Clinical trial NCT03675477
Conditions: Ulcerative Colitis
Sponsor: Reistone Biopharma Company Limited
Start date: 2019-04-13; Completion date: 2021-02-03
Enrollment: 164 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The proposed study is a randomized, double-blind,placebo-controlled, multicenter phase II study to investigate the safety and efficacy of SHR0302 in patients with moderate to severe active ulcerative colitis. The study aims to evaluate the optimal dose of SHR0302 and time needed to induce clinical response in active ulcerative colitis patients.

This is an 8+8 weeks study, in which participants who complete the first 8 weeks treatment phase, will have the option to enter a blinded active arms 8-week extension phase. Early withdrawn subjects during the first treatment phase can not enter the extension phase. The total duration of the study participation, including extension and follow-up, will be approximately 18 weeks.

SHR0302 is a Janus kinase 1(JAK1) inhibitor, capable of blocking Janus kinase-signal transducer and activator of transcription (JAK-STATs) pathway and controlling inflammation. Therefore it has the potential to be a treatment for ulcerative colitis.

Detailed description:

Arms: arm 1: Participants randomized in this arm will receive SHR0302 8mg QD for the treatment phase. All participants that had completed the 8-week treatment phase (non-responders or responders) had the option to enter a blinded 8-week extension phase to continue to receive SHR0302 8mg QD.

Those who had completed the first 8-week of the treatment phase, but decided not to enter into the extension phase were also required to attend the 2-week follow-up visit. Participants who immaturely withdrew during the first treatment phase could not enter the extension phase.

SHR0302: The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a JAK inhibitor). arm 2: Participants randomized in this arm will receive SHR0302 4mg BD for the treatment phase. All participants that had completed the 8-week treatment phase (non-responders or responders) had the option to enter a blinded 8-week extension phase to continue to receive SHR0302 4mg BD.

Those who had completed the first 8-week of the treatment phase, but decided not to enter into the extension phase were also required to attend the 2-week follow-up visit. Participants who immaturely withdrew during the first treatment phase could not enter the extension phase.

SHR0302: The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a JAK inhibitor). arm 3: Participants randomized in this arm will receive SHR0302 4mg QD for the treatment phase. All participants that had completed the 8-week treatment phase (non-responders or responders) had the option to enter a blinded 8-week extension phase to continue to receive SHR0302 4mg QD.

Those who had completed the first 8-week of the treatment phase, but decided not to enter into the extension phase were also required to attend the 2-week follow-up visit. Participants who immaturely withdrew during the first treatment phase could not enter the extension phase.

SHR0302: The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a JAK inhibitor). arm 4: Participants randomized in this arm will receive the placebo until week 8, and then will be re-randomized into one of the 3 active arms ( 4mg QD, 4mg BD, 8mg QD of SHR0302) in a 1:1:1 allocation ratio until the end of the study at week 16.

Those who had completed the first 8-week of the treatment phase, but decided not to enter into the extension phase were also required to attend the 2-week follow-up visit. Participants who immaturely withdrew during the first treatment phase could not enter the extension phase.

SHR0302: The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a JAK inhibitor).

Placebos: Placebo Oral Tablet
Interventions: intervention 1: SHR0302 intervention 2: Placebo
Intervention descriptions: intervention 1: The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a Janus kinase inhibitor). intervention 2: Placebo Oral Tablet

Protocol documents:
Prot_000.pdf: 
Reistone Biopharma 
Confidential 
RSJ10101 
v3.1 20AUG2020 
Page 1  of 105 
 
 
 
 
 
 
 
 
 
 
 
TITLE: A Phase II randomized, placebo controlled, double-blind, 4 arms dose-ranging study to 
evaluate the efficacy and safety of SHR0302 compared to placebo in patients with moderate to 
severe active Ulcerative Colitis. 
 
 
 
 
 
 
 
 
Compound Number   : SHR0302 
Compound Name 
: 
Protocol number 
: RSJ10101 
Version Number 
: v3.1   20AUG 2020 
IND Number 
: 140183 
Effective Date 
: -20-AUG-2020 
NCT number  
: NCT03675477 
EudraCT 
: 2018-003364-31 
Protocol Amendment Number: 03 
Author (s) 
: Aik Goh, Min Irwin, Robert Ma, Tao Zhang, Yanfei Tai, Lan Liu, 
Yingxue Cathy Liu 


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v3.1 20AUG2020 
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Rivision History 
 
Version Number 
Version Date 
Summary of Changes 
v1.1 12NOV2018 
12NOV2018 
Original Protocol 
v2.0 16APR 2019 
16APR 2019 
Amendment No.01 
Number the inclusion and exclusion criteria. 
Refine the Chinese translation of “……and allow 
central over read turn over before randomization” as 
inclusion criteria to clarify the central reading result for 
endoscopy need to be ready before randomization. 
Clarify subjects who had inadequate response, loss of 
response or intolerance to conventional treatment 
(immune-suppressants or corticoserioids) could be 
included, whether the subjects previoulsy exposed to 
biological therapy or not. 
Clarify the definition of treatment naïve subjects in 
exclusion criteria. Correct the typos to claify the 
exclusion criteria for biological therapy use, “subjects 
receiving interferon therapy within 12 weeks prior to 
baseline and anti-TNFα therapy/other biological 
therapies within 12 weeks prior to baseline” will be 
excluded, instead of 8 weeks, in order to keep 
consistency with Section 5.2 Inclusion Criteria. Clarify 
subjects with hematopoietic disorders at screening 
should be excluded. 
Correct the typos in Table 1 in Section 5.12 Time and 
Event Table, and the footnotes to ensure the procedures 
are consistent with subject selection criteria. Clarify 
chext X-ray to be performed if no chest X-ray or CT 
scan available within 3 months of Visit 1 instead of 6 
months in footnote 2. Typo correction to clarify the 
follow up visit is not a phone-call contact and clarify 
any SAEs will be recorded from the time of consent in 
footnote 7. Allow T-Spot as an alternative test for TB 
infection screening. Clarify only serum β-Human 
Chorionic Gonadotrophin (β-HCG) is requested for 
pregnancy testing at screening visit and urine test is to 
be done from baseline. Clarify concurrent medication 
assessment should be done in Follow up/EW visit, in 
order to keep consistent with Section 6.6 Concomitant 
Medications. Clarify the early withdrawal visit should 


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Version Number 
Version Date 
Summary of Changes 
be done within 2 weeks after last dose/decision of 
withdrawal rather than after 2 weeks of last 
dose/decision of withdrawal in footnote 11. FSH test is 
listed in the table to confirm postmenopausal status at 
screening. 
Provide oral steroids tapering guidance in Section 6.6.1 
Permitted Concomitant Medications and refine the 
Chinese translation of oral steroids permission 
Remove the time period of “within baseline”, to clarify 
the prohibition is throughout the duration of the study to 
avoid confusion in Section 6.6.2 Prohibited 
Medications. And add live vaccines immunization as 
prohibited mdications. 
Clarify that the images/video clips of endoscopy will be 
sent to central lab for central reading in Section 7.2.5 
Mayo Score Assessment. 
Refine the Chinese translation of the intervals of 3 
ECGs in Section 7.3.2, to clarify “Triplicate ECG 
measurements are collected at rate of 3 ECGs with 5 
minutes between each.”. 
Allow T-Spot test as an alternative test for TB infection 
screening according to local availability in Section 7.3.4 
QuantiFERON test/or T-Spot test. And provide the 
guidance on initial QFT-G/or T-Spot is indeterminate. 
Correct typos in Table 3 in Section 7.3.5 Clinical 
Laboratory Testing. 
Update the reference. 
v3.0 30JUL2019 
30JUL 2019 
Amendment No.02 
Update Section 4.1 Study Design, Section 4.2 
Discussion of the design and Section 5.12 Time and 
Event Table, to revise the screening period to  -28 days 
to -1 day prior to baseline, based on the feasibility of the 
clinical procedure in each country. 
Update Section 5.2 Inclusion Criteria, to clarify the 
subjects deemed by the treating physician as having 


v3.1 20AUG2020 
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Version Number 
Version Date 
Summary of Changes 
inadequate response, loss of response or intolerance to 
the conventional treatment include subjects with 
previous exposed to oral 5-ASA only. Clarify oral 
corticosteroids as permitted medications during study 
treatment is not applicable to subjects with previous 5- 
ASA treatment only. List the detailed discontinuation 
time prior to baseline of the biological treatment 
according to its half life. 
Clarify the definition of treatment naïve patients 
according clinical practice in the Section 5.3 Exclusion 
Criteria. Update the discontinuation time prior to 
baseline of interferon therapy to 8 weeks. In conjunction 
to the inclusion criteria regarding the requirement of 
discontinuation of biologicals, remove related 
requirement in exclusion criteria. Clarify the subjects 
with clinically significant infections or within 1 month 
of baseline instead of 6 months, will be excluded. 
Remove the requirement regarding to household contact 
with vaccinated individuals during study in exclusion 
criteria. 
Update Section 6.6.1 Permitted Concomitant 
Medications, clarify dose of steroids can be reduced at 
the discretion of the investigator if subject develops 
intolerance or significant saftey concerns to the oral 
steroids dose during the treatment phase. 
Update Section 7.3.10 Pregnancy, clarify the pregnancy 
occurs after first dose must be reported and the newborn 
should be followed up to 1 month after birth as 
pregnancy outcome. 
v3.1 20AUG2020 
20AUG2020 
Update safety related features according to the FDA’s 
recommendation. This includes safety related 
inclusion/exclusion criteria in Section 5.2, subject 
stopping criteria in Section 5.9, Adverse Event of 
Special Interest (AESI) in Section 7.3.15. These are to 
protect subject safety according to the new safety advice 
by the FDA. 


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Reistone Biopharma 
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Reistone Biopharma Company Limited 
298, Xiangke Road, 
2/F, 203, Zhangjiang High-tech Park, 
Pudong, 201210, Shanghai, China 
Contact Telephone: 00 86 (0)21-6092 7289 
 
Sponsor Medical Monitor 
Dr. Bei Zhang, MD 
Medical Monitor 
Reistone Biopharma Company Limited 
298, Xiangke Road, 
2/F, 203, Zhangjiang High-tech Park, 
Pudong, 201210, Shanghai, China 
Contact Telephone: 00 86 (0)21-6092 7289 
 
Dr. Alex Sun, MD 
Medical Monitor 
Reistone Biopharma Company Limited 
298, Xiangke Road, 
2/F, 203, Zhangjiang High-tech Park, 
Pudong, 201210, Shanghai, China 
Contact Telephone: 00 86 (0)21-6092 7289 
 
Back-up Medical Monitor. 
Dr. Aik Goh, MD 
Medical Monitor 
Reistone Biopharma Company Limited 
298, Xiangke Road, 
2/F, 203, Zhangjiang High-tech Park, 
Pudong, 201210, Shanghai, China 
Contact Telephone: 00 86 (0)21-6092 7289 
 
SAE reporting line 24hr: 
Country 
Toll-Free-Fax-No 
Toll-Free Phone-No 
Ukraine 
000-11  Pause 8778409626 
000-11 Pause 877-772-3834 
United States 
855-638-1674 
855 564-2229 
Poland 
00-800-1212045 
00-800-1212044 
China 
4001-202369 
10-800-712-2867 
10-800-120-2867 
Sponsor Signatory 
 
Date   
 
 
   


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Project Physician 


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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
Protocol RSJ10101 
I confirm agreement to conduct the study in compliance with the protocol. 
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or 
supervise the described clinical study. 
I agree to ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations. Mechanisms are in place to ensure that site staff 
receives the appropriate information throughout the study. 
 
 
 
Investigator Name:    
 
Investigator Signature 
Date 


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Table of Contents 
 
LIST OF ABBREVIATIONS  
12 
1. 
Protocol Summary  
13 
1.1 Rationale  
13 
1.2 
Objectives  
14 
1.3 Study Design  
14 
1.4 Study Endpoints  
15 
1.4.1 Primary Efficacy Endpoint  
15 
1.4.2 Secondary Efficacy Endpoints  
16 
1.4.3 Safety Endpoints  
16 
2. Introduction  
16 
2.1 Background  
16 
2.2 Rationale  
17 
2.3 Dose Selection Rationale  
18 
2.4 Risk: Benefit Assessment  
19 
3. Objectives  
20 
3.1 Primary Objectives  
20 
3.2 Secondary Objectives  
20 
4. Investigational Plan  
20 
4.1 Study Design  
20 
4.2 Discussion of the design  
21 
5. Subject Selection and Withdrawal Criteria  
21 
5.1 Number of subjects  
22 
5.2 Inclusion Criteria  
22 
5.3 Exclusion Criteria  
23 
5.4 Contraception advice  
26 
5.4.1 Women of Non‐Childbearing Potential  
26 
5.4.2 Women of Childbearing Potential  
26 
5.4.3 Pregnancy Testing  
27 
5.4.4 Males  
27 
5.5 Randomization Criteria  
27 
5.6 Withdrawal Criteria  
28 
5.7 Pre-Screen and Screen Failure  
29 
5.8 Early Withdrawal  
29 


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5.9 Stopping Criteria  
30 
5.10 Premature Study Termination  
31 
5.11 Safety Review Committee (SRC)  
32 
5.12 Time and Event Table  
33 
6. Study Treatments  
36 
6.1 Investigational Product/Placebo Supply  
36 
6.1.1 Study Drug Dispensing  
36 
6.1.2 Study Drug Administration  
36 
6.2 Treatment Assignment  
37 
6.3 Blinding  
37 
6.4 Drug Storage and Accountability  
38 
6.5 Treatment Compliance  
38 
6.6 Concomitant Medications  
39 
6.6.1 Permitted Concomitant Medications  
39 
6.6.2 Prohibited Medications  
40 
6.6.3 Traditional Chinese and Herbal Medicines  
40 
6.7 Treatment after study completion  
40 
6.8 Study Drug Overdose Management  
40 
7. Study Assessments and Procedures  
41 
7.1 Critical Baseline Assessments  
41 
7.2 Efficacy Endpoints Assessments  
41 
7.2.1 Primary Efficacy Endpoints  
41 
7.2.2 Secondary Efficacy Endpoints  
41 
7.2.3 Safety Endpoints  
42 
7.2.4 Patient Diary Assessment  
42 
7.2.5 Mayo Score Assessment  
43 
7.2.6 9-point Modified Mayo Score  
43 
7.2.7 Partial Mayo Score Assessments  
44 
7.2.8 Colonoscopy  
44 
7.3 Safety Assessment  
44 
7.3.1 Vital Signs  
44 
7.3.2 12 lead ECG  
44 
7.3.3 Tuberculin Test (PPD)  
45 
7.3.4 QuantiFERON test/or T-Spot test  
45 


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7.3.5 Clinical Laboratory Testing  
45 
7.3.6 C-Reactive Protein (CRP)  
47 
7.3.7 Fecal Calprotectin  
48 
7.3.8 Lipid Profile Testing  
48 
7.3.9 Liver Chemistry – Stopping and Follow-up Criteria  
48 
7.3.10 Pregnancy  
51 
7.3.11 Adverse Events  
52 
7.3.12 Definition of AE  
52 
7.3.13 Definition of SAE  
53 
7.3.14 AE and SAE reporting requirement and timeline  
54 
7.4 Pharmacokinetics  
55 
8. Data Management  
56 
9. Data Analysis and Statistical Considerations  
56 
9.1 Hypothesis  
56 
9.2 Study Design Considerations  
57 
9.2.1 Sample Size Assumptions  
57 
9.3 Data Analysis Considerations  
58 
9.3.1 Analysis Dataset  
58 
9.3.2 Treatment Comparison of interest: Primary and others  
58 
9.3.3 Interim Analysis  
58 
9.3.4 Key Elements of Analysis Plan  
58 
10. Study Conduct Considerations  
61 
10.1 Regulatory and Ethical Consideration to GCP standard  
61 
10.2 Institutional Review Board (IRB)/Independent Ethics Committee (IEC)  
61 
10.3 Informed Consent Process  
62 
10.4 Study Monitoring and Quality Control  
62 
10.5 Study Site Closure  
62 
10.6 Record Retention  
63 
10.7 Independent Data Monitoring Committee (IDMC)  
63 
10.8 Provision of study results to Investigators, posting to the Clinical Trial Registry and 
Publication.  
63 
11. Reference  
64 
12. 
Appendices  
65 
Appendix 1 Mayo Scoring System for Assessment of Ulcerative Colitis Activity*  
65 
Appendix 2 Cockcroft-Gault Calculation  
67 


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Appendix 3 ECG Exclusion criteria  
68 
Appendix 4 Prohibited Concomitant Medications  
70 
Protocol Amendment No.01  
72 


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LIST OF ABBREVIATIONS 
 
 
AUC 
Area Under the Curve 
AV 
Atrioventricular 
CD 
Crohn’s Disease 
β-hCG 
Beta-human Chorionic Gonadotropin 
CI 
Confidence Interval 
Cmax 
Maximal Plasma Concentration 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
EW 
Early Withdrawal 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
FSH 
Follicle Stimulating Hormone 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
IB 
Investigator’s Brochure 
JAK 
Janus Kinase 
IBDQ 
Inflammatory Bowel Disease Questionnaires 
IEC 
Independent Ethics Committee 
IgM 
Immunoglobulin M 
IND 
Investigational New Drug 
IRB 
Independent Review Board 
ITT 
Intent-to-Treat 
IVRS 
Interactive Voice Response System 
IUD 
Intra-Uterine Device 
LDH 
Lactate Dehydrogenase 
LLoQ 
Lower Limit of Quantification 
Mcg 
Micrograms 
MedRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PPD 
Purified Protein Derivatives 
RA 
RAP 
Rheumatoid Arthritis 
Reporting and Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SPM 
Study Procedures Manual 
SRC 
Tlast 
Safety Review Committee 
Time of the Last Quantifiable Concentration 
UC 
Ulcerative Colitis 


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ULN 
Upper Limit of Normal 
 
 
 
1. Protocol Summary 
1.1 Rationale 
 
Ulcerative Colitis (UC) is a debilitating disease resulting in high morbidity and severely 
affect patients’ quality of life. Patients with UC will experience periods of remission and flare 
up. It is a disease affecting the colon, characterized by altered bowel habit, bloody diarrhea, 
abdominal pain, weight loss and anaemia. The prevalence of UC is about 200/100,000 in the 
west compared to 50-60/100,000 in China or Japan. Its incidence has been higher in the West 
compared to the East. However, over the last decade, the prevalence has increased in the East. 
(1) The cause of UC remains unknown; it is thought to be closely linked to autoimmunity to 
large bowel mucosal. (2) UC can develop at any age, but peak incidence is between the ages of 
20 and 30 years. It mainly affects the rectum, and a variable extent of the colon proximal to the 
rectum. Inflammation of the rectum is referred to as proctitis, and inflammation of the rectum 
and sigmoid as proctosigmoiditis. Symptoms of active disease or relapse include bloody 
diarrhoea, an urgent need to defaecate and abdominal pain. 
 
Currently the only way to “cure” the disease is by total colectomy which is not without its 
risk and complication. The treatment goal in UC is to induce response in those in active stage 
and to continue maintaining remission, ultimately ensuring patients have minimal symptoms and 
good quality of life. Over many decades, these were achieved by applying oral and intravenous 
immune-suppressants. Conventional immune-suppressants treatments include oral 
glucocorticoids, mesalamine, and methotrexate. The introduction of biological treatment nearly 
two decades ago such as, anti-TNFα, a IgG monoclonal antibody has changed the treatment 
paradigm for moderate to severe UC over the last decide and has now become a gold standard. 
However, its use is still limited by its cost in some regions. 
 
The understanding of cytokines and intracellular messenger pathway in UC has led to the 
discovery of Janus Kinase (JAK) enzymes, and their role in the activation of Signal Transducers 
and Activators of Transcription (STATs) via auto phosphorylation (3). The JAK-STATs pathway 
regulates the signaling of various interferon and interleukin which are implicated in the 
pathogenesis of UC. By blocking this pathway, it is thought that this immune-regulated 
inflammation could be halted, hence controlling the disease (4). 
 
There are a number of Janus kinase (JAK) inhibitors currently under investigation for the 
treatments of immune-induced diseases, such as Rheumatoid Arthritis (RA), Psoriatic Arthritis, 
Psoriasis, Ulcerative Colitis, Crohn’s Disease, and Ankylosing Spondylitis. These JAK inhibitors 
can be given orally, which could be an advantage compared to the intravenously given biological 
treatments. There is also an advantage of not having the risk of developing loss of response due 
to immunogenicity. 


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Tofacitinib, a ‘pan-JAK inhibitor’, blocking JAK3 and JAK1 and to a lesser extent JAK2 
has been approved in the US for the treatment of RA. It has recently been approved for the 
treatment of Ulcerative Colitis in the US. Other JAK inhibitors with varying JAK selectivity 
profiles have already shown to be efficacious in RA, and some are under investigation for 
Ulcerative Colitis and Crohn’s Disease indication. While inhibition of JAK1 and JAK3 
contributed to the efficacy of RA treatment, inhibition of JAK2 may contribute to the safety 
concerns of anemia, and thrombocytopenia, by interfering with signaling through erythropoietin, 
thrombopoietin and colony-stimulating factors such as granulocytemacrophage colony- 
stimulating factor (5). 
 
