  An event that prevents normal everyday activities 
Table 5: Classification of Adverse Events by Relationship to Study Drug 
UNRELATED:  This category applies to those AEs that are clearly and incontrovertibly due to 
extraneous causes (disease, environment, etc.). 
UNLIKELY:  This category applies to those AEs that are judged to be unrelated to the test drug, but 
for which no extraneous cause may be found.  An AE may be considered unlikely to be related to 
study drug if or when it meets 2 of the following criteria:  (1) it does not follow a reasonable temporal 
sequence from administration of the test drug; (2) it could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered to the patient; (3) 
it does not follow a known pattern of response to the test drug; or (4) it does not reappear or worsen 
when the drug is re-administered. 
POSSIBLY: This category applies to those AEs for which a connection with the test drug 
administration appears unlikely but cannot be ruled out with certainty.  An AE may be considered 
possibly related if or when it meets 2 of the following criteria: (1) it follows a reasonable temporal 
sequence from administration of the drug; (2) it could not readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered to the patient; or 
(3) it follows a known pattern of response to the test drug. 
PROBABLY: This category applies to those AEs that the investigator feels with a high degree of 
certainty are related to the test drug.  An AE may be considered probably related if or when it meets 3 
of the following criteria: (1) it follows a reasonable temporal sequence from administration of the drug; 
(2) it could not be reasonably explained by the known characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the patient; (3) it disappears 
or decreases on cessation or reduction in dose (note that there are exceptions when an AE does not 
disappear upon discontinuation of the drug, yet drug-relatedness clearly exists; for example, as in 
bone marrow depression, fixed drug eruptions, or tardive dyskinesia); or (4) it follows a known pattern 
of response to the test drug. 
DEFINITELY: This category applies to those AEs that the investigator feels are incontrovertibly 
related to test drug.  An AE may be assigned an attribution of definitely related if or when it meets all 
of the following criteria: (1) it follows a reasonable temporal sequence from administration of the drug; 
(2) it could not be reasonably explained by the known characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the patient; (3) it disappears 
or decreases on cessation or reduction in dose and recurs with re-exposure to drug (if rechallenge 
occurs); and (4) it follows a known pattern of response to the test drug. 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the event should be noted.  If the intensity category changes 
over a number of days, then those changes should be recorded separately (with 
distinct onset dates). 


 
 
 
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11.8.2 Serious Adverse Events 
An AE is considered “serious” if in the view of either the Investigator or Sponsor, it 
meets 1 or more of the following criteria:  
 Is fatal 
 Is life-threatening 
 Results in inpatient hospitalization or prolongation of existing hospitalization 
 Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 
 Is a congenital anomaly/birth defect 
Other important medical events that may not be immediately life-threatening or result 
in death or hospitalization, based upon appropriate medical judgment, are 
considered SAEs if they are thought to jeopardize the patient and/or require medical 
or surgical intervention to prevent one of the outcomes defining an SAE.  Since 
SAEs are critically important for the identification of significant safety problems, it is 
important to take into account both the Investigator’s and the Sponsor’s assessment.  
If either the Sponsor or the Investigator believes that an event is serious, the event 
must be considered serious and evaluated by the Sponsor for expedited reporting. 
SAE Reporting 
An SAE occurring during the study or within 2 weeks of stopping the treatment must 
be reported to the inVentiv Health Clinical Pharmacovigilance Group and will be 
communicated to the Sponsor.  Any such SAE due to any cause, whether or not 
related to the study drug, must be reported within 24 hours of occurrence or when 
the Investigator becomes aware of the event.  The investigator should report any 
SAE occurring after these time periods that is believed to be related to study drug or 


 
 
 
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protocol-specific procedures.  Notification can be made using the dedicated fax line 
or telephone line for the inVentiv Health Clinical Pharmacovigilance Group: 
inVentiv Health Clinical Pharmacovigilance Fax Number:  +44 1628 461184   
inVentiv Health Clinical Pharmacovigilance Telephone Number:  +44 1628 408408 
If the Investigator contacts the inVentiv Health Clinical Pharmacovigilance Group by 
telephone, then a written report must follow within 24 hours and is to include a full 
description of the event and sequelae in the format detailed in the SAE reporting 
form. 
The event must also be recorded on the standard AE eCRF.  Preliminary reports of 
SAEs must be followed by detailed descriptions later on, including clear and 
anonymized photocopies of hospital case reports, consultant reports, autopsy 
reports, and other documents when requested and applicable.  SAE reports must be 
made whether or not the Investigator considers the event to be related to the 
investigational drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response 
should be recorded.  Clinical, laboratory, and diagnostic measures should be 
employed as needed in order to determine the etiology of the problem.  The 
Investigator must report all additional follow-up evaluations to the inVentiv Health 
Clinical Pharmacovigilance Group within 10 calendar days.  All SAEs will be followed 
until the Investigator and Sponsor agree the event is satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the 
patient’s participation in the study is to be followed until it either resolves, stabilizes, 
returns to baseline values (if a baseline value is available), or is shown to not be 
attributable to the study drug or procedures. 
11.8.3 Pregnancy 