SHR0302 is a highly selective JAK1 inhibitor. An in vitro study has demonstrated that its 
selectivity to JAK1 compared to JAK2 is about 16 times more than tofacitinib, and baricitinib, 
while 10 times more than filgotinib. In an animal model study, SHR0302 significantly attenuated 
gross bleeding and stool consistency while also relieved body weight loss in DSS-induced Colitis 
mice. Meanwhile the study has also demonstrated SHR0302’s ability in reducing colon 
inflammation score by reducing crypt score and inflammation score in these mice to the extent 
comparable to tofacitinib, an active comparator. These in vitro and animal studies have 
demonstrated the potential efficacy of SHR0302 in addressing colon inflammation, hence the 
potential for the treatment of IBD. The high selectivity of SHR0302 to JAK1 also makes it a 
favourable candidate from a benefit risk safety perspective (6). 
 
1.2Objectives 
 
The primary objective is to evaluate the efficacy of SHR0302 at 4mg once daily (QD), 8mg 
QD, and 4mg twice daily (BD) given orally compared to placebo in inducing clinical response in 
adult subjects with moderate to severe active Ulcerative Colitis at 8-week. 
 
 
1.3 Study Design 
 
This is an 8+8 weeks, randomized, double-blind, multi-center, placebo controlled, parallel 
group study to include adult patients with moderate to severe active Ulcerative Colitis. The study 
consists of an 8-week blinded treatment phase, followed by 8-week of blinded active arms 
extension phase. The primary endpoint is assessed at the end of treatment phase at week 8. 
 
Eligible subjects will be randomized to either one of the 3 doses of active drugs or placebo 
in 1:1:1:1 ratio for 4mg QD, 4mg BD, 8mg QD and placebo group respectively for treatment 
phase. The total number of subjects to be randomized is 152. There will be a total of 9 outpatient 
clinic visits. Subjects randomized into placebo in treatment phase will also have a pre-assigned 
randomized treatment sequence for extension phase, which are 3 active groups (placebo -> 4mg 
QD, placebo -> 4mg BD, and placebo -> 8mg QD) in a 1:1:1 ratio. Subjects randomized to the 
active arms for treatment phase will remain in the same dose group in the extension phase. 


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At Visit 1 (screening), subject will be screened and if the subject meets the 
inclusion/exclusion criteria, the subject can be consented and enrolled into the study with a 
subject identifier number. 
 
At Visit 2 (Day 0), subject will be randomized into the study if there is no further change to 
subject’s criteria. 
 
After randomization, the subject will be followed-up at week 1, week 4, and week 8, 
corresponding to Visit 3, Visit 4, and Visit 5 at treatment phase respectively. At Visit 5 (week 8) 
the primary endpoint assessment will be conducted. Following this treatment phase, subjects 
have the option to enroll into a further 8 weeks of active arms extension phase. 
 
All subjects that have completed the initial 8 weeks (non-responders or responders) have the 
option to enter a blinded active arm 8-week extension phase according to the group they were 
randomized to for extension phase. All subjects have the option not enrolling into the extension 
phase after first 8 weeks of treatment. All subjects in the extension phase are followed-up for 
further 2 weeks until week 18 (last visit). Subjects who have completed the first 8-week of 
treatment phase, but decided not entering into extension phase are required to attend the 2-week 
follow-up visit. Early withdrawn subjects during the first treatment phase cannot enter the 
extension phase. 
 
The total duration of the study participation, including extension and follow-up, will be 
approximately 18 weeks. 
 
1.4 Study Endpoints 
 
1.4.1 Primary Efficacy Endpoint 
 
The percentage of subjects that achieve clinical response at week 8, defined as decrease 
from baseline in 9-point modified Mayo score of at least 2 points and at least 30%, with an 
accompanying decrease in the subscore for rectal bleeding of at least 1 point or absolute subscore 
for rectal bleeding of 0 or 1. 
 
(Mayo Score is a scoring system designed to measure UC disease activity. It consists of 4 
subscore, stool frequency, rectal bleeding, endoscopy score - findings of centrally read 
colonoscopy, and physician global assessment (PGA). Each graded from 0 to 3 with higher 
scores indicating more severe disease. These scores are summed up to give a total score from 0 
to 12, where higher score indicate more severe disease. 
 
9-point modified Mayo score is the Mayo score excluding physician global assessment 
(PGA)subscore, hence the maximum is 9 points and minimum 0 point 
 
Partial Mayo score is the Mayo score excluding endoscopy subscore, hence the maximum is 
9 points and minimum 0 point) 


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1.4.2 Secondary Efficacy Endpoints 
 
• The percentage of subjects that achieve clinical remission per 9-point modified Mayo 
score at week 8, where stool frequency subscore ≤ 1, rectal bleeding subscore of 0, and 
endoscopic subscore ≤ 1 
• The percentage of subjects that achieve clinical remission at week 8 as per total Mayo 
score of 2 points or lower than 2, with no individual subscore exceeding 1point and a 
rectal bleeding subscore of 0. 
• The percentage of subjects that achieve endoscopic remission (mucosal healing) at week 
8, defined by Mayo endoscopic subscore ≤ 1 point. 
• Change from baseline in 9 point modified Mayo score at week 8. 
• Change from baseline in total Mayo score at week 8. 
• Change from baseline in partial Mayo score (Mayo score without endoscopy) at week 1, 
4, 8, 9, 12 and 16. 
• Change from baseline in the level of biomarkers CRP, faecal calprotectin. 
• The systemic exposure of SHR0302 in steady state in Ulcerative Colitis patients (i.e. 
concentration and area under the curve). 
 
1.4.3 Safety Endpoints 
 
• To evaluate the safety and tolerability by laboratory parameters. 
• To evaluate the safety and tolerability by collection of AE/SAE incidence 
• To measure vital signs (blood pressure (BP), heart rate (HR), and body temperature) 
• To measure subject’s total lipid profile, which includes Triglyceride, LDL and HDL. 
• To measure subject’s thyroid profile: TSH, fT4 and fT3. 
• 12 –lead ECG 
 
2. Introduction 
2.1 Background 
 
Ulcerative colitis is an autoimmune disease resulting in the chronic inflammation of colon 
mucosal characterized by relapsing–remitting pattern. UC is a lifelong disease that is associated 
with significant morbidity. It can also affect patient’s social and psychological wellbeing, if 
poorly managed. Current medical approaches focus on treating active disease to address 
symptoms, to improve quality of life, and thereafter to maintain remission. The treatment chosen 
for active disease is likely to depend on clinical severity, extent of disease and the patient’s 
preference, and may include the use of aminosalicylates, corticosteroids or biological drugs. 
These drugs can be oral or topical (per rectum), and corticosteroids may be administered 


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intravenously in people with acute severe disease.  Currently the only way to “cure” the disease 
is by total colectomy – the removal of the entire colon. This is a major surgery which carries risk 
and complications. Surgery is often reserved for those not responding to drug treatment. 
 
The treatment goal in UC is to induce and maintain remission. Conventional treatments 
include oral glucocorticoids, mesalamine, and methotrexate. The introduction of biological 
treatment such as, anti-TNFα, a IgG monoclonal antibody has changed the treatment paradigm 
for moderate to severe UC over the last decade and has now become a gold standard. However, 
its use is still limited by its cost in some area. 
 
The understanding of cytokines and intracellular messenger pathway in the pathophysiology 
of Ulcerative Colitis has led to the discovery of Janus Kinase (JAK) enzymes, and their role in 
the activation of Signal Transducers and Activators of Transcription (STATs) via auto 
phosphorylation. The JAK-STATs pathway regulates the signaling of various interferon and 
interleukin which are implicated in the pathogenesis of UC. By blocking this pathway, it is 
thought that this immune-regulated inflammation could be halted, hence controlling the disease 
(3,4). 
 
There are a number of Janus kinase (JAK) inhibitors currently under investigation for the 
treatments of immune-induced diseases, such as Rheumatoid Arthritis, Psoriatic Arthritis, 
Psoriasis, Ulcerative Colitis, Crohn’s Disease, and Ankylosing Spondylitis. These JAK inhibitors 
can be given orally, which could be an advantage compared to the intravenously given biological 
treatments. Small molecule, unlike biological treatment, has no risk of developing loss of 
response due to immunogenicity. 
 
2.2 Rationale 
 
Chronic inflammation in Ulcerative Colitis is thought to be caused by the dysregulation of 
the human body immune system. Dysregulation of the immune system decreases immune 
tolerance of intestinal commensal flora, which induces an abnormal immune response in the 
form of the overproduction of pro-inflammatory cytokines and adhesion molecules, ultimately 
resulting in excessive activation of T cells and a reduction in T cell apoptosis. 
 
JAK pathway has been well established with evidence showing that if the JAK is inhibited 
the down steam cytokine mediated inflammation could be halted. JAK1 inhibitor such as 
tofacitinib has been demonstrated to be effective in the treatment of RA and Ulcerative Colitis. It 
was recently approved by the US FDA for the induction and maintenance treatment of moderate 
to severe acute ulcerative colitis. Other JAK inhibitors, such as upadacitinib, baracitinib and 
filgotinib have been investigated for the treatment of UC and CD. 
 
SHR0302 is a highly selective JAK1 inhibitor. An in vitro study has demonstrated that its 
selectivity to JAK1 compared to JAK2 is about 16 times more than tofacitinib, and baricitinib, 
while 10 times more than filgotinib. In an animal model study, SHR0302 significantly attenuated 
gross bleeding and stool consistency while also relieved body weight loss in DSS-induced Colitis 
mice (6). Meanwhile the study has also demonstrated SHR0302’s ability in reducing colon 
inflammation score by reducing crypt score and inflammation score in these mice to the extent 


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comparable to tofacitinib, an active comparator. These in vitro and animal studies have shown 
the efficacy of SHR0302 in addressing colon inflammation, hence the potential for the treatment 
of IBD. Its high selectivity to JAK1 also makes it a favourable candidate from a safety 
perspective. 
2.3 Dose Selection Rationale 
 
In this phase II study, enrolled subjects will be randomized to receive 3 different daily 
active doses of SHR0302, 4mg, 8mg once daily, 4mg twice daily or placebo for the treatment 
phase. The choice of the doses is based on the efficacy, tolerability, and safety data derived from 
three completed phase I, and one ongoing phase II studies in RA patients. 
 
Phase I single ascending dose (SAD) study investigated the oral dose range from 1mg to 
100mg in healthy volunteers. 64 subjects were enrolled and completed the study with no early 
withdrawal. Within the investigated dose range, SHR0302 was well tolerated. All 64 subjects 
were included for safety analysis, where 16 subjects (25%) reported Adverse Events (AEs), of 
which majority of cases were Grade I to II AEs with neutrophils reduction and lymphocytes 
increase, except for a case of grade III neutrophils reduction in the 100mg group. All the AEs 
resolved and all patients recovered. There was no serious adverse events (SAEs) reported. 
 
Phase I Multiple Ascending Dose (MAD) study investigated 2mg, 5mg and 10mg given 
orally once daily for 7 days in subjects with Rheumatoid Arthritis. The study revealed SHR0302 
is well tolerated among these patients. SHR0302 and its metabolite, SHR161279, plasma 
concentration reached stable state after 4 days dosing. After repeat dosing, SHR0302 Cmax and 
AUCss showed a linear dose proportionality. Repeat dose after 7 days does not cause 
accumulation. There is no significant difference in PK characteristic between healthy volunteer 
and RA patients. From the pharmacodynamics (PD) perspective, SHR0302 has demonstrated 
various degree of improvement in PD parameters e.g. DAS28-3, CRP, and pSTAT3 between 
active drug and placebo. The dose dose-response effect between 5mg and 10mg groups was not 
well demonstrated, however there is numerical difference between the 5mg/10mg and 2mg 
groups. Out of the total 36 RA patients randomized into this study, 20 subjects (55.6%) reported 
AEs. All were regarded as Grade I AE with full recovery. 
 
Overall the Phase I SAD, and MAD studies demonstrated SHR0302 is readily absorbed 
after oral administration. Median Tmax is 1.0hr, and the half-life (T1/2) increases slightly with 
increasing dose, it is between 8.33h – 9.87h. Its main metabolite SHR161279 (M3-4) has a Tmax 
between 2.0h – 3.0h, and half-life of 8.00h – 9.50h. The metabolite SHR161279 (M3-4) total 
exposure is 9.09% - 11.54% of its parent compound. Within the 1-100mg dose range, SHR0302 
exhibits linear dose proportional pharmacokinetic (PK) characteristic. Its metabolite 
(SHR161279 (M3-4)) also exhibits similar linear dose proportional PK characteristic at 5mg- 
25mg dose range. There is no significant difference in PK characteristic between these two 
compounds. SHR0302 within dose range 2-10mg were tolerated with no SAEs reported, or 
subject withdrawn due to AE. 
 
Based on these information, we aim to carry forward 4mg, 8mg once daily and 4mg twice 
daily in the 8-week phase II study in UC subjects. This phase II study will further characterize 
SHR0302’s efficacy and safety in inducing response in moderate to severe active UC patients. 


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The dose interval with increment of a fold should enable sufficient exposure variability to 
distinguish efficacy differences between the treatment groups. 
 
SHR0302 with a half-live of about 8-9 hours will enable sustained JAK1 inhibition over a 
24-hour period and enable a once daily dosing regimen. This was supported by PD evidence 
from the SAD study where pSTAT3 inhibition could be sustained for 24hr after once daily 
dosing. The study has also included a 4mg twice daily dose to further determine this dosing 
regimen. This phase II proof-of-concept and dose-ranging study in UC patients aims to evaluate 
the efficacy in clinical practice providing further clinical evidence to support the dose selection. 
 
The selection of 8 weeks as study duration was based on the reported clinical practice 
experience where 8-12 weeks are sufficient to observe the clinical benefit of treatment induction 
in acute management. This was evidenced in similar class of medicine; where tofacitinib uses 8 
weeks (7,8) and filgotinib 10 weeks to demonstrate the induction period for UC (9). Hence the 
selection of 8-week induction period is reasonable. 
 
In conclusion, Reistone is of the opinion believes that with the wealth of scientific evidence 
on JAK/STAT involvement in IBD, the data from similar class of new drugs and the current 
early phase data on SHR0302, support the rationale to proceed with phase II studies to evaluate 
the efficacy and safety of SHR0302 in patients with moderate to severe active UC. 
 
2.4 Risk: Benefit Assessment 
 
At present, there is no pharmacological therapy that is curative of UC and the current 
treatment goal is to induce remission followed by maintaining remission. To strike the balance 
between maintaining remission with the conventional immunosuppressant and preventing the 
side effects of these therapies have always been a challenge to the treating physicians. Therefore, 
identification of new effective and safe therapies is an important area of research. 
In the phase I studies to date, SHR0302 has been well tolerated without any reported SAEs 
or death. There were AEs that are consistent with the drug mechanism of action. In the MAD 
study, there were subclinical TSH elevation found on laboratory blood chemistry, but were 
reversed towards baseline after stopping the trial medication. The reversibility was not confirmed 
due to limited follow-up duration. Subjects were asymptomatic with no residual clinical 
complication. Based on the available PK, PD, safety and tolerability of single and repeat doses of 
SHR0302, doses of 4mg, 8mg QD and 4mg BD have been selected for investigation in this 
proposed study. 
It is recognised that the phase I studies were short in duration, hence in this proposed phase 
II study, subject’s laboratory blood chemistry will be closely monitored. The clinical team will 
review the blinded safety data and laboratory parameters closely if any potential safety signal is 
suspected. The risk of adverse effects in the proposed study is being minimised by careful 
selection of subjects through detailed inclusion criteria, particularly in terms of risk of infection, 
previous history of liver or thyroid disease. 
The doses of SHR0302 have been selected for which the predicted exposure is supported by 
previous safety and tolerability data in phase I healthy volunteers and patients, and allows an 


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appropriate safety margin below the NOAEL limits in animal toxicological studies. The duration 
of 8+8week study has also been covered by the long-term repeat-dose toxicology study. 
The efficacy, safety, tolerability, and anti-inflammatory data generated by this proposed 
phase II study will be essential for evaluating the potential of this promising, novel anti- 
inflammatory agent as a treatment for moderate to severe active ulcerative colitis so that one or 
two doses can be selected to progress into further clinical development. 
In consideration of the risk factors outlined above and steps taken to mitigate these risks, the 
potential benefit of this study still outweighs the risks associated with the conduct of this Phase II 
study. 
3. Objectives 
3.1 Primary Objectives 
 
The primary objective is to evaluate the efficacy of SHR0302 at 4mg, 8mg QD, and 4mg 
BD given orally compared to placebo in inducing clinical response in adult subjects with 
moderate to severe active Ulcerative Colitis at Week 8. 
3.2 Secondary Objectives 
 
The secondary objectives are; 
 
• To evaluate the safety and tolerability of oral SHR0302 in subjects with moderate to severe 
ulcerative colitis. 
• To evaluate the efficacy of oral SHR0302 in inducing clinical remission in subjects with 
moderate to severe ulcerative colitis. 
• To evaluate the efficacy of oral SHR0302 in inducing mucosal healing in subjects with 
moderate to severe ulcerative colitis. 
• To evaluate the change from baseline in the following biomarkers; CRP, fecal calprotectin. 
• To further evaluate the efficacy of SHR0302 in maintaining remission. 
• To characterize the pharmacokinetics of SHR0302 in moderate to severe active Ulcerative 
Colitis patients, and explore the correlation of exposure-response. 
4. Investigational Plan 
4.1 Study Design 
 
See Figure 1. 


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Figure 1. Study design diagram 
 
4.2 Discussion of the design 
 
This is a multi-national, multi-center, double-blind, randomized, placebo controlled phase II 
dose- ranging study to include 152 subjects with moderate to severe active ulcerative colitis. The 
study consists of an 8-week blinded treatment phase, followed by an 8-week active arms 
extension phase. Subjects will be screened between -28 days to -1 day before baseline visit (visit 
2 at Day 0). 
 
At the baseline visit, subjects with moderate-to-severe active ulcerative colitis, with a 
modified 9-point Mayo score of 5 to 9 points and endoscopic subscore of 2 to 3, and fulfilling all 
the inclusion/exclusion criteria will be randomized into one of the four treatment arms for the 
treatment phase; three active and one placebo; 4mg QD, 8mg QD, 4mg BD of SHR0302 or 
placebo. Subjects randomized into placebo in treatment phase will also have a pre-assigned 
randomized treatment sequence for extension phase, which are 3 active groups (placebo -> 4mg 
QD, placebo -> 4mg BD, and placebo -> 8mg QD) in a 1:1:1 ratio. Subjects randomized to the 
active arms for treatment phase will remain in the same dose group in the extension phase. 
 
All the subjects will be stratified according to whether they have previously exposed to anti- 
TNFα/biological treatment. The double-blind treatment period will last for 8 weeks. Primary 
endpoint is collected at week 8. At the completion of treatment period, all subjects, responders or 
non-responders, have the option to enter a blinded active arms 8-week extension phase according 
to the group they were randomized to for the extension phase. All subjects are followed-up for 
further 2 weeks until week 18 (last visit). All the subjects have the option not enrolling into the 
extension phase after first 8 weeks of treatment. Early withdrawn subjects during the first 
treatment phase cannot enter the extension phase. The end-of-study is defined as the date of the 
last subject’s last visit or the actual date of follow-up visit/contact, whichever is later. 
5. Subject Selection and Withdrawal Criteria 


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5.1 Number of subjects 
 
152 eligible subjects will be randomized to achieve an estimated 140 evaluable subjects in 
the study. The following eligibility criteria are designed to select subjects for whom protocol 
treatment is considered appropriate. All relevant medical and non-medical conditions should be 
taken into consideration when deciding whether a particular subject is suitable to participate in 
this study. Subject eligibility should be reviewed and documented by an appropriately qualified 
member of the investigator’s study team before subjects are included in the study. Subject must 
be able to provide an informed consent to participate in this study at his own will. 
 
5.2 Inclusion Criteria 
 
Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the 
study; 
 
1. Male and Female subject age ≥ 18 and ≤75 years of age at randomization. 
 
2. Active ulcerative colitis with a 9-point modified Mayo score of 5 to 9 points and 
endoscopic subscore of 2 to 3 (The duration of the time between endoscopy and baseline 
should not exceed 10 days and allow central over read turn over before randomization). 
 
3. Subject should have at least three-month history of Ulcerative Colitis diagnosis at 
randomization. 
 
4. Subjects deemed by the treating physician as having inadequate response, loss of 
response or intolerance to the conventional treatment (oral 5-ASA, immune-suppressants 
or corticosteroids), or previously exposed to anti-TNF therapy (e.g. infliximab, 
adalimumab) or other biological treatment (e.g. Vedolizumab) having discontinued the 
treatment for: 
- 
Infliximab: a minimum of 8 weeks prior to baseline 
- 
Adalimumab: a minimum of 10 weeks prior to baseline 
- 
Ustekinumab: a minimum of 14 weeks prior to baseline 
- 
Vedolizumab: a minimum of 17 weeks prior to baseline 
- 
For the other biological treatments, they should discontinue for a minimum of 5 half- 
lives prior to baseline. 
 
5. If subjects are currently receiving the following treatment for UC, they are eligible for the 
study, provided they are on stable dose for the required period of time: 
 
− Oral 5 ASA or Sulfasalazine, stable dose for at least 2 weeks prior to baseline and 
during the study treatment period. 
 
AND/OR 


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− Oral corticosteroids (prednisolone ≤ 30mg/day or less or equivalent) stable dose for at 
least 2 weeks prior to baseline. This is not applicable to the subjects who have only 
exposed to 5-ASA previously as per inclusion criteria 4. 
 
6. Subject must have no evidence of active, latent, or inadequately treated infection with 
Mycobacterium tuberculosis (i.e., tuberculosis [TB]), as defined by the following: 
 
− A negative Mantoux Purified Protein Derivative (PPD) skin test result (≤ 5 mm of 
induration), or negative QuantiFERON TB Gold (QFT Gold test) /or T-Spot test 
performed within the 3 months prior to/within screening; 
AND 
− Subject must have a chest radiograph, taken within the 3 months prior to/within 
screening, and showing no changes suggestive of active TB infection. 
AND 
− Subject must have no history of either untreated or inadequately treated latent or 
active TB infection 
 
7. All women of childbearing potential and all men must be willing to use at least one highly 
effective method of contraception from signing of informed consent, throughout the duration 
of the study, and for 1 month after last dose of study medication: (refer to Section 5.4 for 
further details on contraception requirements for this study) 
- Male subjects with a female partner of childbearing potential must be willing to use 
condom in addition to a highly effective contraceptive method. 
 
8. Subjects who are willing and able to comply with the scheduled visits and treatment plan, 
laboratory testing and other study procedures. 
 
9. Capable of providing a signed and dated informed consent form indicating the subject has 
been informed of all pertinent aspect of the study. 
 
5.3 Exclusion Criteria 
 
Subjects presenting with any of the following will not be included in the study: 
 
1. Diagnosis of indeterminate colitis, or clinical findings suggestive of Crohn’s disease. 
 
2. Subjects with ulcerative colitis, which is confined to a proctitis (distal 15 cm or less). 
 
3. Treatment naïve subjects diagnosed with ulcerative colitis (without previous exposure to 
any of the following therapies for UC treatment: oral 5-ASA, corticosteroids, immune- 
suppressants, or biological treatments). 
 
4. Subjects displaying clinical signs of ischemic colitis, fulminant colitis or toxic 
megacolon. 


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5. Subject who have had previous surgery as a treatment for ulcerative colitis or likely to 
require surgery during the study period. 
 
6. Subjects who have evidence of pathogenic bowel infection. Subjects had Clostridium 
difficile or other intestinal infection within 30 days of screening endoscopy, or test 
positive at screening for C. difficile toxin or other intestinal pathogens. 
 
7. Subjects receiving the following therapy: 
- 
Azathioprine/6-mercaptopurine, methotrexate, thalidomide within 7 days prior to 
baseline. 
- 
Cyclosporine, mycophenolate, tacrolimus within 4 weeks prior to baseline. 
- 
Interferon therapy within 8 weeks prior to baseline. 
- 
Intravenous corticosteroids or rectally administered formulation of corticosteroids or 
5-ASA within 2 weeks prior to baseline. 
 
8. Subjects who have previously received JAK inhibitors, such as tofacitinib, baricitinib, 
upadacitinib, filgotinib. Please discuss with the medical monitor if need clarification. 
 
9. Subjects with evidence of hematopoietic disorders at screening: 
- 
Hemoglobin levels <9.0 g/dL or hematocrit <30%. 
- 
An absolute white blood cell (WBC) count of <3.0 x 109/L (<3000/mm3) or Absolute 
Neutrophil Count (ANC) of <1.2 X 109/L (<1200/mm3). 
- 
Thrombocytopenia, as defined by a platelet count <100 x 109/L (<100,000/mm3). 
 
10. Subjects with evidence of total bilirubin, aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) more than 2 times the upper limit of normal at screening visit. 
Patients with liver cirrhosis will be excluded. 
 
11. Subjects with eGFR ≤60 ml/min based on Cockcroft-Gault calculation (Appendix 2), or 
patient currently undergoes regular haemodialysis. 
 
12. Subjects with current or recent history of severe, progressive, or uncontrolled renal, 
hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, or 
neurological disease. 
 
13. Subjects with current clinically significant infections or within 1 month of baseline (e.g. 
those requiring hospitalization or parenteral antimicrobial therapy or opportunistic 
infections), or those with a history of more than one episode of herpes zoster, a history 
(single episode) of disseminated zoster, a history of any infection otherwise judged by the 
investigator to have the potential for exacerbation by participation in the study or any 
infection requiring antimicrobial therapy within 2 weeks of screening. 
 
14. Subjects who may have current immunization with any live virus vaccine or history of 
immunization with any live virus vaccine within 8 weeks of baseline. 
 
15. Subjects with a first-degree relative with a hereditary immunodeficiency. 


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16. History of any lymphoproliferative disorder (such as EBV-related lymphoproliferative 
disorder, as reported in some subjects on other immunosuppressive drugs), history of 
lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs and 
symptoms suggestive of current lymphatic disease. 
 
17. Any prior treatment with lymphocyte-depleting agents/therapies (such as CamPath® 
[Alemtuzab], alkylating agents [eg Cyclophosphamide or Chlorambucil], total lymphoid 
irradiation, etc). Subjects who have received Rituximab or other selective B lymphocyte 
depleting agents are eligible if they have not received such therapy for at least 1 year 
prior to baseline. 
 
18. Subjects who have any condition possibly affecting oral drug absorption eg gastrectomy, 
or clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery 
such as gastric bypass. (Procedures such as gastric banding, gastric balloon that simply 
divide stomach into separate chambers, are NOT exclusionary.) 
 
19. Women who are pregnant or lactating, or planning pregnancy while enrolled in the study. 
 
20. History of alcohol or drug abuse with less than 6 months of abstinence prior to baseline. 
 
21. Screening 12-lead ECG that demonstrates clinically relevant abnormalities which may 
affect subject safety if being enrolled into the study or interpretation of study results. 
(Appendix 3 ECG exclusion criteria) 
 
22. Subjects that have donated blood in excess of 500 mL within 2 months prior to baseline. 
 
23. Subjects that have undergone significant trauma or major surgery within 4 weeks of 
screening visit. 
 
24. Subjects with a temperature of 38°C or higher at screening or baseline. 
 
25. Subjects with malignancies or with a history of malignancies with the exception of 
adequately treated or excised non-metastatic basal cell or squamous cell cancer of the 
skin. 
 
26. Subjects infected with human immunodeficiency virus (HIV) or hepatitis B or C viruses. 
 
27. Subjects who currently suffered from thyroid disorders, including hyperthyroidism, 
hypothyroidism, or currently on thyroid replacement therapy. Subjects with abnormal 
TSH, fT4 and fT3 at screening blood check must be excluded. 
 
28. Subjects who have previously participated in any study that received SHR0302. 
 
29. Subjects who have received any investigational drug or device within 3 months prior to 
baseline. 


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30. Subjects receiving or are expected to receive prohibited concomitant medication(s) (see 
Appendix 4) in the 4 weeks prior to the first dose of study drug. 
 
31. Subjects who, in the opinion of the investigator or Reistone, will be uncooperative or 
unable to comply with study procedures. 
 
32. Any other condition which in the opinion of the investigator would make the subject 
unsuitable for inclusion in the study. 
 
33. Subjects with historical or current evidence of clinically significant cardiovascular, 
neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, 
nervous system, musculoskeletal, skin, sensory, endocrine (including uncontrolled 
diabetes or thyroid disease) or hematological abnormalities that are uncontrolled. 
Significant is defined as any disease that, in the opinion of the Investigator, would put the 
safety of the subject at risk through participation, or which would affect the efficacy or 
safety analysis if the disease/condition exacerbated during the study. 
 
34. Subjects with a history thrombotic events, including deep vein thromboses (DVT), 
pulmonary embolism (PE) and those with known inherited conditions that predispose to 
hypercoagulability. 
 
 
5.4 Contraception advice 
 
Contraceptive measures for both males and females of childbearing potential should be 
documented in the source documents. 
 
5.4.1 Women of Non‐Childbearing Potential 
 
Female subjects of non‐childbearing potential must meet at least one of the following 
criteria: 
 
− Postmenopausal females who are at least 45 years of age with amenorrhea for at least 
2 years. To confirm postmenopausal status (FSH level >30 IU/L), FSH testing should 
be performed for women within 5 years from their last menses; 
OR  
− Females with a physician documented hysterectomy, bilateral salpingectomy and/or a 
bilateral oophorectomy. 
 
All other female subjects (including females with tubal ligations) will be considered to be of 
childbearing potential. 
 
5.4.2 Women of Childbearing Potential 


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Female subjects of childbearing potential and their male partner must use at least 1 highly 
effective contraceptive method from the following list: 
 
a. Combined (oestrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal or transdermal). 
b. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable). 
c. Placement of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
d. Documented bilateral tube occlusion at least 4 weeks before screening. 
e. Vasectomised partner with medical confirmation of absence of sperm in the ejaculate at 
least 4 weeks before screening. 
 
Female subjects and their male partners must be willing to continue use of these 
contraceptive methods from signing of informed consent, throughout the duration of the study, 
and for 1 month after last dose of study medication. Within these limits, the specific forms of 
contraception employed are left to the discretion of the subject, the principal investigator, and/or 
the subject’s physician. 
 
Absolute sexual abstinence, when this is consistent with the preferred and usual lifestyle of 
the subject, may be considered an acceptable method of contraception at the discretion of the 
investigator. 
 
5.4.3 Pregnancy Testing 
 
Female subjects of childbearing potential will be tested for serum beta‐human chorionic 
gonadotropin (β-hCG) at screening visit. In addition, urine β-hCG test will be done at 
baseline and at each study visit until the end of follow‐up period. If at any point there is a case of 
a positive urine β-hCG test, and this is confirmed by serum β-hCG, the subject will be withdrawn 
from the study and all the necessary follow up will be conducted. 
 
5.4.4 Males 
 
Non-vasectomized males with female partners of childbearing potential must be willing to 
use a condom, from signing of informed consent, throughout the duration of the study, and for 1 
month after last dose of study medication, in addition to having their female partner use a highly 
effective form of contraception as described in Section 5.4.2: 
 
Vasectomized males with female partners of childbearing potential are not required to use 
an additional form of contraception providing that surgical sterilization has been successful 
and an absence of sperm in the ejaculate has been confirmed at least 4 weeks before screening. 
 
5.5 Randomization Criteria 
 
Subjects will be randomized into the study in a 1:1:1:1 allocation ratio to SHR0302 8mg 
QD, placebo, SHR0302 4mg BD or SHR0302 4mg QD for the treatment phase provided they 
have satisfied all inclusion/exclusion criteria at randomization visit (Visit 2). Subjects will be 


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stratified according to whether or not they have had previous exposure to anti-TNFα/biological 
treatment. A computer-generated randomization schedule will be used to assign subjects to the 
treatment sequences. Subjects will be assigned a subject number in the order of their acceptance 
into the study. This identifying number will be retained throughout the study. Subjects 
randomized into placebo in treatment phase will also have a pre-assigned randomized treatment 
sequence for extension phase, which are 3 active groups (placebo -> 4mg QD, placebo -> 4mg 
BD, and placebo -> 8mg QD) in a 1:1:1 ratio. Subjects randomized to the active arms for 
treatment phase will remain in the same dose group in the extension phase. 
 
After the completion of treatment phase, subject may choose to enroll into the extension 
phase according to the group they were randomized to for the extension phase. All the subjects 
have the option not entering into the extension phase after first 8 weeks of treatment phase. Early 
withdrawn subjects during the first treatment phase cannot enter the extension phase. 
 
5.6 Withdrawal Criteria 
 
A subject may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or Reistone Biopharma for behavioral 
or administrative reasons. 
 
If a subject develops a serious infection during the study, defined as any infection (viral, 
bacterial, and fungal) requiring hospitalization or parenteral antimicrobials, he/she must be 
discontinued from the study. 
 
All abnormal laboratory events of clinical significance should be followed until the 
laboratory values have returned to normal or baseline levels. In addition, any subject with a 
confirmed increase in serum creatinine at the end of study or at discontinuation of at least 0.2 
mg/dL and at least 10% above the average of screening and baseline value will be followed up 
with retesting every one to two weeks until the creatinine elevation has fully reversed to within 
10% of the subject's baseline value or has stabilized. 
 
If a subject has any clinically significant, study-related abnormalities at the conclusion of 
the study, the medical monitor (or designated representative) should be notified and every effort 
should be made to arrange follow-up evaluations at appropriate intervals to document the course 
of the abnormalities. 
 
The reason for a subject discontinuing from the study will be recorded in the eCRF. A 
discontinuation occurs when a randomized subject ceases participation in the study, 
regardless of the circumstances, prior to completion of the protocol. The investigator must 
determine the primary reason for discontinuation. Withdrawal due to adverse events should 
be distinguished from withdrawal due to insufficient response according to the definition of 
adverse event noted in Section 7.3.11 . The final evaluation required by the protocol will be 
performed at the time of the study discontinuation. The investigator will record the reason for 
study discontinuation, provide or arrange for appropriate follow-up if required. 


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5.7 Pre-Screen and Screen Failure 
 
Subjects will be assigned a subject number after completing written informed consent and 
completing at least one additional study procedure (study procedures do not include washout of 
any medication). 
 
A screen failure is defined as any subject who has been assigned a subject number, but does 
not continue in the study beyond Visit 1 (Screening) or any subject who completes Visit 1 and 
enters the run-in period but is subsequently found to be ineligible for the study based procedures 
(e.g., laboratory, ECG, or Endoscopy) conducted at Visit 1. The study interactive voice response 
system (IVRS) used to track study enrolment, will be contacted to report screen failures. 
Additionally, the following information will be collected in the eCRF for screen failures: 
 
• 
Date of Screening Visit 
• 
Subject number 
• 
Demography information including race, age, and gender 
• 
Inclusion/exclusion criteria 
• 
Reason subject failed screening 
• 
Primary method of subject recruitment 
• 
Serious Adverse Events (SAEs) information,  if any 
In most circumstances, subjects who are screen failures cannot be re-screened. In rare 
instances, subjects may be eligible for re-screening. However, the re-screening of subjects must 
be approved by the study Medical Monitor prior to re-screening. 
Subjects who meet all the Visit 1 eligibility criteria, but are not randomized will be 
considered Run-In failures. In addition to the information described above for screen failures, the 
reason for the Run-In failure will be recorded in the eCRF for Run-In failures. 
 
5.8 Early Withdrawal 
 
The definition of an early subject withdrawal from the study will be any subject who is 
randomized to double-blind medication and, for any reason, is withdrawn prior to completion of 
the Visit 5 procedures. 
 
A subject may voluntarily discontinue participation in the study at any time.  The 
investigator may also, at his/her discretion; discontinue the subject from participating in the 
study at any time. In addition, the investigator must make every effort to have the subject return 
to the clinic as soon as possible after discontinuation of study drug for an Early Withdrawal 
Visit. An Early Withdrawal Visit may occur at a regular scheduled clinic visit or between clinic 
visits.  The following evaluations and procedures should be completed and recorded in the eCRF. 
• 
Concomitant medication assessment 
• 
AE/SAE assessment 


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• 
Physical examination (recorded in source documents only) 
• 
Vital signs 
• 
Collect and review electronic diary 
• 
Collect used study medication (blinded study medication) 
• 
Assess compliance with investigational drug 
• 
12-Lead ECG 
• 
Laboratory assessments (including chemistry, haematology, and pregnancy test for females 
of childbearing potential and routine urinalysis) 
• 
Call IVRS to report subject’s early withdrawal from the study 
• 
Endoscopy, Mayo score, 9-point modified Mayo score, and partial Mayo score, if feasible. 
A subject that is withdrawn from the study after being randomised to treatment cannot be 
re-screened and subjects who are withdrawn from the study will not be replaced. If the subject 
withdraws from the study, and also withdraws consent for disclosure of future information, no 
further evaluations should be performed, and no additional data should be collected. The sponsor 
may retain and continue to use any data collected before. 
Thyroid specific criteria: 
Subjects with deranged TSH level (outside of normal range) only, but normal free T4 or free 
T3. Investigator can follow-up the subject with thyroid function test and assess clinically in 4 
weeks. 
Deranged TSH level, with associated deranged free T4 and/or free T3(outside of normal 
range), the investigator should assess subject’s clinical condition and decide if the subject should 
be withdrawn. 
Subject with signs and/or symptoms suggestive of hypothyroidism or hyperthyroidism 
should have laboratory thyroid function performed. If any of the thyroid parameters (TSH, free 
T4, or free T3) were outside of normal range, the subject is to be withdrawn. 
 
 
5.9 Stopping Criteria 
 
The stopping safety criteria are as below: Subject who fulfil the following criteria should 
discontinue the study. 
• Liver chemistry threshold stopping criteria have been designed to assure subject safety and to 
evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety 
guidance) Study treatment will be stopped if the liver chemistry stopping criteria is met. 
Refer to Section 7.3.9 Liver Chemistry Stopping and Follow-up Criteria. 
• A subject that meets the QTc criteria below will be withdrawn from the study. The QT 
correction formula used to determine discontinuation should be the same one used 
throughout the study. 


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-QTc, QTcB/QTcF > 500 ms 
-Change from baseline: QTc >60 ms 
Use the averaged QTc values of the 3 ECGs to determine whether the subject should be 
discontinued from the study. 
• Abnormal laboratory values of interests. (modified from CTCAE 5.1 criteria) 
 
➢ Hemoglobin (Hgb) <7.0 g/dL; or when blood transfusion is indicated. 
➢ Neutrophil count < 500/mm3 
➢ Platelet count < 25,000/mm3 
➢ Lymphocyte count < 200/mm3 
➢ Leukocyte count < 2000/mm3 
 
• Subject who develops Venous Thrombosis (eg Deep Vein Thrombosis). 
 
• Subject who develops Pulmonary Embolism. 
 
• Subject who develops Cerebrovascular Events (eg Thromboembolic Stroke, Transient 
Ischemic Attack (TIA), Myocardiac Infarction) 
• An unacceptable adverse event, as determined by the Investigator and the medical monitor. 
• Any unacceptable adverse event that is thought to be related to the investigational product 
may result in the study being terminated. 
• Significant protocol deviation. The discovery that post-randomization the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health. 
• If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 7.3.10. 
 
 
5.10 Premature Study Termination 
 
The sponsor may discontinue the study if the study becomes unjustifiable for medical ethical 
reasons, for poor enrollment, or because of discontinuation of clinical development of the 
investigational product. 
The clinical study may be terminated prematurely or suspended at the request of health 
authorities or if new safety or efficacy information leads to an unfavorable risk benefit judgment 
for the investigational product. 
If a study is prematurely terminated or discontinued, Reistone will promptly notify the 
investigator. After notification, the investigator must contact all participating subjects and the 
hospital pharmacy (if applicable) within 7 days. As directed by Reistone, all study materials 
must be collected and all eCRFs completed to the greatest extent possible. 


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5.11 Safety Review Committee (SRC) 
 
An SRC will be established in this study to assess overall safety data and early safety signal in 
order to protect the ethical and safety interests of the subjects recruited into the study, while 
maintaining, as far as possible, the scientific validity of the study. The SRC is independent of the 
study team and will comprise of at least one external independent statistician and an external 
independent physician. 
 
During the study, the SRC will convene at least twice to review the safety and tolerability data 
after the study recruited the 50th and 100th subject treated for first 8 weeks of treatment phase. 
Based on the safety information, the SRC has the discretion to make recommendation to the 
study team based on predefined SRC Charter. 


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5.12 Time and Event Table 
See Table1. 
 