 
 
 
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Female patients of childbearing potential must have a negative pregnancy test at 
screening.  Following administration of study drug, any known cases of pregnancy in 
female patients will be reported until the patient completes or withdraws from the 
study.  The pregnancy will be reported immediately by phone and by faxing/emailing 
a completed Pregnancy Report to the Sponsor (or designee) within 24 hours of 
knowledge of the event.  The pregnancy will not be processed as an SAE; however, 
the Investigator will follow the patient until completion of the pregnancy and must 
assess the outcome in the shortest possible time but not more than 30 days after 
completion of the pregnancy.  The Investigator should notify the Sponsor (or 
designee) of the pregnancy outcome by submitting a follow-up Pregnancy Report.  If 
the outcome of the pregnancy meets the criteria for immediate classification of an 
SAE (eg, spontaneous or therapeutic abortion [any congenital anomaly detected in 
an aborted fetus is to be documented], stillbirth, neonatal death, or congenital 
anomaly), the Investigator will report the event by phone and by faxing a completed 
SAE form to the Sponsor (or designee) within 24 hours of knowledge of the event.   
11.8.4 Overdose 
The Investigator must immediately notify the Sponsor of any occurrence of overdose 
with study drug. 
12 STATISTICAL ANALYSIS 
A Statistical Analysis Plan (SAP) will be prepared after the protocol is approved.  
This document will provide further details regarding the definition of analysis 
variables and analysis methodology to address all study objectives.  The SAP 
supersedes the protocol’s analysis sections in case of differences. 
The statistical evaluation will be performed using Statistical Analysis Software (SAS®) 
Version 9.2 or higher (SAS Institute, Cary, NC).  All data will be listed, and summary 
tables will be provided.  Summary statistics will be presented by treatment group.  
For continuous variables, data will be summarized with the number of patients, 


 
 
 
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mean, standard deviation, median, minimum, and maximum by treatment group.  
For categorical variables, data will be tabulated with the number and percentage of 
patients for each category by treatment group. 
One interim analysis is planned. 
12.1 Determination of Sample size 
Simon’s randomized Phase 2 design was used.9  The average remission rate of 
placebo is approximately 0.2.9  With a type I error of 0.05, power of 0.8, and the 
difference in remission rates between the best treatment and the other treatments 
≥0.18, each arm requires 17 patients, giving the total number of patients to be 
enrolled as 51 
12.2 Analysis Populations 
Intent-to-treat Population 
The intent-to-treat (ITT) population will include all randomized patients who received 
at least one dose of study medication irrespective of any deviation from the protocol 
or premature discontinuation.  The treatment group assignment will be designated 
according to initial randomization.  The ITT population will serve as the basis for the 
analysis of efficacy. 
Per-protocol Population 
The per-protocol population is a subset of the intent-to-treat population.  The 
per-protocol population consists of all patients who do not violate the terms of the 
protocol in a way that would impact the study outcome significantly, as determined 
by the Medical Monitor who is blinded to study drug assignment.  All decisions to 
exclude patients from the per-protocol population dataset will be made prior to the 
unblinding of the study. 
Analyses using the per-protocol population may be provided as a sensitivity analysis. 