Table 1. Time and Event Table 
 
Period 
Screening 
Baseline 
Treatment Phase 
End of 
Treatment 
Phase 
Extension Phase 
End of 
Extension 
Phase 
Follow- 
up/EW11 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
-4 to -1 
0 
1 
4 
8 
9 
12 
16 
18 
Day 
-28 to -1 
0 
7± 2 days 
28± 3 days 
56± 3 days 
63± 2 days 
84± 3 days 
112± 3 days 
126± 5 days 
Procedures 
Written Informed Consent1 
x 
Demography/Medical 
History 
x 
Physical Examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chest X-ray2 
x 
Inclusion/Exclusion Criteria 
x 
Randomisation Criteria 
x 
Study medication 
dispensing 
x 
x 
x 
x 
Study medication 
accountability 
x 
x 
x 
x 
x 12 
Register Visit in IVRS3 
x 
x 
x 
x 
x 
x 
x12 
Endoscopy (colonoscopy)4 
x 4 
x 
x12 
Efficacy Assessments 
Patient Dairy5 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mayo Score 
x 
x 
x12 
9-point Modified Mayo 
Score 
x 
x 
x12 
Partial Mayo Score 
x 
x 
x 
x 
x 
x 
x 
x 
Safety Assessments 
12-lead ECG 
x 
x 
x 
x 
x 
x 
x 
Vital Signs6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Event Assessment7 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory Assessments 


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Period 
Screening 
Baseline 
Treatment Phase 
End of 
Treatment 
Phase 
Extension Phase 
End of 
Extension 
Phase 
Follow- 
up/EW11 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
-4 to -1 
0 
1 
4 
8 
9 
12 
16 
18 
Day 
-28 to -1 
0 
7± 2 days 
28± 3 days 
56± 3 days 
63± 2 days 
84± 3 days 
112± 3 days 
126± 5 days 
Procedures 
Haematology and 
Chemistry Tests 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Lipid Profile (Fasting) 
x 
x 
x 
x 
x 
x 
TSH, fT4, fT3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
QuantiFERON /or T-Spot 
/or PPD test 8 
x 
Hep B sur Ag, Hep C Ab, 
HIV test 
x 
Stool culture/ microscopy 
x 
CRP 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Faecal Calprotectin 
x 
x 
x 
x 
Urine Pregnancy Test9 
x 
x 
x 
x 
x 
x 
x 
x 
β-HCG (blood)10 
x 
PK Sampling 
x13 
x14 
FSH15 
x 
Medication 
Concurrent Medication 
Assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
1. Written informed consent must be obtained prior to performing any Visit 1 procedures or initiating any alterations in a subject’s medications 
2. Only to be performed if there is no chest X-ray or CT scan available within 3 months of Visit 1 
3. IVRS is a randomisation machine used to record all the patient visit. 
4. Colonoscopy is completed by baseline (visit 2 – Day 0). The duration of time between endoscopy and baseline is no more than -10 days. 
5. 
Subject use an electronic diary to record disease related medical problems experienced during the study. 
6. 
Vital signs include resting blood pressure, heart rate, and body temperature. It is advised to measure them before any procedures or questionnaires. 
7. 
Adverse events and Serious Adverse Events to be collected from the start of the study drug (visit 2) until the Follow-Up contact. However, any serious 
adverse events will be recorded from the time of consent. 
8. 
Investigator has the option to use PPD test, QuantiFERON Gold test or T-Spot for TB screening. Subjects who have previously receive BCG vaccination 
will be tested by QuantiFERON Gold test/or T-Spot test, and the result will determine the subject eligibility for participation. 
9. 
Urine pregnancy test to be done in females of childbearing potential only 


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10. β-Human Chorionic Gonadotrophin(β-HCG) to be done in females of childbearing potential at screening visit, and only to be done if urine pregnancy test 
positive at other study visits. 
11. Early withdrawal visit should be done within 2 weeks after last dose/decision of withdrawal. 
12. Only to be conducted in the early withdrawn subjects. 
13. At Week 4, a pre-dose PK blood sample is collected before medication. A post-dose PK blood sample is taken at any time between 1 to 2hrs after 
medication. Subject is to take study medication at the site. The medication intake time and the post dose blood sampling time need to be recorded in the eCRF. 
14. At Week 8, a pre-dose PK blood sample is collected before medication. A post-dose PK blood sample is taken at any time between 2 to 8hrs after 
medication. Subject is to take study medication at the site. The medication intake time and the post dose blood sampling time need to be recorded in the eCRF. 
15. FSH to confirm postmenopausal status at screening visit only. 


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6. Study Treatments 
 
6.1 Investigational Product/Placebo Supply 
 
SHR0302 and matching placebo tablets will be provided by the sponsor and dispensed for 
oral administration. Subjects will be randomized to receive 4mg QD, 4mg BD, 8mg QD or 
Placebo in a ratio of 1:1:1:1 respectively for the first 8 week of treatment phase. Subjects 
randomized into placebo in treatment phase will also have a pre-assigned randomized treatment 
sequence for extension phase, which are 3 active groups (placebo -> 4mg QD, placebo -> 4mg 
BD, and placebo -> 8mg QD) in a 1:1:1 ratio. Subjects randomized to the active arms for 
treatment phase will remain in the same dose group in the extension phase. 
 
SHR0302 will be provided as combination of 4mg tablets, including the matching placebo 
by the Sponsor. At study visits on Day 0, and Week 4, sufficient trial medication will be 
dispensed to complete dosing for four weeks. 
 
For subjects enrolled into the blinded active arm extension phase, trial medications will be 
dispensed at week 8 and week 12, where trial medications will be dispensed sufficient for 4 
weeks. At visits Week 4, Week 8, Week 12, and Week 16 (end of extension phase), or at follow- 
up visit/contact if the subject is withdrawn, the subject must return all trial medication and the 
amount returned will be recorded. 
 
Note that only those patients enrolled into the extension phase will be dispensed with trial 
medications at week 8 and week 12. 
 
6.1.1 Study Drug Dispensing 
 
Investigational product will be assigned to subjects at the baseline visit once successfully 
randomized through the tele-randomization system. The investigator or appropriate delegate at 
the site will access the tele-randomization system (IVRS) at baseline visit to receive correct 
container numbers to be dispensed to the subject. All medication dispensed or returned will be 
documented in the eCRF. 
 
After the completion of first 8-week treatment phase, all completers may be enrolled into 
the extension phase according to the group they were randomized to for the extension phase. 
 
6.1.2 Study Drug Administration 
 
Study medication will be self-administered by the subject twice daily, one (2 tablets) in the 
morning, another (2 tablets) in the afternoon. Approximately 8 - 12 hours between the morning 
and afternoon doses. 


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However, at baseline (Day 0) the first dose will be taken in the clinic. At Week 4 and at the 
end of treatment (Week 8) subjects should take their morning oral dose at the clinic. Study 
medication may be taken with or without food. 
6.2 Treatment Assignment 
 
Subjects will be randomized into the trial in a 1:1:1:1 allocation ratio to SHR0302 8mg QD, 
placebo, SHR0302 4mg QD or SHR0302 4mg BD for the treatment phase provided they have 
satisfied all inclusion/exclusion criteria. Subjects will be stratified according to whether or not 
they have had previous exposure to anti-TNFα/biological treatment and randomized at baseline 
according to a computer generated pseudo random code using the method of permutated blocks 
balanced within each randomization strata. Subjects randomized into placebo in treatment phase 
will also have a pre-assigned randomized treatment sequence for extension phase, which are 3 
active groups (placebo -> 4mg QD, placebo -> 4mg BD, and placebo -> 8mg QD) in a 1:1:1 
ratio. Subjects randomized to the active arms for treatment phase will remain in the same dose 
group in the extension phase. 
After the completion of treatment phase, subject may choose to enroll into the extension 
phase according to the group they were randomized to for the extension phase. All the subjects 
that have completed the first treatment phase have the option not entering into the extension 
phase after first 8 weeks of treatment. Early withdrawn subjects during the first treatment phase 
cannot enter the extension phase. 
 
6.3 Blinding 
 
Investigational product taken during the 8-week treatment period will be double-blind. 
Neither the subject nor the study physician will know which study medication the subject is 
receiving. In the subsequent 8-week extension phase, although subjects are given active 
treatments, both the subjects and investigators are blinded to which dose of SHR0302 they are 
randomized to. 
 
In order to preserve blinding and ensure patients compliance throughout the study, the study 
drug packaging has been designed with detailed consideration. All the arms are administered 
under twice daily (BD) dosing regime and placebo is used according to the schedule in the table 
below. (Table 2) 
 
Table 2. Study drug packaging design for treatment arms 
 


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At each dosing time (morning, am or afternoon, pm), subject will be taking two tablets. In 
one day, a subject will take a total of four tablets, two tablets in the morning and two tablets in 
the afternoon. 
 
The investigator or treating physician may unblind a subject’s treatment assignment only in 
the case of an emergency, when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject. Whenever possible, the investigator 
must first discuss options with the Reistone Biopharma/designated CRO Medical Monitor or 
appropriate Reistone Biopharma/designated CRO study personnel before unblinding the 
subject’s treatment assignment. If this is impractical, the investigator must notify Reistone 
Biopharma/designated CRO as soon as possible, but without revealing the treatment assignment 
of the unblinded subject, unless that information is important for the safety of subjects currently 
in the study. The date and reason for the unblinding must be recorded in the appropriate data 
eCRF. 
 
Reistone Biopharma/designated CRO staff may unblind the treatment assignment for any 
subject with an SAE. If the SAE requires that an expedited regulatory report be sent to one or 
more regulatory agencies, a copy of the report, identifying the subject’s treatment assignment, 
may be sent to clinical investigators in accordance with local regulations. 
Subjects will be withdrawn if the treatment code becomes unblinded. The primary reason for 
discontinuation (the event or condition which led to the unblinding) will be recorded in the 
eCRF. 
 
6.4 Drug Storage and Accountability 
 
SHR0302 must be stored according to the labeled storage conditions in a locked area with 
restricted access. The investigator or appropriate delegate at the site (eg pharmacist), will ensure 
that all study drug is stored in a secured area, under recommended storage condition, and in 
accordance with regulatory requirements. 
 
The investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the investigational product(s). To ensure adequate records, all drug supplies will 
be accounted for in the drug accountability inventory forms as instructed by Reistone 
Biopharma/designated CRO and will be monitored by counting of unused medications returned 
by the subject at Week 4, 8, 12 and 16 or at follow-up visit/contact if the subject is withdrawn. 
 
At the end of trial, Reistone Biopharma/designated CRO will provide instructions as to the 
disposition of any unused investigational product. If Reistone/designated CRO authorizes 
destruction at the trial site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any special 
instructions provided by Reistone Biopharma/designated CRO. Destruction must be adequately 
documented. SHR0302 will not be made available to subjects at the end of study. 
 
6.5 Treatment Compliance 
 
Investigational product compliance will be assessed by the site at each clinic visit following 


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baseline (Day 0) up to the end of treatment. Non-compliance is defined as taking 
less than 80% of study drug products as directed by the dosing instructions. The investigator has 
the discretion to withdraw any subject from the study for reasons of non-compliance with the 
dosing regimen. Investigators should indicate on the appropriate eCRF page noncompliance with 
study treatment and provide an explanation. 
 
Inventory control of all study medications must be rigorously maintained throughout the 
duration of the study until all medication has been accounted for and returned to the sponsor. 
Any discrepancies noted between drug dispensing records and the drug inventory must be 
reported to Reistone Biopharma/designated CRO. 
 
6.6 Concomitant Medications 
 
6.6.1 Permitted Concomitant Medications 
 
All concomitant medication(s) taken during the trial must be recorded with indication, daily 
dose, and start and stop dates of administration. All subjects will be questioned about 
concomitant medication at each clinic visit. Following therapy for ulcerative colitis are 
allowed providing they are stable for the specified period of time: 
 
• Oral 5-ASA or sulfasalazine are allowed providing that the dose is stable for at least 2 
weeks prior to baseline and during the study treatment period. 
 
• Oral steroids are allowed during the study up to the dose of 30 mg/day of prednisolone or 
equivalent, providing that the dose has not been commenced or changed within 2 weeks 
of baseline and until to the end of treatment phase (Week 8). During the treatment phase, 
if the subject cannot tolerate the oral steroids dose or there is a significant safety risk 
associated with continued use of the steroids, the dose may be reduced at the discretion of 
the investigator and the reasons for dose reduction need to be documented in the medical 
records. During the extension phase, tapering of the oral steroid dose can be commenced 
for subjects at investigator’s discretion. Tapering scheduled treatment is provided as 
below: 
 
− Subjects receiving > 10 mg/day prednisolone or equivalent: taper dose by 5 
mg/week until a 10 mg/day dose (or equivalent) is reached, then continue tapering 
at 2.5 mg/week until 0 mg/day. 
− Subjects receiving ≤ 10 mg/day prednisolone or equivalent: taper dose by 2.5 
mg/week until 0 mg/day. 
 
If subject experiences worsening of signs or symptoms during the tapering schedule, in the 
opinion of the investigator, due to reduction in oral steroid daily dose, the daily oral steroid 
dosage for the subject could be reverted to the preceeding daily dosage instructed by the 
investigator, but should not exceed Baseline dose. 


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6.6.2 Prohibited Medications 
 
The following medications are prohibited throughout the duration of the study: 
 
• azathioprine, 6-mercaptopurine, methotrexate and thalidomide; 
• cyclosporine, mycophenolate and tacrolimus; 
• interferon and 
• anti-TNFα therapy/other biological treatment; 
• intravenous corticosteroids or rectally administered formulation of corticosteroids or 5- 
ASA. 
• Oral JAK inhibitors (except the trial medication) 
 
In addition, concomitant administration of CYP3A inducers and moderate to potent CYP3A 
inhibitors with systemic effects should be avoided for the duration of the study. 
Examples of medications that are prohibited from use from 28 days prior to the first dose of 
study medication until completion of follow up period, due to potential for drug interactions or 
confounding of data interpretation, are listed in Appendix 4. 
 
All live vaccines immunization are prohibited from signing of informed consent, throughout 
the duration of the study, and for 1 month after last dose of study medication. 
6.6.3 Traditional Chinese and Herbal Medicines 
 
The following categories of traditional or herbal medicines are prohibited at Visit 1 and any 
time during the study: 
• Traditional or herbal medicines used for the treatment of UC, including those that 
investigator believe to contain corticosteroids. 
• Traditional or herbal medicines that have known effects on platelets and that increase the 
tendency to cause bleeding. 
 
6.7 Treatment after study completion 
 
The investigator is responsible for ensuring that consideration has been given to the post- 
study care of the patient’s medical condition whether or not Reistone Biopharma/designated 
CRO is providing specific post study treatment after week 16. Reistone Biopharma/designated 
CRO has provided an 8-week extension phase of active therapy, and will not provide post-study 
treatment after the extension phase. Post-treatment UC therapy should not be entered into the 
eCRF. 
 
6.8 Study Drug Overdose Management 
 
An overdose is defined as a dose greater than the total doses described above which results 
in clinical signs and symptoms. These should be recorded by the investigator on the AE/SAE 
pages. In the event of an overdose of study medication, the investigator should use clinical 
judgment in treating the overdose and contact the study medical monitor. 


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Reistone Biopharma/designated CRO is not recommending specific treatment guidelines for 
overdose and toxicity management. The investigator is advised to refer to the relevant 
document(s) for detailed information regarding warnings, precautions, contraindications, adverse 
events, and other significant data pertaining to the study drug being used in this study. Such 
documents may include, but not be limited to, the IB or equivalent document provided by 
Reistone Biopharma/designated CRO. 
7. Study Assessments and Procedures 
7.1 Critical Baseline Assessments 
 
The following critical baseline assessments will be conducted at Visit 1: 
 
• Demographic history (including gender, ethnic origin, date of birth, height and weight) 
• Medical history of Ulcerative Colitis comprised of date of diagnosis (year of diagnosis is 
acceptable) and previous and/or current medical conditions 
• Physical examination 
• Heart rate, blood pressure, and body temperature measurement 
• 12-Lead ECG 
• Chest x-ray (or historical chest x-ray/CT-Scan obtained within 3 months of Screening 
(Visit 1)) 
• Clinical laboratory assessments (including chemistry, hematology,  pregnancy test) 
• Mayo Score – Mayo Scoring System for Ulcerative Colitis. 9-point modified Mayo score 
will be used to confirm patient eligibility for the study at baseline. The duration of the 
time between endoscopy and baseline should not exceed 10 days. Mayo score and Partial 
Mayo score will also be calculated and collected prior to randomization. 
 
7.2 Efficacy Endpoints Assessments 
 
7.2.1 Primary Efficacy Endpoints 
 
The percentage of subject achieve clinical response at week 8, defined as decrease from 
baseline in 9-point modified Mayo score of at least 2 points and at least 30%, with an 
accompanying decrease in the subscore for rectal bleeding of at least 1 point or absolute subscore 
for rectal bleeding of 0 or 1. 
 
7.2.2 Secondary Efficacy Endpoints 
 
• The percentage of subjects achieve clinical remission per 9-point modified Mayo score at 
week 8, where stool frequency subscore ≤ 1, rectal bleeding subscore of 0, and 
endoscopic subscore ≤ 1 


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• The percentage of subjects achieve clinical remission at week 8 as per total Mayo score 
of 2 points or lower than 2, with no individual subscore exceeding 1point and a rectal 
bleeding subscore of 0. 
• The percentage of subjects achieve endoscopic remission (mucosal healing) at week 8, 
defined by Mayo endoscopic subscore ≤ 1 point. 
• Change from baseline in 9-point modified Mayo score at week 8. 
• Change from baseline in total Mayo score at week 8. 
• Change from baseline in partial Mayo score (Mayo score without endoscopy) at week 1, 
4, 8, 9, 12 and 16. 
• Change from baseline in the level of biomarkers CRP, fecal calprotectin. 
• The systemic exposure of SHR0302 in steady state in Ulcerative Colitis patients (i.e. 
concentration and area under the curve). 
 
7.2.3 Safety Endpoints 
 
• To evaluate the safety and tolerability by laboratory parameters. 
 
• To evaluate the safety and tolerability by collection of AE/SAE incidence 
 
• To measure the vital signs (BP, HR, and Body temperature) 
 
• To measure subject’s total lipid profile, which includes Triglyceride, LDL and HDL. 
 
• To measure subject’s thyroid profile: TSH, free T4 and free T3. 
 
• 12 –lead ECG. 
 
7.2.4 Patient Diary Assessment 
 
Subjects will be provided with an electronic diary at screening visit in order to collect the 
patient reported outcome components of the total Mayo score (see Appendix 1), including the 
following information: 
 
• ‘Normal’ number of stools per day, when not having a flare, and will be collected only 
once. 
• Number of stools currently per day. 
• Presence of rectal bleeding currently (if any). 
 
Diary data will be assessed at the clinic, at each study visit from baseline (Day 0) until the 
end of follow up period (Week 18). The information extracted will be used for calculation of 
Mayo score taking into account the data recorded over the last 3 days prior to each study 
visit. Should any bowel preparation be required to perform the endoscopy examination 
(colonoscopy), last 3 days patient diary must be completed and assessed prior to any bowel 


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preparations. If data on any of these days is missing, the last 3 days closer to that day of bowel 
preparation/visit within the last 7 days before the day for bowel preparation/visit will used for 
calculation. In order to encourage consistent diary recording, subjects are required to enter diary 
data continuously throughout the study. 
 
7.2.5 Mayo Score Assessment 
 
Mayo score is an instrument designed to measure disease activity of ulcerative colitis. Mayo 
score ranges from 0 to 12 points. It consists of 4 subscores, each graded from 0 to 3 with 
higher scores indicating more severe disease (see Appendix 1) 
 
• stool frequency (0-3) 
• rectal bleeding (0-3) 
• findings of colonoscopy (0-3) 
• physician global assessment (PGA) (0-3) 
 
Mayo score is assessed at baseline and Week 8. If the subject scores ≥2 on the endoscopic 
sub-score of the Mayo Score at baseline and meet all other inclusion/exclusion criteria, the 
subject will be randomized. Should any bowel preparation be required to perform the 
colonoscopy, 3-day patient diary must be completed and assessed prior to any bowel preparation. 
For the baseline endoscopy, the duration of the time between endoscopy and baseline should not 
exceed 10 days.Baseline (Day 0 -Visit 2) endoscopy images/films (eligibility assessment) and 
Week 8 endoscopy images/films will be submitted to central lab for central reading. The central 
lab will send eligibility report to confirm eligibility. 
 
The physician global assessment (PGA) acknowledges the three other criteria: the patient’s 
daily recollection of abdominal discomfort and general sense of wellbeing, and other 
observations, such as physical findings and the patient’s performance status. 
 
Clinical response is defined as a decrease from baseline in Mayo score of at least 3 points 
and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at 
least 1 point or absolute subscore for rectal bleeding of 0 or 1. Clinical remission is defined as a 
total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point. 
 
Endoscopic response is defined as decrease from baseline in the findings of the colonoscopy 
subscore of the Mayo Score ≥ 1. Endoscopic remission is defined as the findings of colonoscopy 
subscore of the Mayo score equals 0. 
 
7.2.6 9-point Modified Mayo Score 
 
9-point modified Mayo score is the Mayo score excluding physician global assessment 
(PGA)subscore, hence the maximum is 9 points and minimum 0 point. By removing the PGA, it 
removes the subjective view/assessment from the physicians hence reducing bias. It is also a 
recommended assessment by the regulators. 9-point modified Mayo score will be collected as a 
primary endpoint at baseline (Visit 2) and week 8 (Visit 5). This has been advised by the US 
FDA according to FDA guidance on ulcerative colitis trial (10). 


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7.2.7 Partial Mayo Score Assessments 
 
A partial Mayo score (Mayo score without endoscopy component) will be assessed at 
baseline, week 1, week 4, week 8, week 9, week 12, week 16 and week 18, as secondary 
endpoints. 
 
7.2.8 Colonoscopy 
 
Endoscopy examination (colonoscopy) will be required at baseline and Week 8 and it will 
be performed in order to establish Mayo endoscopic subscore and confirm patient eligibility for 
the study at baseline. The duration of the time between endoscopy and baseline should not 
exceed 10 days. As per Surveillance Guidelines for patients with ulcerative colitis, all subjects 
who have not had colonoscopy performed within last 10 years from onset of symptoms will 
require colonoscopy procedure for screening surveillance. An appropriately trained endoscopist 
should perform the colonoscopy. Where possible the same endoscopist should perform the 
endoscopy for both baseline and Week 8 visits, where this is not possible it should be clearly 
documented who performed each endoscopy procedure. 
 
7.3 Safety Assessment 
 
7.3.1 Vital Signs 
 
Vital signs measurements will include heart rate and systolic and diastolic blood pressure, 
and body temperature. Vital signs will be obtained after subjects have rested for approximately 5 
minutes and before performing ECG. A single set of values will be obtained. 
 
Vital signs will be performed using equipment provided by investigational sites and will be 
obtained at visits and time points as detailed in the Section 5.12 –Time and Event Table. 
 
7.3.2 12 lead ECG 
 
12-lead ECG measurement and rhythm strip (10 seconds) will be obtained after 
measurement of vital signs. Triplicate ECG measurements are collected at rate of 3 ECGs over 5 
minutes period. After vital signs are obtained subjects should be placed in the supine position for 
the ECG measurements. 
ECG measurements will be taken at various visits and time points as detailed in Section 
5.12 –Time and Event Table. The investigator, a designated sub-investigator, or other 
appropriately trained site personnel will be responsible for performing 12-lead ECG assessments. 
The investigator must provide his/her dated signature on the original paper tracing, attesting to 
the authenticity of the ECG machine interpretation. The investigator will review the ECG and 
determine if the subject should continue the study. 


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7.3.3 Tuberculin Test (PPD) 
 
Subjects must have a screening tuberculin test (PPD) administered and then evaluated by a 
health care professional (nurse or doctor) 48 to 72 hours later in order to be eligible for the 
study, unless performed and documented within the last 3 months. The test consists of 
intracutaneous injection of Tuberculin, concentration as per local medical standard of 
practice, on the volar aspect of the forearm, using a short beveled 26- or 27- gauge needle 
(Mantoux test). The test is positive if the induration’s diameter (not erythema) is ≥5 mm 48 
to 72 hours after injection. Subjects who have previously received BCG vaccination will be 
tested by QuantiFERON Gold/or T-Spot test in place of Mantoux PPD and have these results 
determine patient eligibility for participation. 
 
7.3.4 QuantiFERON test/or T-Spot test 
 
At the discretion of the investigator, a QuantiFERON Gold®™ (11) test /or T-Spot test (11) 
conducted in local lab may be substituted for the PPD skin test. A description of the 
QuantiFERON Gold test follows: “This Enzyme-linked Immunosorbent Assay (ELISA) test 
detects the release of Interferon-gamma (IFN-γ) in fresh heparinized whole blood from 
sensitized persons when it is incubated with mixtures of synthetic peptides simulating two 
proteins present in M. tuberculosis: Early Secretory Antigenic Target-6 (ESAT-6) and 
Culture Filtrate Protein-10 (CFP-10). ESAT-6 and CFP-10 are secreted by all M. 
tuberculosis and pathogenic M. bovis strains. Because these proteins are absent from all Bacille 
Calmette-Guérin (BCG) vaccine strains and from commonly encountered Non 
Tuberculous. Mycobacteria (NTM) except M. kansasii, M. szulgai, and M. marinum, QFT-G is 
expected to be more specific for M. tuberculosis than tests that use tuberculin Purified Protein 
Derivative (PPD) as the antigen”. 
T-Spot is another IFN-γ release assays in diagnosing M. tuberculosis infection. For this test, 
peripheral blood mononuclear cells (PBMCs) are incubated with two mixtures of peptides, one 
representing ESAT-6 and the other representing CFP-10. The test uses an enzyme-linked 
immunospot assay (ELISpot) to detect increases in the number of cells that secrete IFN-γ. 
In the situation QFT-G or T-Spot is unavailable by local testing, incubated whole blood sample 
could be sent to central lab for QFT-G testing. If QFT-G/or T-Spot result is indeterminate, a 
retest is required at earliest to determine the eligibility of the subject. If retest is indeterminate or 
positive, the subject should be screen failed. If retest is negative, the PI should assess the 
subject’s clinical condition and decide if the subject could be included. 
 
7.3.5 Clinical Laboratory Testing 
 
Routine, non-fasting clinical laboratory (hematology and chemistry and urinalysis) tests will 
be performed as detailed in Section 5.12 –Time and Event Table. At the discretion of the 
investigator, additional samples may be taken for safety reasons. All blood samples will be 
measured at a designated central laboratory. 
 
A urine pregnancy test will be performed for all females of child bearing potential as detailed in 
Table 3. 


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The study clinical laboratory tests including analytes for clinical chemistry and hematology are 
shown below in Table 3. 


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Table 3. Clinical Laboratory Testing Lists 
 
CHEMISTRY 
HEMATOLOGY 
Urinalysis 
OTHER 
Albumin 
Haemoglobin 
pH 
Hepatitis B surface antigen1 
Alkaline phosphatase 
Haematocrit 
Protein 
Hepatitis C virus antibody1 
Alanine amino-transferase 
(ALT or SGPT) 
Platelet count 
Glucose 
HIV test1 
Aspartate amino- 
transferase (AST or 
SGOT) 
WBC count 
Bilirubin and White 
Cell Count 
Urine pregnancy test (in clinic)2 
Bilirubin, direct 
RBC count 
FSH 3 
Bilirubin, indirect 
Neutrophils, absolute 
β-HCG blood test 4 
Bilirubin, total 
Neutrophils, segs (%) 
Lipid Profile5 (fasting): Total 
Cholesterol， 
Low Density Lipoprotein (LDL) 
High Density Lipoprotein 
(HDL) Triglycerides 
Calcium 
Neutrophils, bands (%) 
Stool culture /microscopy for: 
Salmonella, 
Shigella, 
Campylobacter， 
Fecal Ova and Parasites 
Chloride 
Basophils (%) 
Clostridium difficile toxin 
CO2 content/Bicarbonate 
Eosinophils (%) 
Fecal calprotectin6 
Creatinine 
Eosinophils , absolute 
Thyroid Function Test, including 
TSH, free T4 and free T3. 
Creatine phosphokinase 
(CPK), total 
Lymphocytes (%) 
PK sampling7 
Gamma glutamyl 
transferase (GGT) 
Monocytes (%) 
CRP 
Glucose 
Phosphorus 
Potassium 
Protein, total serum 
Sodium 
Urea nitrogen (BUN) 
Uric Acid 
1 Assessed at Visit 1 (Screening) only 
2 all visits subsequent to the screening visit 
3 FSH to confirm postmenopausal status at screening visit only 
4 Only for females of child-bearing potential at screening, and if urine pregnancy test positive 
5 fasting lipid profile will be done as per Section 5.12 Time and Event table. 
6 for biomarker assessment 
7 Only done as per Section 7.4 Pharmacokinetics 
 
 
7.3.6 C-Reactive Protein (CRP) 
 
C-reactive protein is considered an acute-phase protein which provides an objective 
criterion of inflammatory activity. CRP has a short half-life (19 hours) and therefore rises early 
after the onset of inflammation and rapidly decreases after resolution of the inflammation (12). It 
is induced by interleukin-6, TNF-α and other proinflammatory cytokines that are produced 


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within the intestinal lamina propria. CRP measurements will be collected at screening, baseline, 
Week 1, 4, 8, 9, 12, 16 and 18 and will be analyzed by a central laboratory. 
 
7.3.7 Fecal Calprotectin 
 
Fecal calprotectin is a 36kDa calcium and zinc binding protein which is neutrophil derived 
and it represents 60% of cytosolic proteins in granulocytes. It is considered as a measurement of 
neutrophil migration to the gastrointestinal tract. Fecal calprotectin is a very stable marker (stable 
for one week at room temperature). There is a growing body of evidence that fecal calprotectin 
correlates well with disease activity and making it a useful tool in monitoring disease and 
treatment (13). Fecal calprotectin measurement will be collected as detailed in Section 5.12 – 
Time and Event table, from screening until the end of study visit (week 18) and will be analyzed 
by a central laboratory. 
 
Subjects will be supplied with stool sample collection kits in advance and will be instructed 
to collect the sample at home, 1 day before the upcoming visit at which they have to provide the 
sample. Fecal samples (~20 g) for analysis of fecal calprotectin will be collected into the labeled 
stool collection containers, at protocol specified times (see Section 5.12 –Time and Event table) 
and shipped to central laboratory based on the laboratory manual. Samples will be analyzed using a 
validated analytical method. 
 
7.3.8 Lipid Profile Testing 
 
A fasting lipid profile blood collection, as per Section 5.12 –Time and Event table, will 
require subjects to refrain from all food and liquids (water and non-study medications permitted) 
for at least 10 hours prior to scheduled laboratory tests. 
 
7.3.9 Liver Chemistry – Stopping and Follow-up Criteria 
 
Phase II liver chemistry stopping and follow up criteria have been designed to assure 
subject safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance). 
 
Phase II liver chemistry stopping criteria 1-5 are defined below: 
 
1. ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) (or ALT ≥3xULN 
and INR>1.5, if INR measured). 
 
NOTE: if serum bilirubin fractionation is not immediately available, study drug should be 
discontinued if ALT ≥3xULN and bilirubin ≥2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury. 
 
2. ALT ≥ 5xULN. 


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3. ALT ≥ 3xULN if associated with the appearance or worsening of symptoms of 
hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash or eosinophilia. 
 
4. ALT ≥ 3xULN persists for ≥ 4 weeks. 
 
5. ALT ≥ 3xULN and cannot be monitored weekly for 4 weeks 
 
When any of the liver chemistry stopping criteria 1-5 is met, do the following: 
 
• Immediately withdraw investigational product. 
 
• Report the event to Reistone/designated CRO within 24 hours of learning its 
occurrence. 
 
• Complete the liver event eCRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% 
direct bilirubin) (or ALT ≥3xULN and INR>1.5, if INR measured; INR 
measurement is not required and the threshold value stated will not apply to patients 
receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). 
 
NOTE: if serum bilirubin fractionation is not immediately available, study drug should be 
discontinued if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury. 
 
• Complete the liver imaging and/or liver biopsy eCRFs if these tests are performed 
• Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below. 
 
• Withdraw the subject from the study (unless further safety follow up is required) 
after completion of the liver chemistry monitoring as described below. 
 
• Do not re-challenge with investigational product. 
 
In addition, for criterion 1: 
 
• Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow-up assessments (see below), and close 
monitoring. 
 
• A specialist or hepatology consultation is recommended. 


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• Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilise or return to within baseline values 
 
For criteria 2, 3, 4 and 5: 
 
• Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (see below) 
 
• Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible. 
 
Subjects with ALT ≥3xULN but <5xULN and bilirubin <2xULN, without hepatitis 
symptoms or rash, and who can be monitored weekly for 4 weeks: 
 
• Notify the Reistone/designated CRO medical monitor within 24 hours of learning of 
the abnormality to discuss subject safety. 
 
• Can continue investigational product. 
 
• Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to within baseline. 
 
• If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above. 
 
• If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values. 
 
For criteria 1-5, make every attempt to carry out the liver event follow up assessments 
described below: 
 
• Viral hepatitis serology including: 
− Hepatitis A IgM antibody; 
− Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
− Hepatitis C RNA; 
− Cytomegalovirus IgM antibody; 
− Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing); 
− Hepatitis E IgM antibody 
 
• Blood sample for pharmacokinetic (PK) analysis, obtained within 24 hours of last dose. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of 
investigational product prior to blood sample draw on the eCRF. If the date or time of the 


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last dose is unclear, provide the subject’s best approximation. If the date/time of the last 
dose cannot be approximated OR a PK sample cannot be collected in the time period 
indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SPM. 
 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
 
• Fractionate bilirubin, if total bilirubin≥2xULN. 
 
• Obtain complete blood count with differential to assess eosinophilia. 
 
• Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form. 
 
• Record use of concomitant medications, acetaminophen, herbal remedies, other over the 
counter medications, or putative hepatotoxins, on the concomitant medications report 
form. 
 
• Record alcohol use on the liver event alcohol intake eCRF. 
 
The following are required for subjects with ALT ≥3xULN and bilirubin ≥2xULN (>35% 
direct) but are optional for other abnormal liver chemistries: 
 
• Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies. 
 
• Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate 
liver disease. 
 
7.3.10 Pregnancy 
 
If the subject is found to be pregnant, the subject must be withdrawn immediately, and any 
sponsor-supplied drug (SHR0302, placebo) should be immediately discontinued. In addition, any 
pregnancies in the partner of a male subject during the study, should also be recorded following 
authorization from the subject’s partner. Any pregnancy that occurs after the first dose of 
investigational drug must be reported using a clinical trial pregnancy form. To ensure subject 
safety, each pregnancy must be reported to Reistone Biopharma/designated CRO within 24 hours 
of learning of its occurrence. The pregnancy must be followed up to determine outcome 
(including premature termination) and status of mother and the newborn should be followed up 
to 1 month after birth. Pregnancy complications and elective terminations for medical reasons 
must be reported as an AE or SAE. Pregnancies will remain blinded to the study team. 
 
Should the pregnancy occur during or after administration of blinded drug, the investigator 
must inform the subject of their right to receive treatment information. If the subject chooses to 


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receive unblinded treatment information, the individual blind should be broken by the 
investigator. Subjects randomized to placebo need not be followed in the treatment phase. 
 
If the female subject and/or female partner of a male subject agrees to the primary care 
physician being informed, the investigator should notify the primary care physician that the 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of treatment the subject received (blinded or unblinded, as 
applicable). 
 
Spontaneous abortions must be reported as an SAE. Any SAE occurring in association with 
a pregnancy brought to the investigator’s attention after the subject has completed the study and 
considered by the investigator as possibly related to the study treatment, must be promptly 
reported to Reistone Biopharma/designated CRO. 
 
7.3.11 Adverse Events 
 
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
 
7.3.12 Definition of AE 
 
Any untoward medical occurrence in a patient or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
 
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a medicinal product. For marketed medicinal products, this also includes failure to produce 
expected benefits (i.e., lack of efficacy), abuse or misuse. 
Events meeting the definition of an AE include: 
 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
• New conditions detected or diagnosed after study treatment administration even though it 
may have been present prior to the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE). 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting 
from lack of efficacy will be reported if they fulfil the definition of an AE or SAE. 


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Events that do not meet the definition of an AE include: 
 
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads 
to the procedure is an AE 
• Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
• The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition 
AEs which meet all of the following criteria: 
• Serious 
• Unexpected (as per assessment according to safety information in Investigator Brochure) 
• There is at least a reasonable possibility that there is a causal relationship between the 
event and the medicinal product 
will be classified as Suspected Unexpected Serious Adverse Reactions (SUSARs) and should be 
reported to the relevant ethics committee and to the relevant Health Authorities in accordance 
with applicable regulatory requirements for expedited reporting. Sponsor/designated CRO will 
report SUSARs to the ethics committee and relevant health authorities. 
 
7.3.13 Definition of SAE 
 
A serious adverse event is any untoward medical occurrence that, at any dose: 
 
a. 
Results in death 
b. Is life-threatening 
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
out-patient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
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d. Results in disability/incapacity, or 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition. These should also be considered serious. Examples of such 
events are invasive or malignant cancers, intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
g. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT ³ 
3xULN and bilirubin ³ 2xULN (>35% direct) (or ALT ³ 3xULN and INR>1.5, if INR 
measured) termed ‘Hy’s Law’ events (INR measurement is not required and the threshold 
value stated will not apply to patients receiving anticoagulants). 
 
NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin elevations 
and suggesting liver injury. If testing is unavailable and a subject meets the criterion of total 
bilirubin ³ 2xULN, then the event is still reported as an SAE. If INR is obtained, include values 
on the SAE form. INR elevations >1.5 suggest severe liver injury. 
 
7.3.14 AE and SAE reporting requirement and timeline 
 
The investigator or site staff is responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE. AEs will be collected from the start of study treatment 
(Visit 2) and until the follow up contact. SAEs will be collected from the time a subject consent 
to participate in the study up to and including any follow up contact. 
 
All SAEs will be reported to Reistone Biopharma/designated CRO within 24 hours. Prompt 
notification of SAEs by the investigator to Reistone Biopharma/designated CRO is essential so 
that legal obligations and ethical responsibilities towards the safety of subjects are met. All SAEs 
will be followed up until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up. Once resolved, the SAE eCRF page will be 
updated. The investigator should report SAE/serious incident per local regulations and local EC 
requirement.  The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the SAE. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 


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Reistone Biopharma/designated CRO has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation according to local regulations. Reistone Biopharma/designated CRO will comply 
with country specific regulatory requirements relating to safety reporting to the regulatory 
authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and 
investigators. 
 
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Reistone Biopharma/designated CRO policy and 
are forwarded to investigators as necessary. 
 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from Reistone 
Biopharma/designated CRO will file it with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
 
7.3.15 Adverse Event of Special Interest (AESI) 
 
The AE of special interest (AESI) (serious or non-serious) are determined based on previous 
knowledge about the disease and the mechanism of action of the investigational drug, as well as 
safety information from a similar class of drug. AESI is one of scientific and medical concern 
specific to the product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor may be appropriate. Such events require heightened surveillance and 
further investigation in order to characterize and understand them. The AESI will be managed and 
follow-up according to the SAE timeline and procedure. The study’s AESI includes. 
 
• Serious infection: Serious infection is defined as any infection (viral, bacterial, and fungal) 
requiring hospitalization or parenteral antimicrobials for more than 3 days. 
 
• Thromboembolic event: Thromboembolic events are divided into two major groups which are 
venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary 
embolism (PE), and arterial thromboembolic events, including arterial thrombosis and 
cerebrovascular accident (CVA). 
 
 
 
7.4 Pharmacokinetics 
 
Blood samples for pharmacokinetic exposure-response analysis of SHR0302 will be collected 
from randomized subjects at the following time points (Table 4): 
 
Table 4 Pharmacokinetic Sampling Schedule 
Week 4 (Visit 4) 
Week 8 (Visit 5) 
In all subjects; 
In all subjects; 


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-One Pre-dose PK blood sample (within 1 
hour before dosing). 
-One Post-dose PK blood sample (1-2 
hours post dose). 
-One Pre-dose PK blood sample (within 
1 hour before dosing). 
-One Post-dose PK blood sample (at any 
time between 2 to 8 hours post dose). 
 
 
For the clinic visits at which blood samples for PK analysis are taken, the exact times and 
dates that the study medication is taken at the visit should be recorded on the source document 
and in the eCRF. The exact time and date of the blood sample collection should also be 
documented in the eCRF. For details regarding PK blood samples collection, processing and 
shipping are provided in the laboratory manual. For SHR0302 pharmacokinetics evaluation, the 
following windows for blood sample collection time are allowed: 
• At Week 4 (Visit 4): a sample within 1 hour prior to dosing and a sample between 1 to 2 
hours post dose 
• At Week 8 (Visit 5): a sample within 1 hour prior to dosing and a sample at any time 
between 2 to 8 hours post dose 
 
On the days of PK sampling at Week 4 and 8, subjects are to take the first dose of study 
medication for the day at the study site. 
Samples will be analyzed using a validated analytical method. Only samples from subjects 
who have received active treatment (i.e., SHR0302 tablets) will be measured for the analytes 
(SHR0302). Contracted PK analysis laboratory personals will be unblinded for the analysis 
purpose. Samples from subjects receiving placebo will not be analyzed. 
8. Data Management 
 
For this study subject data will be entered into Reistone Biopharma/designated CRO 
defined electronic case report forms (eCRFs), transmitted electronically to Reistone Biopharma 
/designated CRO and combined with data provided from other sources in a validated data 
system. Management of clinical data will be performed in accordance with applicable Reistone 
Biopharma/designated CRO data review, verification and cleaning procedures to ensure the 
integrity of the data, e.g., removing errors and inconsistencies in the data. Adverse events and 
concomitant medications terms will be coded using MedDRA. An appropriate medical dictionary 
that covers all approved drugs in the region will be referenced. eCRFs (including queries and 
audit trails) will be retained by Reistone Biopharma/designated CRO, and copies will be sent to 
the investigator to maintain as the investigator copy. In all cases, subject initials will not be 
collected or transmitted to Reistone Biopharma/designated CRO. 
9. Data Analysis and Statistical Considerations 
9.1 Hypothesis 
 
The primary objective of the study will be evaluated for SHR0302 dose groups (8mg QD, 
4mg BD, 4mg QD) compared to placebo group with respect to the percentage of patients with 
clinical response at week 8. 


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No 
Yes 
Reject all null 
hypotheses and stop 
Test if p (2)>0.05 
Test if p (1)>0.1/3 
No 
Yes 
Yes 
Reject H (02) and H (01) 
and stop 
 
 
The Hochberg method will be used to maintain the 2-sided study-wise Type I error rate at 
0.1. The null and alternative hypothesis for the primary endpoint that will be tested are: 
 
H01: The percentage of patients with clinical response at week 8 in SHR0302 8mg group – the 
percentage of patients with clinical response at week 8 in placebo group = 0; 
H11: The percentage of patients with clinical response at week 8 in SHR0302 8mg group – the 
percentage of patients with clinical response at week 8 in placebo group ≠ 0. 
 
H02: The percentage of patients with clinical response at week 8 in SHR0302 4mg BD group – 
the percentage of patients with clinical response at week 8 in placebo group = 0; 
H12: The percentage of patients with clinical response at week 8 in SHR0302 4mg BD group – 
the percentage of patients with clinical response at week 8 in placebo group ≠ 0. 
 
H03: The percentage of patients with clinical response at week 8 in SHR0302 4mg QD group – 
the percentage of patients with clinical response at week 8 in placebo group = 0; 
H13: The percentage of patients with clinical response at week 8 in SHR0302 4mg QD group – 
the percentage of patients with clinical response at week 8 in placebo group ≠ 0. 
 