 
 
 
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Safety Population 
The safety population will include all randomized patients who receive at least 
1 dose of study drug.  The treatment group assignment in this population will be 
defined by the treatment actually received.  This population will be used for the 
analysis of safety.   
12.3 Demographic and Baseline Characteristics 
All data for background and demographic variables will be listed by treatment group 
and patient.  For these parameters, summary statistics will be provided by treatment 
group.  For continuous data, sample size, mean, standard deviation, minimum, 
median, and maximum will be provided and for categorical data, sample size and 
frequency will be provided. 
Relevant medical history, current medical conditions, results of laboratory screens, 
drug tests, and any other relevant information will be listed by treatment group and 
patient. 
12.4 Efficacy Analysis 
Detailed methodology for the statistical analyses, including details of the data 
summary tables and figures, will be documented in the SAP. 
12.4.1 Analysis of Efficacy Endpoints 
The primary analysis will utilize the ITT population, with non-responder imputation.  
A subject is considered a non-responder if no diary data is available within Day 36 to 
study end or endoscopy within Day 28 to study end.  Remission will be assessed, 
defined by a UCDAI score of ≤1, with a score of 0 for rectal bleeding and stool 
frequency, no mucosal friability, and ≥1 point reduction from baseline in the 
sigmoidoscopy score.  Proportion rates between groups will be summarized with 
95% confidence intervals included.  Treatment groups will be compared using 
analysis of variance (ANOVA).   


 
 
 
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As a supportive analysis, the primary analysis will also be done using the per 
protocol population.  Also, sensitivity analysis to assess the effects of missing data 
may be performed. 
Secondary endpoints corresponding to remission or improvement will be analyzed in 
a manner similar to the primary endpoint.  No adjustments for multiplicity will be 
made. 
Secondary safety endpoints will be listed and summarized by treatment group. 
12.5 Safety Analysis 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities, 
Version 18.0.  The incidence of TEAEs will be summarized.  Events with missing 
onset dates will be included as treatment-emergent.  If a patient experiences more 
than 1 occurrence of the same AE, the occurrence with the greatest severity and the 
closest association with the study drug will be used in the summary tables.  SAEs 
and AEs causing discontinuation will be tabulated.  All AEs will be listed by patient, 
along with information regarding onset, duration, severity, and relationship to study 
drug, action taken with study drug, treatment of event, and outcome. 
Clinical laboratory data and vital signs will be summarized using descriptive statistics 
including mean values and mean change from baseline values, as well as numbers 
of patients with values outside limits of the normal range at each time point. 
Summary tables will be provided for concomitant medications initiated during the 
study period.   
12.6 Interim Analysis 
One interim analysis for the purpose of safety and futility will be conducted after 50% 
of patients have completed the study.  If voluntary withdrawal due to safety and/or 
tolerability exceeds 30% in either of the 2 active treatment groups, then no additional 


 
 
 
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patients will be enrolled into that group.  No further study drug will be administered in 
this group, but patients will be continued to be monitored for safety.  An unblinded 
statistician independent of the blinded study team, for whom firewalls will be 
established and well documented, will be assigned within inVentiv Health 
Biostatistics department to perform this analysis. 
This unblinded statistician will also review accumulated safety data at regular 
intervals throughout the study.  The unblinded statistician will confer with inVentiv 
Pharmacovigilence, as appropriate.  The unblinded statistician can recommend in 
writing to the Sponsor whether to continue, modify, or stop the clinical study on the 
basis of efficacy and safety considerations.  The unblinded statistician’s specific 
duties and specific information regarding interim analyses will be fully described in 
the SAP. 
13 STUDY MANAGEMENT 
13.1 Approval and Consent 
13.1.1 Regulatory Guidelines 
This study will be performed in accordance with ethical principles that have their 
origin in the Declaration of Helsinki and conducted in adherence to the study 
protocol, Good Clinical Practices (GCPs) as defined in Title 21 of the US CFR Parts 
50, 54 56, 312, and Part 11, as well as International Conference on Harmonisation 
(ICH) GCP consolidated guidelines (E6) and applicable regulatory requirements. 
13.1.2 Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted Independent 
Ethics Committee (IEC).  Approval is required for the study protocol, investigational 
drug brochure, protocol amendments, Informed Consent Forms (ICFs), and patient 
information sheets.   
13.1.3 Informed Consent  


 
 