Two-sided p-values for the treatment group differences will be provided for all comparisons by 
using CMH test. Thus, 3 p-values will be gained and start with the least significant comparison 
and continue as long as tests are not significant until the first time when a significant comparison 
occurs and all remaining hypotheses will be rejected. Order the three p values as (p(3), p(2), p(1)), 
where p(3) ≥ p(2) ≥ p(1). The decision rules are provided in below figure (Figure 2). 
 
 
 
 
 
No 
 
 
 
 
 
Figure 2. The decision rules of hypothesis 
 
9.2 Study Design Considerations 
9.2.1 Sample Size Assumptions 
 
The sample size calculation is based on pairwise comparison of clinical response at week 8 
among SHR0302 8mg, 4mg QD, 4mg BD dose group and placebo group at the 2-sided 0.1 
significance level. 57%, 57%, 50%, 30% clinical response are assumed for 8mg QD, 4mg BD 
and 4mg QD dose group, placebo group at week 8 respectively. The planned sample size of 35 
evaluable subjects per treatment group will provide 80% global power to detect at least 1 dose 
None of the 
hypotheses were 
rejected 
Reject H (01)   and stop 
p (3)>0.1 


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group is different from placebo group by using Hochberg’s step up test. The total sample size is 
152 randomized subjects with consideration of 8% drop out rate. 
 
9.3 Data Analysis Considerations 
 
9.3.1 Analysis Dataset 
 
• 
Full analysis set (FAS) 
 
Full analysis set (FAS) will comprise of all randomized subjects who have received any 
amount of IP and have observed analysis data in at least one valid Mayo related score. All 
summaries of baseline and demographic data and all listings will be produced for the FAS 
population. In the full analysis set, subjects will be analyzed according to randomized treatment, 
regardless of the treatment received. 
 
• 
Per protocol Analysis set (PPS) 
 
Per protocol set (PPS) is defined as all subjects from FAS who do not have significant 
protocol violation. 
• 
Safety analysis Set (SS) 
 
The Safety analysis set will comprise all subjects who received any amount of 
investigational product (IP) and will be based on the actual treatment received, if this differs 
from that to which the subject was randomized to. The Safety analysis set will be used for all 
summaries of safety data. 
9.3.2 Treatment Comparison of interest: Primary and others 
Primary comparison: 
SHR0302 8mg QD versus placebo, Week 8; 
SHR0302 4mg BD versus placebo, Week 8; 
SHR0302 4mg QD versus placebo, Week8. 
 
9.3.3 Interim Analysis 
 
The primary analysis will occur after all subjects have the opportunity to complete the 8- 
week treatment phase study visit 
 
9.3.4 Key Elements of Analysis Plan 
 
9.3.4.1 General Approach 
In general, continuous variables will be summarized using number of non-missing 
observations, mean, median, standard deviation (SD), minimum, and maximum. Categorical 
variables will be summarized using frequency counts and percentages. 


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9.3.4.2 Missing Data 
 
Binary data: Non-completers considered failure (NCF) will be used. 
Continuous data: Last-observation-carried-forward (LOCF) approach will be used 
 
9.3.4.3 Efficacy Analysis 
 
Analysis of the Primary Efficacy Endpoint 
 
The primary analysis will be based on the FAS population. In addition, an analysis of the PPS 
population will be used to support the primary efficacy analysis. 
 
For clinical response at week 8, the comparisons of the percentage of subjects achieving clinical 
response in each treatment versus placebo will be made using a stratified Cochran-Mantel- 
Haenszel (CMH) test with stratification according to prior anti- TNFα/biological treatment (with 
or without). Missing data will be imputed as Non-completers considered failure (NCF). 
 
Sensitivity analyses for the primary endpoint include: (1) the same analysis using the 
per-protocol analysis set (2) using last-observation-carried-forward (LOCF) imputation for 
subscore other than endoscopy of Mayo score. 
 
Analysis of the Secondary Efficacy Endpoints 
 
Dichotomized secondary efficacy endpoints listed below will be analyzed by using a CMH Chi- 
Square test with stratification according to prior anti- TNFα treatment (with or without). Missing 
data will be imputed as Non-completers considered failure (NCF). 
 
✓ The percentage of subjects with clinical remission (per 9-point modified Mayo score) at week 
8 
✓ The percentage of subjects with clinical remission (per total Mayo score) at week 8 
✓ The percentage of subjects achieve endoscopic remission at week 8 
 
The continuous secondary endpoints listed below will be analyzed using an analysis of 
covariance (ANCOVA) model including treatment group, baseline value, with/without previous 
exposure to anti-TNFα treatment as main effects. Missing data will be imputed by using Last- 
observation-carried-forward (LOCF) approach for subscore other than endoscopy of Mayo score. 
 
✓ Change from baseline in 9-point modified Mayo score at week 8 
✓ Change from baseline in total Mayo score at week 8 
✓ Changes from baseline in partial Mayo score (Mayo score without endoscopy) at week 1, 4, 
8, 9, 12 and 16. 
✓ Change from baseline in the level of biomarkers CRP, fecal calprotectin. 
 
9.3.4.4 Safety Analysis 
 
Summaries of safety data will be based on the safety analysis set. 


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Adverse events will be grouped by Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class (SOC) and preferred term (PT) and summarized by actual treatment. 
Treatment emergent AEs are defined as AEs which commence on or after the time of start of IP 
administration. Adverse events without an onset date or time or AEs with an onset date of the date 
of IP administration but without an onset time will be defined as treatment emergent, except if an 
incomplete date (e.g., month and year) clearly indicates that the event started before administration 
of IP or if the AE stop date indicates that the event stopped before administration of IP. 
 
Treatment emergent AEs will be summarized for each SHR0302 dose level and placebo. The 
number and percentage of subjects experiencing AEs and the number of TEAEs will be tabulated. 
 
The following summaries will be presented: 
✓ Overall summary of TEAEs. 
✓ All TEAEs by SOC and PT. 
✓ All TEAEs by SOC, PT, and severity. 
✓ All TEAEs by SOC, PT, and relationship to IP. 
✓ Serious AEs by SOC and PT. 
 
 
 
 
Separate listings will be prepared for deaths and AEs leading to study discontinuation. 
Observed values and actual changes from baseline of continuous laboratory parameters 
(hematology and biochemistry), dipstick urinalysis results evaluation (Normal, Abnormal Not 
Clinically Significant, or Abnormal Clinically Significant), vital signs, and ECG parameters will 
be summarized at each protocol scheduled time point, by actual treatment at each time point. 
Actual values and actual changes from baseline will be presented. Categorical outcomes will be 
summarized by frequency tabulations. Abnormal laboratory values will be flagged and will be 
identified in the listings. Microscopy data, if available, will be listed. 
Shift tables representing categorical change of laboratory results from baseline to each post 
baseline visit will be presented. QTcF prolongation and ECG interpretations will be summarized 
by frequency tabulations. 
 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary and will be grouped by PT. The summary tables will show the number and percentage 
of subjects by PT, for all subjects overall. Prior medications are those medications that were 
stopped prior to first study treatment. Concomitant medications are medications taken at least once 
after first study treatment. Medications stopped on the same day as first study treatment will be 
considered as prior medication only. Only concomitant medications will be summarized. Prior 
medications will be listed only. Prior and concomitant medications will be listed separately. For 
the summaries of concomitant medications, subjects who take the same medication (in terms of 
the PT) more than once will only be counted once for that medication. 
 
Physical examination and pregnancy data will be listed only. 


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Pharmacokinetic Analysis 
 
Plasma concentrations of SHR0302 will be summarized by treatment group and time point. 
The population pharmacokinetic analysis will be used to derive the pharmacokinetic parameters 
such as area under the curve (AUC), steady-state drug concentration (Css), maximum 
concentration (Cmax) and minimum concentration (Cmin). 
Pharmacodynamic parameters such as area under the effect curve (AUEC), minimum 
concentration (Cmin) and maximal percentage reduction (PRmax) for the various biomarkers (e.g. 
CPR and Fecal Calprotectin), efficacy and safety outcomes will be generated and summarized by 
treatment group. 
Relationships between the systemic exposure of SHR0302 and pharmacodynamic 
parameters may be explored by treatment group in table format and graphically. If data permit, 
the model will be used to evaluate the correlation between pharmacokinetics and efficacy, safety; 
these analyses and results will be reported separately from the study report. 
10. Study Conduct Considerations 
10.1 Regulatory and Ethical Consideration to GCP standard 
 
Prior to initiation of a study site, Reistone/designated CRO will obtain approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements. 
 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, 
including, but not limited to: 
 
• Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
approval of study protocol and any subsequent amendments. 
• Subject informed consent. 
• Investigator reporting requirements. 
Reistone/designated CRO will provide full details of the above procedures, either verbally, 
in writing, or both. Written informed consent must be obtained from each subject prior to 
participation in the study. 
 
10.2 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, molecular profiling supplement, informed consent forms, and other 
relevant documents, eg, recruitment advertisements, if applicable, from the IRB/IEC. All 
correspondence with the IRB/IEC should be retained in the Investigator File. Copies of IRB/IEC 
approvals should be forwarded to Reistone/designated CRO. 


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The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In that 
event, the investigator must notify the IRB/IEC and Reistone/designated CRO in writing 
immediately after the implementation. 
 
10.3 Informed Consent Process 
 
All parties will ensure protection of subject personal data and will not include subject names 
on any sponsor forms, reports, publications, or in any other disclosures, except where required by 
laws. 
 
In case of data transfer, Reistone/designated CRO will maintain high standards of 
confidentiality and protection of subject personal data. The informed consent form must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements. The informed 
consent form used in this study, and any changes made during the course of the study, must be 
prospectively approved by both the IRB/IEC and Reistone/designated CRO before use. 
 
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible 
risks associated with participation. The investigator, or a person designated by the 
investigator, will obtain written informed consent from each subject before any study-specific 
activity is performed. The investigator will retain the original of each subject's signed consent 
form. 
 
10.4 Study Monitoring and Quality Control 
 
During study conduct, Reistone/designated CRO will conduct periodic monitoring visits to 
ensure that the protocol and GCPs are being followed. The monitors may review source 
documents to confirm that the data recorded on eCRFs is accurate. The investigator and 
institution will allow Reistone/designated CRO monitors or its agents and appropriate regulatory 
authorities direct access to source documents to perform this verification. 
The study site may be subject to review by the institutional review board (IRB)/independent 
ethics committee (IEC), and/or to quality assurance audits performed by Reistone, or companies 
working with or on behalf of Reistone, and/or to inspection by appropriate regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
 
10.5 Study Site Closure 
 
Upon completion or termination of the study, the Reistone/designated CRO monitor will 
conduct site closure activities with the investigator or site staff (as appropriate), in accordance 
with applicable regulations, and GCP requirement. Reistone/designated CRO reserves the right 
to temporarily suspend or terminate the study at any time for reasons including (but not limited 
to) safety issues, ethical issues, or severe non-compliance.  If Reistone/designated CRO 


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determines that such action is required, Reistone/designated CRO will discuss the reasons for 
taking such action with the investigator or head of the medical institution (where applicable). 
When feasible, Reistone/designated CRO will provide advance notice to the investigator or head 
of the medical institution of the impending action. 
 
If a study is suspended or terminated for safety reasons, Reistone/designated CRO will 
promptly inform all investigators, heads of the medical institutions (where applicable), and/or 
institutions conducting the study. Reistone/designated CRO will also promptly inform the 
relevant regulatory authorities of the suspension/termination along with the reasons for such 
action. Where required by applicable regulations, the investigator or head of the medical 
institution must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination. 
 
10.6 Record Retention 
 
To enable evaluations and/or audits from regulatory authorities or Reistone/designated 
CRO, the investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent forms, copies of all CRFs, serious adverse event forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports). The records should be 
retained by the investigator according to ICH, local regulations, or as specified in the Clinical 
Study Agreement, whichever is longer. If the investigator becomes unable for any reason to 
continue to retain study records for the required period (eg, retirement, relocation), 
Reistone/designated CRO should be prospectively notified. The study records must be 
transferred to a designee acceptable to Reistone/designated CRO, such as another investigator, 
another institution, or to Reistone/designated CRO. The investigator must obtain 
Reistone/designated CRO’s written permission before disposing of any records, even if retention 
requirements have been met. 
 
10.7 Independent Data Monitoring Committee (IDMC) 
 
A data monitoring committee for efficacy is not required for this study. Data safety 
monitoring will be conducted on an ongoing basis by the Sponsor study team. 
 
 
10.8 Provision of study results to Investigators, posting to the Clinical Trial 
Registry and Publication. 
 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the opportunity 
to review the complete study results at a Reistone/designated CRO site or other mutually- 
agreeable location. 


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Reistone/designated CRO will also provide the investigator with the full summary of the 
study results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. Reistone/designated CRO will provide the investigator with the 
randomization codes for their site only after completion of the full statistical analysis. 
The results summary will be posted to the Clinical Study Register when appropriate determined 
by Reistone. 
 
In addition, a manuscript will be submitted to a peer-reviewed journal for publication. 
The results summary will be posted to the Clinical Study Register if required by legal agreement, 
local law or regulation. 
 
 
 
 
 
 
 
 
 
 
 
 
11. Reference 
 
1. Prideaux L. Inflammatory bowel disease in Asia: A systemic review. J Gastroenterol Hep 
2012; 27:1266-80. 
 
2. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, 
prevalence and environmental influences. Gastroenterol 2004; 126:1504-17. 
 
3. Johnston JA, Bacon CM, Riedy MC, et al. Signalling by IL-2 and related cytokines: 
JAKs, STATs, and relationship to immunodeficiency. J Leukocyte Biol 
1996;60(4):441-52. 
 
4. Ghoreschi K, et al. Janus kinases in immune signaling. Immunol Rev. 2009 March; 
228(1): 273-287. 
 
5. Tofacitinib US prescribing information. http://ra.xeljanz.com. 
 
6. Data on file; Hengrui Pharmaceutical. 
 
7. Sandborn WJ, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. 
N Engl J Med 2012; 367:616-24. 


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8. Sandborn W, et al. Tofacitinib as induction and maintenance therapy for ulcerative 
colitis. N Engl J Med 2017；376:1723-1736. 
 
9. Vermeire S, et al. Clinical remission in patients with moderate-to-severe Crohn’s disease 
treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, 
randomised, placebo-controlled trial. Lancet 2017; 389: 266–75 
 
10. US FDA. Ulcerative Colitis: Clinical trial endpoints. Guidance for industry. Aug 2016. 
 
11. Updated Guidelines for Using Interferon Gamma Release Assays to Detect 
Mycobacterium tuberculosis Infection – United States, 2010 
https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5905a1.htm 
 
12. Vermiere S, Van Assche G, Rutgeerts P. C-Reactive Protein as a Marker for 
Inflammatory Bowel Disease. Inflamm Bowel Dis 2004; 10:661-665. 
 
13. Smith LA, Gaya DR. Utility of faecal calprotectin analysis in adult inflammatory bowel 
disease. World J Gastroenterol. 2012;18(46):6782-6789. 
 
 
 
 
 
 
12.Appendices 
 
Appendix 1 Mayo Scoring System for Assessment of Ulcerative Colitis Activity* 
 
Stool frequency†: 
0 = Normal no. of stools for this patient 
1 = 1 to 2 stools more than normal 
2 = 3 to 4 stools more than normal 
3 = 5 or more stools more than normal 
Subscore, (0 to 3) =   
  
Rectal bleeding‡: 
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passes 
 
Subscore, (0 to 3) =   
 


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Findings on endoscopy: 
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern) £ 
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions) 
3 = Severe disease (spontaneous bleeding, ulceration) 
 
Subscore, (0 to 3) =   
 
 
Physician’s global assessment§: 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 
 
Subscore, (0 to 3) =   
 
 
 
TOTAL score of (0-12) =   
 
 
* The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease. 
 
† Each patient serves as his or her own control to establish the degree of abnormality of the 
stool frequency. 
 
‡ The daily bleeding score represents the most severe bleeding of the day. 
 
£ Mild friability has been removed according to the guidance issued by the Food and Drug 
Administration. 
 
§ The physician’s global assessment acknowledges the three other criteria, the patient’s 
daily recollection of abdominal discomfort and general sense of wellbeing, and other 
observations, such as physical findings and the patient’s performance status. 
 
9- point modified Mayo score and Partial Mayo score can be derived from the Mayo score. 
 
Adapted from: Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 
1987; 317 (26):1625-9 
Food and Drug Administration, Center for Drug Evaluation and Research(CDER), Ulcerative 
Colitis: Clinical Trial Endpoints Guidance for Industry(August 2016). 


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Appendix 2 Cockcroft-Gault Calculation 
 
The Cockcroft-Gault formula may be used to calculate an Estimated Creatinine Clearance, 
which in turn estimates Glomerular filtration rate (GFR). 
 
Est. Creatinine Clearance (mL/min) = ([140-Age(years)] x Weight(kg) x Factora) 
(72 x Serum Creatinine [mg/dL]) 
a Factor is equal to 0.85 in females, and 1.00 in males 


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Appendix 3 ECG Exclusion criteria 
 
An ECG finding that would preclude a subject from entering the trial is defined as a 12-lead 
tracing that is interpreted as, but not limited to, any of the following: 
• Sinus tachycardia ³110bpm 
*Note: sinus tachycardia ³110bpm should be confirmed by two additional readings at least 5 
minutes apart 
• Sinus bradycardia <45bpm 
*Note: Sinus bradycardia <45bpm should be confirmed by two additional readings at least 5 
minutes apart. 
• Multifocal atrial tachycardia 
• Junctional tachycardia (heart rate >100bpm) 
• Junctional escape complexes 
• Supraventricular tachycardia (>100bpm) 
• Ventricular tachycardias (sustained, polymorphic, or monomorphic) 
• Atrial fibrillation with rapid ventricular response (rate >100bpm) 
• Atrial flutter 


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• Evidence of bigeminy, trigeminy or multifocal premature ventricular complexes 
• Ventricular flutter 
• Ventricular fibrillation 
• Torsades de Pointes 
• R on T phenomenon 
• Wide QRS tachycardia (diagnosis unknown) 
• Electrical alternans 
• Pacemaker 
• Idioventricular rhythm – heart rate <100bpm 
• Evidence of Mobitz type II second degree or third degree atrioventricular (AV) block 
• AV dissociation 
• Bifascicular block 
• Trifascicular block 
• Left bundle branch block 
• For subjects without complete right bundle branch block: QTc(F) ³450msec or an 
ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T 
wave). 
• For subjects with complete right bundle branch block: QTc(F) ³480msec or an ECG 
that is unsuitable for QT measurements (e.g., poor defined termination of the T wave). 
*Note: All potentially exclusionary QT measurements should be confirmed by two 
additional readings at least 5 minutes apart. 
• Accessory pathway (Wolff-Parkinson-White, Lown-Ganong-Levine) 
• Myocardial infarction (anterior, inferior, posterior, lateral, septal, non-Q wave) 
• Pathological Q waves (defined as wide [>0.04 seconds] and deep [>0.4mV (4mm with 
10mm/mV setting)] or >25% of the height of the corresponding R wave, providing the R 
wave was >0.5mV [5mm with 10mm/mV setting], appearing in at least two contiguous 
leads. 
*Note: prior evidence (i.e., ECG obtained at least 12 months prior) of pathological Q waves that 
are unchanged are not exclusionary 


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Appendix 4 Prohibited Concomitant Medications 
 
The list of prohibited concomitant medications includes the following medications with 
moderate to potent inhibitory or inducing CPY3A systemic properties. 
Topical medications, eg, Ketoconazole cream, and grapefruit juice are not prohibited. 
 