 
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For each study patient, written informed consent will be obtained prior to any 
protocol-related activities.  As part of this procedure, the Investigator or one of 
his/her associates must explain orally and in writing the nature, duration, and 
purpose of the study, and the action of the drug in such a manner that the patient is 
aware of the potential risks, inconveniences, or adverse effects that may occur.  The 
patient should be informed that he/she may withdraw from the study at any time, and 
the patient will receive all information that is required by local regulations and ICH 
guidelines.  The Investigator will provide the Sponsor or its representative with a 
copy of the IEC-approved ICF prior to the start of the study. 
13.2 Data Handling  
Any data to be recorded directly on the eCRFs (to be considered as source data) will 
be identified at the start of the study.  Data reported on the eCRF that are derived 
from other source documents should be consistent with the source documents, or 
the discrepancies must be explained. 
Clinical data will be entered on eCRFs for transmission to the Sponsor.  Data on 
eCRFs transmitted via the web-based data system must correspond to and be 
supported by source documentation maintained at the study site, unless the study 
site makes direct data entry to the databases for which no other original or source 
documentation is maintained.  In such cases, the study site should document which 
eCRFs are subject to direct data entry and should have in place procedures to 
obtain and retain copies of the information submitted by direct data entry.  All study 
forms and records transmitted to the Sponsor must carry only coded identifiers such 
that personally identifying information is not transmitted.  The primary method of 
data transmittal is via the secure, Internet-based electronic data capture (EDC) 
system maintained by inVentiv Health Clinical.  Access to the EDC system is 
available to authorized users via the study’s Internet web site, where an assigned 
username and password are required for access.   


 
 
 
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Any changes made to data after collection will be made through the use of Data 
Clarification Forms (DCFs).  eCRFs will be considered complete when all missing 
and/or incorrect data have been resolved.   
13.3 Source Documents 
Source documents are considered to be all information in original records and 
certified copies of original records of clinical findings, observations, data, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the 
study. 
13.4 Record Retention 
Study records and source documents must be preserved for at least 15 years after 
the completion or discontinuation of/withdrawal from the study or 2 years after the 
last approval of a marketing application in an ICH region, whichever is the longer 
time period. 
The investigator agrees to comply with all applicable federal, state, and local laws 
and regulations relating to the privacy of patient health information, 
13.5 Monitoring 
The study will be monitored to ensure that it is conducted and documented properly 
according to the protocol, GCP, and all applicable regulatory requirements.   
On-site monitoring visits will be made at appropriate times during the study.  Clinical 
monitors must have direct access to source documentation in order to check the 
completeness, clarity, and consistency of the data recorded in the eCRFs for 
each patient.   
The Investigator will make available to the clinical monitor source documents and 
medical records necessary to complete eCRFs.  In addition, the Investigator will 
work closely with the clinical monitor and, as needed, provide them appropriate 


 
 
 
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evidence that the conduct of the study is being done in accordance with applicable 
regulations and GCP guidelines.   
13.6 Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control 
activities of this study; however, responsibility for the accuracy, completeness, and 
reliability of the study data presented to the Sponsor lies with the Investigator 
generating the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance 
to ensure that the study is being conducted in compliance with the protocol, standard 
operating procedures, GCP, and all applicable regulatory requirements.  Audits will 
be independent of and separate from the routine monitoring and quality control 
functions.  Quality assurance procedures will be performed at study sites and during 
data management to assure that safety and efficacy data are adequate and well 
documented.   
13.7 Protocol Amendment and Protocol Deviation  
13.7.1 Protocol Amendment 
Amendments to the protocol that entail corrections of typographical errors, 
clarifications of confusing wording, changes in study personnel, and minor 
modifications that have no impact on the safety of patients or the conduct of the 
study will be classed as administrative amendments and will be submitted to the IEC 
for information only.  The Sponsor will ensure that acknowledgement is received and 
filed.  Amendments that are classed as substantial amendments must be submitted 
to the appropriate Regulatory Authorities and the IECs for approval. 
13.7.2 Protocol Deviations 
Should a protocol deviation occur, the Sponsor must be informed as soon as 
possible.  Protocol deviations and the reasons they occurred will be included in the 


 
 
 
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clinical study report.  Reporting of protocol deviations to the IEC and in accordance 
with applicable Regulatory Authority mandates is an Investigator responsibility. 
13.8 Ethical Considerations 
This study will be conducted in accordance with the accepted version of the 
Declaration of Helsinki and/or all relevant federal and local regulations. 
All patients are required to give written informed consent prior to participation in the 
study.   
13.9 Financing and Insurance 
Prior to the study commencing, the Sponsor (or its designee) and the Investigator (or 
the institution, as applicable) will agree on costs necessary to perform the study.  
This agreement will be documented in a financial agreement that will be signed by 
the Investigator (or the institution signatory) and the Sponsor (or its designee).   
The Investigator is required to have adequate current insurance to cover claims for 
negligence and/or malpractice.  The Sponsor will provide insurance coverage for the 
clinical study as required by national regulations. 
13.10 Publication Policy / Disclosure of Data  
Both the use of data and the publication policy are detailed within the clinical study 
agreement.  Intellectual property rights (and related matters) generated by the 
Investigator and others performing the clinical study will be subject to the terms of a 
clinical study agreement that will be agreed between the Institution and the Sponsor 
or their designee.  With respect to such rights, the Sponsor or its designee will solely 
own all rights and interests in any materials, data, and intellectual property rights 
developed by Investigators and others performing the clinical study described in this 
protocol, subject to the terms of any such agreement.  In order to facilitate such 
ownership, Investigators will be required to assign all such inventions either to their 