CYP3A INHIBITORS 
CYP3A INDUCERS 
Atazanavir 
Barbiturates 
Telithromycin 
Carbamazepine 
Clarithromycin 
Efavirenz 
Clotrimazole 
Modafinil 
Delaviridine 
Nevirapine 
Fluvoxamine 
Phenobarbital 
Indinavir 
Phenytoin 
Itraconazole 
Rifabutin 
Ketoconazole 
Rifampin 
Mibefradil 
Saint John’s Wort 
Mifepristone 
Nevaripine 
Nefazodone 
Oxcarbazepine 
Nelfinavir 
Troglitazone 
Ritonavir 
Saquinavir 
Aprepitant 


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Erythromycin 
Fluconazole 
Diltiazem 


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Protocol Amendment No.01 
 
1. Section 1.4.2 Secondary Efficacy Endpoints, page 13, 14 
Change from 
1.4.2 Secondary Efficacy Endpoints 
 
• The percentage of subjects that achieve clinical remission per 9-point modified Mayo 
score at week 8, where stool frequency subscore ≤ 1, rectal bleeding subscore of 0, and 
endoscopic subscore ≤ 1 
• The percentage of subjects that achieve clinical remission at week 8 as per total Mayo 
score of 2 points or lower ≤2, with no individual subscore exceeding 1point and a rectal 
bleeding subscore of 0. 
· 
…… 
Change to 
1.4.2 Secondary Efficacy Endpoints 
 
• The percentage of subjects that achieve clinical remission per 9-point modified Mayo 
score at week 8, where stool frequency subscore ≤ 1, rectal bleeding subscore of 0, and 
endoscopic subscore ≤ 1 
• The percentage of subjects that achieve clinical remission at week 8 as per total Mayo 
score of 2 points or lower than 2, with no individual subscore exceeding 1point and a 
rectal bleeding subscore of 0. 
· 
…… 
Rationale: Refine Chinese translation of related secondary efficacy endpoints. 
2. Section 2.3 Dose Selection Rationale, page 16 
Change from 
Phase I single ascending dose (SAD) study investigated the oral dose range from 1mg to 100mg 
in healthy volunteers. 64 subjects were enrolled and completed the study with no early 
withdrawal. Within the investigated dose range, SHR0302 was well tolerated. All 64 subjects 
were included for safety analysis, where 16 subjects (25%) reported Adverse Events (AEs), of 
which majority of cases were Grade I to II AEs with neutrophils and lymphocytes reduction, 
except for a case of grade III neutrophils reduction in the 100mg group. All the AEs resolved and 
all patients recovered. There was no serious adverse events (SAEs) reported. 
Change to 
Phase I single ascending dose (SAD) study investigated the oral dose range from 1mg to 100mg 
in healthy volunteers. 64 subjects were enrolled and completed the study with no early 
withdrawal. Within the investigated dose range, SHR0302 was well tolerated. All 64 subjects 


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were included for safety analysis, where 16 subjects (25%) reported Adverse Events (AEs), of 
which majority of cases were Grade I to II AEs with neutrophils reduction and lymphocyte 
increase, except for a case of grade III neutrophils reduction in the 100mg group. All the AEs 
resolved and all patients recovered. There was no serious adverse events (SAEs) reported. 
 
Rationale: Typo correction to ensure the description consistent with SHR0302 Investigator 
Brochure. 
3. Section 5.2 Inclusion Criteria and 5.3 Exclusion Criteria, page 20 to 24 
Change from 
Bullet 
Change to 
Number 
Rationale: Number the inclusion and exclusion criteria. 
4. Section 5.2 Inclusion Criteria, page 20, 21 
Change from 
 
2. Active ulcerative colitis with a 9-point modified Mayo score of 5 to 9 points and endoscopic 
subscore of 2 to 3 (The duration of the time between endoscopy and baseline should not 
exceed 10 days and allow central over read turn over before randomization). 
 
4. Subjects previously not exposed to anti-TNF treatment (e.g., anti-TNF-naïve) or subjects 
previously exposed to anti-TNF therapy (eg; infliximab, adalimumab or certolizumab pegol) 
or other biological treatment (eg Vedolizumab) at a dose registered for the treatment of UC. 
The patients previously exposed to biological therapy should have discontinued the treatment 
for a minimum of 12 weeks prior to baseline. Subjects deemed by the treating physician as 
having inadequate response or intolerance to the conventional immune-suppressants (eg 
azathioprine, 6-mercaptopurine), anti-TNF or other biological treatments, or unable to 
receive these treatments for other reasons. 
 
6.   Subject must have no evidence of active, latent, or inadequately treated infection with 
Mycobacterium tuberculosis (i.e., tuberculosis [TB]), as defined by the following: 
 
A negative Mantoux Purified Protein Derivative (PPD) skin test result (≤ 5 mm of 
induration), or negative QuantiFERON TB Gold (QFT Gold test) performed within the 3 
months prior to/within screening; 
AND 
Subject must have a chest X-ray, taken within the 3 months prior to/within screening, and 
showing no changes suggestive of active TB infection. 


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AND 
Subject must have no history of either untreated or inadequately treated latent or active TB 
infection 
Change to 
 
2. Active ulcerative colitis with a 9-point modified Mayo score of 5 to 9 points and endoscopic 
subscore of 2 to 3 (The duration of the time between endoscopy and baseline should not 
exceed 10 days and allow central over read turn over before randomization). 
 
4. Subjects deemed by the treating physician as having inadequate response, loss of 
response or intolerance to the conventional treatment (immune-suppressants or 
corticosteroids), AND 
 
− Naïve to anti-TNF treatment (e.g. infliximab, adalimumab or certolizumab 
pegol) or other biological treatment (e.g. Vedolizumab); 
  OR 
− Previously exposed to anti-TNF therapy or other biological treatment having 
discontinued the treatment for a minimum of 12 weeks prior to baseline. 
 
6. Subject must have no evidence of active, latent, or inadequately treated infection with 
Mycobacterium tuberculosis (i.e., tuberculosis [TB]), as defined by the following: 
 
− A negative Mantoux Purified Protein Derivative (PPD) skin test result (≤ 5 mm of 
induration), or negative QuantiFERON TB Gold (QFT Gold test) /or T-Spot test 
performed within the 3 months prior to/within screening; 
AND 
− Subject must have a chest radiograph, taken within the 3 months prior to/within 
screening, and showing no changes suggestive of active TB infection. 
AND 
− Subject must have no history of either untreated or inadequately treated latent or active 
TB infection 
 
Rationale: Refine the Chinese translation of the 2nd inclusion criteria, to clarify the central 
reading result of endoscopy need to be ready before randomization. Clarify subjects who had 
inadequate response, loss of response or intolerance to conventional treatment (immune- 
suppressants or corticoserioids) could be included, whether the subjects previoulsy exposed to 
biological therapy or not. Allow T-Spot as an alternative test for TB infection screening. 
 
5. Section 5.3 Exclusion Criteria, page 21, 22 
Change from 


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3. Treatment naïve subjects diagnosed with ulcerative colitis (without previous exposure to 
treatment). 
7. Subjects receiving the following therapy: 
− Azathioprine/6-mercaptopurine, methotrexate, thalidomide within 7 days prior to 
baseline. 
− Cyclosporine, mycophenolate, tacrolimus within 4 weeks prior to baseline. 
− Interferon therapy within 8 weeks prior to baseline. 
− Anti-TNFα therapy/other biological therapies within 8 weeks prior to baseline. 
− Intravenous corticosteroids or rectally administered formulation of corticosteroids or 5- 
ASA within 2 weeks prior to baseline. 
9. Subjects with evidence of hematopoietic disorders: 
- 
Hemoglobin levels <9.0 g/dL or hematocrit <30% at screening visit or within the 3 
months prior to baseline. 
- 
An absolute white blood cell (WBC) count of <3.0 x 109/L (<3000/mm3) or Absolute 
Neutrophil Count (ANC) of <1.2 X 109/L (<1200/mm3) at screening visit or within 
the 3 months prior to baseline. 
- 
Thrombocytopenia, as defined by a platelet count <100 x 109/L (<100,000/mm3) at 
screening visit or within the 3 months prior to baseline. 
 
Change to 
 
3. Treatment naïve subjects diagnosed with ulcerative colitis, (without previous exposure to any 
of the following therapies for UC treatment: corticosteroids, immune-suppressants, or 
biological treatments). 
 
7. Subjects receiving the following therapy: 
− Azathioprine/6-mercaptopurine, methotrexate, thalidomide within 7 days prior to 
baseline. 
− Cyclosporine, mycophenolate, tacrolimus within 4 weeks prior to baseline. 
− Interferon therapy within 12 weeks prior to baseline. 
− Anti-TNFα therapy/other biological therapies within 12 weeks prior to baseline. 
− Intravenous corticosteroids or rectally administered formulation of corticosteroids or 5- 
ASA within 2 weeks prior to baseline. 
9. Subjects with evidence of hematopoietic disorders at screening: 
- 
Hemoglobin levels <9.0 g/dL or hematocrit <30%. 
- 
An absolute white blood cell (WBC) count of <3.0 x 109/L (<3000/mm3) or Absolute 
Neutrophil Count (ANC) of <1.2 X 109/L (<1200/mm3). 
- 
Thrombocytopenia, as defined by a platelet count <100 x 109/L (<100,000/mm3). 
 
Rationale: Clarify the definition of treatment naïve subjects in exclusion criteria. Claify the 
exclusion criteria for biological therapy use, in order to keep consistency with Section 5.2 
Inclusion Criteria. Refine the Chinese translation to clarify subjects receiving 5-ASA in rectally 
administrated formulation within 2 weeks prior to baseline should be excluded. Clarify subjects 
with hematopoietic disorders at screening should be excluded. 


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6. Section 5.7 Pre-Screen and Screen Failure, page 27 
 
Change from 
· 
…… 
• 
Reason subject failed screening 
• 
Primary method of subject recruitment 
• 
Serious Adverse Events (SAEs) information, if applicable only for any SAE considered 
as related to study participation (e.g., study treatment, protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a concomitant medication 
 
Change to 
· 
…… 
• 
Reason subject failed screening 
• 
Primary method of subject recruitment 
• 
Serious Adverse Events (SAEs) information, if any 
Rationale: Clarify SAEs will be recorded for screen failures, if any. 
7. Section 5.8 Early Withdrawal, page 28 
Change from 
· 
…… 
• 
Laboratory assessments (including chemistry, haematology, and pregnancy test for 
females of childbearing potential and routine urinalysis) 
• 
Evaluation of smoking status and smoking cessation counselling 
• 
Call IVRS to report subject’s early withdrawal from the study 
• 
Endoscopy, Mayo score, 9-point modified Mayo score, and partial Mayo score. 
 
Change to 
· 
…… 
• 
Laboratory assessments (including chemistry, haematology, and pregnancy test for 
females of childbearing potential and routine urinalysis) 
• 
Call IVRS to report subject’s early withdrawal from the study 
• 
Endoscopy, Mayo score, 9-point modified Mayo score, and partial Mayo score, if 
feasible. 
 
 
Rationale: Typo corretion. Clarify if data avalible, Endoscopy, and relevant Mayo scoring will 
be assessed. 


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8.   Section 5.9 Stopping Criteria, page 29 
Change from 
 
 
Withdrawal decisions are to be based on an average QTc value of triplicate ECGs. If an ECG 
demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief period, and then use the 
averaged QTc values of the 3 ECGs to determine whether the subject should be discontinued 
from the study. 
 
Change to 
Use the averaged QTc values of the 3 ECGs to determine whether the subject should be 
discontinued from the study. 
 
 
Rationale: Clarify the procedure of ECG to keep consistent with the Section 7.3.2 12 lead ECG, 
that triplicate ECGs mesurements are required, no matter the QT interval prolonged or not. 


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9.   Section 5.12 Time and Event Table, page 30-32 
 
Change from 
5.12 Time and Event Table 
See Table1. 
 
Table 1. Time and Event Table 
 
Period 
Screening 
Baseline 
Treatment Phase 
End of 
Treatment 
Phase 
Extension Phase 
End of 
Extension 
Phase 
Follow- 
up/EW11 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
-3 to -1 
0 
1 
4 
8 
9 
12 
16 
18 
Day 
-21 to -4 
0 
7± 2 days 
28± 3 days 
56± 3 days 
63± 2 days 
84± 3 days 
112± 3 days 
126± 5 days 
Procedures 
Written Informed Consent1 
x 
Demography/Medical 
History 
x 
Physical Examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chest X-ray2 
x 
Inclusion/Exclusion Criteria 
x 
Randomisation Criteria 
x 
Study medication 
dispensing 
x 
x 
x 
x 
Study medication 
accountability 
x 
x 
x 
x 
x 12 
Register Visit in IVRS3 
x 
x 
x 
x 
x 
x 
x12 
Endoscopy (colonoscopy)4 
x 4 
x 
x12 
Efficacy Assessments 
Patient Dairy5 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mayo Score 
x 
x 
x12 
9-point Modified Mayo 
Score 
x 
x 
x12 
Partial Mayo Score 
x 
x 
x 
x 
x 
x 
x 
x 
Safety Assessments 
12-lead ECG 
x 
x 
x 
x 
x 
x 
x 


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Vital Signs6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Event Assessment7 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory Assessments 
Haematology and 
Chemistry Tests 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Lipid Profile (Fasting) 
x 
x 
x 
x 
x 
x 
TSH, fT4, fT3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
QuantiFERON / PPD test 8 
x 
Hep B sur Ag, Hep C Ab, 
HIV test 
x 
Stool culture/ microscopy 
x 
CRP 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Faecal Calprotectin 
x 
x 
x 
x 
Urine Pregnancy Test9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
β-HCG (blood)10 
x 
PK Sampling 
x13 
x14 
Medication 
Concurrent Medication 
Assessment 
x 
x 
x 
x 
x 
x 
x 
x 
 
1. Written informed consent must be obtained prior to performing any Visit 1 procedures or initiating any alterations in a 
subject’s medications 
2. Only to be performed if there is no chest X-ray or CT scan available within 6 months of Visit 1 
3. IVRS is a randomisation machine used to record all the patient visit. 
4. Colonoscopy is completed by baseline (visit 2 – Day 0). The duration of time between endoscopy and baseline is no more than -10 days. 
5. 
Subject use an electronic diary to record disease related medical problems experienced during the study. 
6. 
Vital signs include resting blood pressure, heart rate, and body temperature. It is advised to measure them before any procedures or questionnaires. 
7. Adverse events and Serious Adverse Events to be collected from the start of the study drug (visit 2) until the 
Follow-Up phone call contact. However, any serious adverse events recorded as related to study participation 
will be recorded from the time of consent. 
8. Subjects who have previously receive BCG vaccination may be tested by QuantiFERON Gold test, and the 
result will determine the subject eligibility for participation. Investigator also has the option to use alternative 
PPD test. 
9. Urine pregnancy test to be done in females of childbearing potential only 
10. β-Human Chorionic Gonadotrophin(β-HCG) to be done in females of childbearing potential only if urine pregnancy test positive 
11. Early withdrawal visit should be done 2 weeks after last dose/decision of withdrawal. 
12. Only to be conducted in the early withdrawn subjects. 
13. At Week 4, a pre-dose PK blood sample is collected before medication. A post-dose PK blood sample is taken at any time between 1 to 2hrs after 
medication. Subject is to take study medication at the site. The medication intake time and the post dose blood sampling time need to be recorded in the eCRF. 


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14. At Week 8, a pre-dose PK blood sample is collected before medication. A post-dose PK blood sample is taken at any time between 2 to 8hrs after 
medication. Subject is to take study medication at the site. The medication intake time and the post dose blood sampling time need to be recorded in the eCRF. 
 
Change to 
5.12 Time and Event Table 
See Table1. 
 
Table 1. Time and Event Table 
 
Period 
Screening 
Baseline 
Treatment Phase 
End of 
Treatment 
Phase 
Extension Phase 
End of 
Extension 
Phase 
Follow- 
up/EW11 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
-3 to -1 
0 
1 
4 
8 
9 
12 
16 
18 
Day 
-21 to -4 
0 
7± 2 days 
28± 3 days 
56± 3 days 
63± 2 days 
84± 3 days 
112± 3 days 
126± 5 days 
Procedures 
Written Informed Consent1 
x 
Demography/Medical 
History 
x 
Physical Examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chest X-ray2 
x 
Inclusion/Exclusion Criteria 
x 
Randomisation Criteria 
x 
Study medication 
dispensing 
x 
x 
x 
x 
Study medication 
accountability 
x 
x 
x 
x 
x 12 
Register Visit in IVRS3 
x 
x 
x 
x 
x 
x 
x12 
Endoscopy (colonoscopy)4 
x 4 
x 
x12 
Efficacy Assessments 
Patient Dairy5 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mayo Score 
x 
x 
x12 
9-point Modified Mayo 
Score 
x 
x 
x12 
Partial Mayo Score 
x 
x 
x 
x 
x 
x 
x 
x 
Safety Assessments 


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Period 
Screening 
Baseline 
Treatment Phase 
End of 
Treatment 
Phase 
Extension Phase 
End of 
Extension 
Phase 
Follow- 
up/EW11 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
-3 to -1 
0 
1 
4 
8 
9 
12 
16 
18 
Day 
-21 to -4 
0 
7± 2 days 
28± 3 days 
56± 3 days 
63± 2 days 
84± 3 days 
112± 3 days 
126± 5 days 
Procedures 
12-lead ECG 
x 
x 
x 
x 
x 
x 
x 
Vital Signs6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Event Assessment7 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory Assessments 
Haematology and 
Chemistry Tests 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Lipid Profile (Fasting) 
x 
x 
x 
x 
x 
x 
TSH, fT4, fT3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
QuantiFERON /or T-Spot 
/or PPD test 8 
x 
Hep B sur Ag, Hep C Ab, 
HIV test 
x 
Stool culture/ microscopy 
x 
CRP 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Faecal Calprotectin 
x 
x 
x 
x 
Urine Pregnancy Test9 
x 
x 
x 
x 
x 
x 
x 
x 
β-HCG (blood)10 
x 
PK Sampling 
x13 
x14 
FSH15 
x 
Medication 
Concurrent Medication 
Assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
1. Written informed consent must be obtained prior to performing any Visit 1 procedures or initiating any alterations in a subject’s medications 
2. Only to be performed if there is no chest X-ray or CT scan available within 3 months of Visit 1 
3. IVRS is a randomisation machine used to record all the patient visit. 
4. Colonoscopy is completed by baseline (visit 2 – Day 0). The duration of time between endoscopy and baseline is no more than -10 days. 
5. 
Subject use an electronic diary to record disease related medical problems experienced during the study. 
6. 
Vital signs include resting blood pressure, heart rate, and body temperature. It is advised to measure them before any procedures or questionnaires. 


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7. Adverse events and Serious Adverse Events to be collected from the start of the study drug (visit 2) until the Follow-Up contact. However, any serious 
adverse events will be recorded from the time of consent. 
8. Investigator has the option to use PPD test, QuantiFERON Gold test or T-Spot for TB screening. Subjects who have previously receive BCG 
vaccination will be tested by QuantiFERON Gold test /or T-Spot test, and the result will determine the subject eligibility for participation. 
9. Urine pregnancy test to be done in females of childbearing potential only 
10. β-Human Chorionic Gonadotrophin(β-HCG) to be done in females of childbearing potential at screening visit, and only to be done if urine pregnancy test 
positive at other study visits. 
11. Early withdrawal visit should be done within 2 weeks after last dose/decision of withdrawal. 
12. Only to be conducted in the early withdrawn subjects. 
13. At Week 4, a pre-dose PK blood sample is collected before medication. A post-dose PK blood sample is taken at any time between 1 to 2hrs after 
medication. Subject is to take study medication at the site. The medication intake time and the post dose blood sampling time need to be recorded in the eCRF. 
14. At Week 8, a pre-dose PK blood sample is collected before medication. A post-dose PK blood sample is taken at any time between 2 to 8hrs after 
medication. Subject is to take study medication at the site. The medication intake time and the post dose blood sampling time need to be recorded in the eCRF. 
15. FSH to confirm postmenopausal status at screening visit only. 
 
Rationale: Correct the typos in Table 1 in Section 5.12 Time and Event Table, and the footnotes to ensure the procedures are 
consistent with subject selection criteria. Clarify chext X-ray to be performed if no chest X-ray or CT scan available within 3 months 
of Visit 1 instead of 6 months in footnote 2. Typo correction to clarify the follow up visit is not a phone-call contact and clarify any 
SAEs will be recorded from the time of consent in footnote 7. Allow T-Spot as an alternative test for TB infection screening.Clarify 
only serum β-Human Chorionic Gonadotrophin (β-HCG) is requested for pregnancy testing at screening visit and urine test is to be 
done from baseline. Clarify concurrent medication assessment should be done in Follow up/EW visit, in order to keep consistent with 
Section 6.6 Concomitant Medications. Clarify the early withdrawal visit should be done within 2 weeks after last dose/decision of 
withdrawl rather than after 2 weeks of last dose/decision of withdrawl in footnote 11. FSH test is listed in the table to confirm 
postmenopausal status at screening. 


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10. Section 6.1 Investigational Product/Placebo Supply, page 33 
 
Change from 
SHR0302 will be provided as combination of 4mg tablets, including the matching placebo by the 
Sponsor. At study visits on Day 0, and Week 4, sufficient trial medication will be dispensed to 
complete dosing for four weeks. 
 
Change to 
SHR0302 will be provided as combination of 4mg tablets, including the matching placebo by the 
Sponsor. At study visits on Day 0, and Week 4, sufficient trial medication will be dispensed to 
complete dosing for four weeks. 
 
 
Rationale: Refine the Chinese translation. 
 
 
11. Section 6.6.1 Permitted Concomitant Medications, page 36 
Change from 
• Oral 5-ASA or sulfasalazine are allowed providing that the dose is stable for at least 2 
weeks prior to baseline and during the study treatment period. 
 
• Oral steroids are allowed during the study up to the dose of 30 mg/day of prednisolone or 
equivalent, providing that the dose has not been commenced or increased within 2 weeks 
of baseline. 
Change to 
 
• Oral 5-ASA or sulfasalazine are allowed providing that the dose is stable for at least 2 
weeks prior to baseline and during the study treatment period. 
 
• Oral steroids are allowed during the study up to the dose of 30 mg/day of prednisolone or 
equivalent, providing that the dose has not been commenced or changed within 2 weeks 
of baseline and until to the end of treatment phase (Week 8). During the extension 
phase, tapering of the oral steroid dose can be commenced for subjects at 
investigator’s discretion, in accordance with the predefined tapering scheduled 
treatment: 
 
− Subjects receiving > 10 mg/day prednisolone or equivalent: taper dose by 5 
mg/week until a 10 mg/day dose (or equivalent) is reached, then continue 
tapering at 2.5 mg/week until 0 mg/day. 
− Subjects receiving ≤ 10 mg/day prednisolone or equivalent: taper dose by 2.5 
mg/week until 0 mg/day. 
If subject experiences worsening of signs or symptoms during the tapering 
schedule, in the opinion of the investigator, due to reduction in oral steroid daily 


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dose, the daily oral steroid dosage for the subject could be reverted to the preceding 
daily dosage instructed by the investigator, but should not exceed Baseline dose. 
 