 
 
 
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Institution or directly to the Sponsor or its designee, as will be set forth in the clinical 
study agreement. 
 
 


 
 
 
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14 REFERENCES 
 
1. 
Guideline on the development of new medicinal products for the treatment of 
ulcerative colitis, European Medicines Agency, Committee for Medicinal 
Products for Human Use, Document Reference CHMP/EWP/18463/2006, 
January 2008.   
2. 
Delzicol® (mesalamine delayed-release capsule), Prescribing Information. 
Version revised February 2013. Available online at: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm  
3. 
Cada DJ, Baker DE, Levien T. Mesalamine. Formulary Drug Reviews, June 
2007;42:543-552. 
4. 
Investigator’s Brochure, IBD98-M Delayed-release Capsules. Holy Stone 
Healthcare Co., Ltd. Edition Final 5.0, released 09 February 2015. 
5. 
Vantrappen G, Geboes K. Glycosaminoglycans and the gut. Lancet. 
1993;341:730-731. 
6. 
Head KA, Jurenka JS. Inflammatory bowel disease Part 1: ulcerative colitis--
pathophysiology and conventional and alternative treatment options. Altern Med 
Rev. 2003;8:247-283. 
7. 
Murch SH, MacDonald TT, Walker-Smith JA, Levin M, Lionetti P, Klein NJ. 
Disruption of sulphated glycosaminoglycans in intestinal inflammation. Lancet. 
1993;341:711-714. 
8. 
Soldati D, Rahm F, Pasche P. Mucosal wound healing after nasal surgery. A 
controlled clinical trial on the efficacy of hyaluronic acid containing cream. Drugs 
Exp Clin Res. 1999;25:253-261. 


 
 
 
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9. 
Su C. Outcomes of placebo therapy in inflammatory bowel disease. Inflamm 
Bowel Dis. 2006;12(4):328-333. 
10. Sutherland LR, Martin F, Greer S, et al. 5-Aminosalicylic acid enema in the 
treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. 
Gastroenterology. 1987;92:1894–1898. 
 
 
 
 


 
 
 
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15 APPENDICES 
APPENDIX 1 Modified Ulcerative Colitis-Disease Activity Index Scoring System 
 
 
 
Note: Modified from Sutherland et al.  (mucosal friability moved from a score of 1 to 2)
10 


 
 
 
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APPENDIX 2 LABORATORY ABNORMALITY CRITERIA  
Criteria for assessing marked abnormalities in safety laboratory parameters are 
based on Grade 2 moderate intensity levels from the Division of AIDS table for 
grading the severity of adult and pediatric adverse events (Version 1.0, December, 
2004; Clarification August 2009). 
Marked Abnormality Criteria for Safety Laboratory Parameters 
Parameter 
Units 
Direction of
Change 
Marked Abnormalities 
HEMATOLOGY 
 
 
 
Hemoglobin 
g/dL 
Low Only 
≤ 7.0 g/dL 
Absolute Lymphocyte 
Count 
109 
Low Only 
<0.5 X109 
Leukocytes 
mm3 
Low Only 
Absolute Value < 2,000/ mm3 
Platelets 
mm3 
Low Only 
<75,000/ mm3 
Absolute Neutrophil 
Count 
mm3 
Low Only 
<1000 mm3 
 
 
 
 
Prothrombin Time 
% 
High Only
>1.25 x ULN 
 
 
 
 
CHEMISTRY 
 
 
 
SGPT 
ULN 
High Only
>3.0 x ULN 
SGOT 
ULN 
High Only
>3.0 x ULN 
Bilirubin 
ULN 
High Only
>2.0 x ULN 


 
 
 
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APPENDIX 3 Inflammatory Bowel Disease Questionnaire (IBDQ) 


 
 
 
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APPENDIX 4 36-Item Short-Form Questionnaire (SF-36)


 
 
 
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