Rationale: Provide oral steroids tapering guidance in permitted concomitant medications and 
refine the Chinese translation of oral steroids permittion. 
12. Section 6.6.2 Prohibited Medications, page 36, 37 
Change from 
The following medications are prohibited throughout the duration of the study: 
 
• azathioprine, 6-mercaptopurine, methotrexate and thalidomide within 7 days of baseline; 
• cyclosporine, mycophenolate and tacrolimus within 4 weeks of baseline; 
• interferon within 8 weeks of baseline and 
• anti-TNFα therapy/other biological treatment within 8 weeks of baseline; 
• intravenous corticosteroids or rectally administered formulation of corticosteroids or 5- 
ASA within 2 weeks prior to baseline. 
• Oral JAK inhibitors (except the trial medication) 
 
In addition, concomitant administration of CYP3A inducers and moderate to potent CYP3A 
inhibitors with systemic effects should be avoided for the duration of the study. 
 
Examples of medications that are prohibited from use from 28 days prior to the first dose of 
study medication until completion of follow up period, due to potential for drug interactions or 
confounding of data interpretation, are listed in Appendix 4. 
Change to 
The following medications are prohibited throughout the duration of the study: 
 
• azathioprine, 6-mercaptopurine, methotrexate and thalidomide; 
• cyclosporine, mycophenolate and tacrolimus; 
• interferon and 
• anti-TNFα therapy/other biological treatment; 
• intravenous corticosteroids or rectally administered formulation of corticosteroids or 5- 
ASA. 
• Oral JAK inhibitors (except the trial medication) 
 
In addition, concomitant administration of CYP3A inducers and moderate to potent CYP3A 
inhibitors with systemic effects should be avoided for the duration of the study. 
 
Examples of medications that are prohibited from use from 28 days prior to the first dose of 
study medication until completion of follow up period, due to potential for drug interactions or 
confounding of data interpretation, are listed in Appendix 4. 


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All live vaccines immunization are prohibited from signing of informed consent, 
throughout the duration of the study, and for 1 month after last dose of study medication. 
 
Rationale: Remove the time period of “within baseline”, to clarify the prohibition is throughout 
the duration of the study to avoid confusion. Refine the Chinese translation to clarify 5-ASA in 
rectally administrated formulation is prohibited. And add live vaccines immunization as 
prohibited medications. 
13. Section 7.1 Critical Baseline Assessments, page 38 
Change from 
· 
…… 
• 12-Lead ECG 
• Chest x-ray (or historical CT-Scan obtained within 6 months of Screening (Visit 1)) 
• Clinical laboratory assessments (including chemistry, hematology, urine pregnancy test) 
· 
…… 
 
Change to 
· 
…… 
• 12-Lead ECG 
• Chest x-ray (or historical chest x-ray/CT-Scan obtained within 3 months of Screening 
(Visit 1)) 
• Clinical laboratory assessments (including chemistry, hematology, pregnancy test) 
· 
…… 
 
 
Rationale: Typo correction. 
14. Section 7.2.2 Secondary Efficacy Endpoints, page 38 
Change from 
7.2.2 Secondary Efficacy Endpoints 
 
• The percentage of subjects achieve clinical remission per 9-point modified Mayo score at 
week 8, where stool frequency subscore ≤ 1, rectal bleeding subscore of 0, and 
endoscopic subscore ≤ 1 
• The percentage of subjects achieve clinical remission at week 8 as per total Mayo score 
of 2 points or lower ≤2, with no individual subscore exceeding 1point and a rectal 
bleeding subscore of 0. 


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· 
…… 
Change to 
7.2.2 Secondary Efficacy Endpoints 
 
• The percentage of subjects achieve clinical remission per 9-point modified Mayo score at 
week 8, where stool frequency subscore ≤ 1, rectal bleeding subscore of 0, and 
endoscopic subscore ≤ 1 
• The percentage of subjects achieve clinical remission at week 8 as per total Mayo score 
of 2 points or lower than 2, with no individual subscore exceeding 1point and a rectal 
bleeding subscore of 0. 
· 
…… 
 
Rationale: Refine Chinese translation of related secondary efficacy endpoints. 
 
15. Section 7.2.4 Patient Diary Assessment, page 39 
Change from 
Subjects will be provided with an electronic diary at screening visit and at baseline visit in 
order to collect the patient reported outcome components of the total Mayo score (see 
Appendix 1)…… 
 
Change to 
 
Subjects will be provided with an electronic diary at screening visit in order to collect the 
patient reported outcome components of the total Mayo score (see Appendix 1)…… 
 
Rationale: Correct electronic diary is provided at screening visit. 
 
 
16. Section 7.2.5 Mayo Score Assessment, page 40 
Change from 
Mayo score is assessed at baseline and Week 8. If at baseline the subject scores ≥ 4 points on 
the Mayo score excluding the endoscopy sub-score, appropriate endoscopy examination 
(colonoscopy) will be performed. If the subject scores ≥2 on the endoscopic sub-score of the 
Mayo Score at baseline and meet all other inclusion/exclusion criteria, the subject will be 
randomized. Should any bowel preparation be required to perform the colonoscopy, 3-day 
patient diary must be completed and assessed prior to any bowel preparation. For the baseline 
endoscopy, the duration of the time between endoscopy and baseline should not exceed 10 days. 
 
Change to 


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Mayo score is assessed at baseline and Week 8. If the subject scores ≥2 on the endoscopic sub- 
score of the Mayo Score at baseline and meet all other inclusion/exclusion criteria, the subject 
will be randomized. Should any bowel preparation be required to perform the colonoscopy, 3- 
day patient diary must be completed and assessed prior to any bowel preparation. For the 
baseline endoscopy, the duration of the time between endoscopy and baseline should not exceed 
10 days.Baseline (Day 0 -Visit 2) endoscopy images/films (eligibility assessment) and Week 
8 endoscopy images/films will be submitted to central lab for central reading. The central 
lab will send eligibility report to confirm eligibility. 
 
Rationale: According the study procedure, endoscopy is completed by baseline, remove the 
requirement of “If at baseline the subject scores ≥ 4 points on the Mayo score excluding the 
endoscopy sub-score, appropriate endoscopy examination (colonoscopy) will be performed”, to 
avoid misunderstanding. Clarify that the images/films of endoscopy will be sent to central lab for 
central reading. 
 
17. Section 7.3.2 12 Lead ECG, page 41 
Change from 
12-lead ECG measurement and rhythm strip (10 seconds) will be obtained after measurement of 
vital signs. Triplicate ECG measurements are collected at rate of 3 ECGs over 5 minutes period. 
After vital signs are obtained subjects should be placed in the supine position for the ECG 
measurements. 
 
Change to 
 
12-lead ECG measurement and rhythm strip (10 seconds) will be obtained after measurement of 
vital signs. Triplicate ECG measurements are collected at rate of 3 ECGs over 5 minutes period. 
After vital signs are obtained subjects should be placed in the supine position for the ECG 
measurements. 
 
Rationale: Refine Chinese translation of the intervals of 3 ECGs. 
 
 
18. Section 7.3.3 Tuberculin Test (PPD), page 41, 42 
Change from 
Subjects must have a screening tuberculin test (PPD) administered and then evaluated by a 
health care professional (nurse or doctor) 48 to 72 hours later in order to be eligible for the 
study, unless performed and documented within the last 3 months. The test consists of 
intracutaneous injection of Tuberculin, concentration as per local medical standard of 
practice, on the volar aspect of the forearm, using a short beveled 26- or 27- gauge needle 
(Mantoux test). The test is positive if the induration’s diameter (not erythema) is ≥5 mm 48 
to 72 hours after injection. Subjects who have previously received BCG vaccination may be 
tested by QuantiFERON Gold in place of Mantoux PPD and have these results determine patient 
eligibility for participation. 


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Change to 
 
Subjects must have a screening tuberculin test (PPD) administered and then evaluated by a 
health care professional (nurse or doctor) 48 to 72 hours later in order to be eligible for the 
study, unless performed and documented within the last 3 months. The test consists of 
intracutaneous injection of Tuberculin, concentration as per local medical standard of 
practice, on the volar aspect of the forearm, using a short beveled 26- or 27- gauge needle 
(Mantoux test). The test is positive if the induration’s diameter (not erythema) is ≥5 mm 48 
to 72 hours after injection. Subjects who have previously received BCG vaccination will be 
tested by QuantiFERON Gold /or T-Spot test in place of Mantoux PPD and have these results 
determine patient eligibility for participation. 
 
Rationale: Allow T-Spot test as an alternative test for TB infection screening for subjects who 
have previously received BCG vaccination. 
 
19. Section 7.3.4 QuatiFERON test, page 42 
Change from 
7.3.4 QuantiFERON test 
 
At the discretion of the investigator, subject to local testing availability, a QuantiFERON 
Gold®™ (11) test may be substituted for the PPD skin test. A description of the 
QuantiFERON Gold test follows: “This Enzyme-linked Immunosorbent Assay (ELISA) test 
detects the release of Interferon-gamma (IFN-γ) in fresh heparinized whole blood from 
sensitized persons when it is incubated with mixtures of synthetic peptides simulating two 
proteins present in M. tuberculosis: Early Secretory Antigenic Target-6 (ESAT-6) and 
Culture Filtrate Protein-10 (CFP-10). ESAT-6 and CFP-10 are secreted by all M. 
tuberculosis and pathogenic M. bovis strains. Because these proteins are absent from all Bacille 
Calmette-Guérin (BCG) vaccine strains and from commonly encountered Non 
Tuberculous. Mycobacteria (NTM) except M. kansasii, M. szulgai, and M. marinum, QFT-G is 
expected to be more specific for M. tuberculosis than tests that use tuberculin Purified Protein 
Derivative (PPD) as the antigen”. 
Change to 
 
7.3.4 QuantiFERON test/or T-Spot test 
 
At the discretion of the investigator, a QuantiFERON Gold®™ (11) test /or T-Spot test 
(11) conducted in local lab may be substituted for the PPD skin test. A description of the 
QuantiFERON Gold test follows: “This Enzyme-linked Immunosorbent Assay (ELISA) test 
detects the release of Interferon-gamma (IFN-γ) in fresh heparinized whole blood from sensitized 
persons when it is incubated with mixtures of synthetic peptides simulating two proteins present 
in M. tuberculosis: Early Secretory Antigenic Target-6 (ESAT-6) and Culture Filtrate Protein-10 
(CFP-10). ESAT-6 and CFP-10 are secreted by all M. tuberculosis and pathogenic M. bovis 
strains. Because these proteins are absent from all Bacille Calmette-Guérin (BCG) vaccine 
strains and from commonly encountered Non Tuberculous.  Mycobacteria (NTM) except M. 


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kansasii, M. szulgai, and M. marinum, QFT-G is expected to be more specific for M. 
tuberculosis than tests that use tuberculin Purified Protein Derivative (PPD) as the antigen”. 
T-Spot is another IFN-γ release assays in diagnosing M. tuberculosis infection. For this 
test, peripheral blood mononuclear cells (PBMCs) are incubated with two mixtures of 
peptides, one representing ESAT-6 and the other representing CFP-10. The test uses an 
enzyme-linked immunospot assay (ELISpot) to detect increases in the number of cells that 
secrete IFN-γ. 
In the situation QFT-G or T-Spot is unavailable by local testing, incubated whole blood 
sample could be sent to central lab for QFT-G testing. If QFT-G/or T-Spot result is 
indeterminate, a retest is required at earliest to determine the eligibility of the subject. If 
retest is indeterminate or positive, the subject should be screen failed. If retest is negative, 
the PI should assess the subject’s clinical condition and decide if the subject could be 
included. 
 
Rationale: Allow T-Spot as an alternative test for TB infection screening according to local 
availability. And provide the guidance on initial QFT-G/or T-Spot is indeterminate. 


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20. Section 7.3.5 Clinical Laboratory Test, page 43 
Change from 
Table 3. Clinical Laboratory Testing Lists 
 
CHEMISTRY 
HEMATOLOGY 
Urinalysis 
OTHER 
Albumin 
Haemoglobin 
pH 
Hepatitis B surface antigen1 
Alkaline phosphatase 
Haematocrit 
Protein 
Hepatitis C virus antibody1 
Alanine amino-transferase 
(ALT or SGPT) 
Platelet count 
Glucose 
HIV test1 
Aspartate amino- 
transferase (AST or 
SGOT) 
WBC count 
Bilirubin and White 
Cell Count 
Urine pregnancy test (in clinic)2 
Bilirubin, direct 
Neutrophils, absolute 
FSH 3 
Bilirubin, indirect 
Neutrophils, segs (%) 
β-HCG blood test 4 
Bilirubin, total 
Neutrophils, bands (%) 
Stool culture5 /microscopy for: 
Salmonella, 
Shigella, 
Campylobacter， 
Fecal Ova and Parasites 
Calcium 
Basophils (%) 
Clostridium difficile toxin 
Chloride 
Eosinophils (%) 
Fecal calprotectin6 
CO2 content/Bicarbonate 
Eosinophils , absolute 
Lipid Profile (fasting): Total 
Cholesterol， 
Low Density Lipoprotein (LDL) 
High Density Lipoprotein 
(HDL) Triglycerides 
Creatinine 
Lymphocytes (%) 
Thyroid Function Test, including 
TSH, free T4 and free T3. 
Creatine phosphokinase 
(CPK), total 
Monocytes (%) 
PK sampling7 
Gamma glutamyl 
transferase (GGT) 
Glucose 
Phosphorus 
Potassium 
Protein, total serum 
Sodium 
Urea nitrogen (BUN) 
Uric Acid 
1 Assessed at Visit 1 (Screening) only, result is not exclusionary 
2 all visits subsequent to the screening visit 
3 FSH to confirm postmenopausal status at screening visit only 
4 Only females of child-bearing potential if urine pregnancy test positive 
5 fasting lipid profile will be done as per Section 5.12 Time and Event table. 
6 for biomarker assessment 
7 Only done as per Section 7.4 Pharmacokinetics 
Change to 


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Table 3. Clinical Laboratory Testing Lists 
 
CHEMISTRY 
HEMATOLOGY 
Urinalysis 
OTHER 
Albumin 
Haemoglobin 
pH 
Hepatitis B surface antigen1 
Alkaline phosphatase 
Haematocrit 
Protein 
Hepatitis C virus antibody1 
Alanine amino-transferase 
(ALT or SGPT) 
Platelet count 
Glucose 
HIV test1 
Aspartate amino- 
transferase (AST or 
SGOT) 
WBC count 
Bilirubin and White 
Cell Count 
Urine pregnancy test (in clinic)2 
Bilirubin, direct 
RBC count 
FSH 3 
Bilirubin, indirect 
Neutrophils, absolute 
β-HCG blood test 4 
Bilirubin, total 
Neutrophils, segs (%) 
Lipid Profile5 (fasting): Total 
Cholesterol， 
Low Density Lipoprotein (LDL) 
High Density Lipoprotein 
(HDL) Triglycerides 
Calcium 
Neutrophils, bands (%) 
Stool culture /microscopy for: 
Salmonella, 
Shigella, 
Campylobacter， 
Fecal Ova and Parasites 
Chloride 
Basophils (%) 
Clostridium difficile toxin 
CO2 content/Bicarbonate 
Eosinophils (%) 
Fecal calprotectin6 
Creatinine 
Eosinophils , absolute 
Thyroid Function Test, including 
TSH, free T4 and free T3. 
Creatine phosphokinase 
(CPK), total 
Lymphocytes (%) 
PK sampling7 
Gamma glutamyl 
transferase (GGT) 
Monocytes (%) 
CRP 
Glucose 
Phosphorus 
Potassium 
Protein, total serum 
Sodium 
Urea nitrogen (BUN) 
Uric Acid 
1 Assessed at Visit 1 (Screening) only 
2 all visits subsequent to the screening visit 
3 FSH to confirm postmenopausal status at screening visit only 
4 Only for females of child-bearing potential at screening, and if urine pregnancy test positive 
5 fasting lipid profile will be done as per Section 5.12 Time and Event table. 
6 for biomarker assessment 
7 Only done as per Section 7.4 Pharmacokinetics 


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Rationale: Typo correction in the table and footnotes. Add RBC count and CRP test items listed 
in the table, and clarify HBV, HCV and HIV test is for exclusionary purpose. 
 
21. Section 7.3.14 AE and SAE reporting requirement and timeline, page 50 
Change from 
The investigator or site staff is responsible for detecting, documenting and reporting events that 
meet the definition of an AE or SAE. AEs will be collected from the start of study treatment 
(Visit 2) and until the follow up phone contact. SAEs will be collected over the same time period 
as stated above for AEs. However, any SAEs assessed, will be recorded from the time a subject 
consent to participate in the study up to and including any follow up contact. 
Change to 
 
The investigator or site staff is responsible for detecting, documenting and reporting events that 
meet the definition of an AE or SAE. AEs will be collected from the start of study treatment 
(Visit 2) and until the follow up contact. SAEs will be collected from the time a subject consent 
to participate in the study up to and including any follow up contact. 
Rationale: Typo correction to clarify the follow up visit is not a phone-call contact. Clarify any 
SAEs will be recorded from the time of consent. 
 
22. Section 11 Reference, page 60 
Change from 
11. Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium 
tuberculosis Infection, US: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm. 
Change to 
 
11. Updated Guidelines for Using Interferon Gamma Release Assays to Detect 
Mycobacterium tuberculosis Infection – United States, 2010 
  
https:// 
www.cdc.gov/mmwr/preview/mmwrhtml/rr5905a1.htm Rationale: 
Reference update. 


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Protocol Amendment No.02 
 
1. Section 4.1 Study design, page 19 
Change from 
 
 
 
 
 
 
 
 
 
 
 
 
Change to 
 
 
Rationale: Revise the screening period from 3 weeks to -4 days prior to baseline to 4 weeks to - 
1 day prior to baseline, based on the feasibility of the clinical procedure in each country. 
2. Section 4.2 Discussion of the design, page 19 
Change from 
This is a multi-national, multi-center, double-blind, randomized, placebo controlled phase II 
dose- ranging study to include 152 subjects with moderate to severe active ulcerative colitis. The 
study consists of an 8-week blinded treatment phase, followed by an 8-week active arms 
extension phase. Subjects will be screened between -21 days to -4 days before baseline visit 
(visit 2 at week 0). 
Change to 


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This is a multi-national, multi-center, double-blind, randomized, placebo controlled phase II 
dose- ranging study to include 152 subjects with moderate to severe active ulcerative colitis. The 
study consists of an 8-week blinded treatment phase, followed by an 8-week active arms 
extension phase. Subjects will be screened between -28 days to -1 day before baseline visit (visit 
2 at week 0). 
Rationale: Revise the screening period from 3 weeks to -4 days prior to baseline to 4 weeks to - 
1 day prior to baseline, based on the feasibility of the clinical procedure in each country, and 
keep consistent with study design diagram. 
3. Section 5.2 Inclusion Criteria, page 20 
Change from 
3.   …… 
 
4. Subjects deemed by the treating physician as having inadequate response, loss of 
response or intolerance to the conventional treatment (immune-suppressants or 
corticosteroids), AND 
 
−  
Naïve to anti-TNF treatment (e.g. infliximab, adalimumab or certolizumab 
pegol) or other biological treatment (e.g. Vedolizumab); 
OR 
−  
Previously exposed to anti-TNF therapy or other biological treatment 
having discontinued the treatment for a minimum of 12 weeks prior to 
baseline. 
 
5. If subjects are currently receiving the following treatment for UC, they are eligible for the 
study, provided they are on stable dose for the required period of time: 
 
− Oral 5 ASA or Sulfasalazine, stable dose for at least 2 weeks prior to baseline and 
during the study treatment period. 
 
AND/OR 
 
− Oral corticosteroids (prednisolone ≤ 30mg/day or less or equivalent) stable dose for at 
least 2 weeks prior to baseline. 
6.   …… 
 
Change to 
3.   …… 
 
4. Subjects deemed by the treating physician as having inadequate response, loss of 
response or intolerance to the conventional treatment (oral 5-ASA, immune-suppressants 
or corticosteroids), or previously exposed to anti-TNF therapy (e.g. infliximab, 
adalimumab) or other biological treatment (e.g. Vedolizumab) having discontinued 
the treatment for: 
- 
Infliximab: a minimum of 8 weeks prior to baseline 
- 
Adalimumab: a minimum of 10 weeks prior to baseline 


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- 
Ustekinumab: a minimum of 14 weeks prior to baseline 
- 
Vedolizumab: a minimum of 17 weeks prior to baseline 
- 
For the other biological treatments, they should discontinue for a minimum of 5 
half-lives prior to baseline. 
 
5. If subjects are currently receiving the following treatment for UC, they are eligible for the 
study, provided they are on stable dose for the required period of time: 
 
− Oral 5 ASA or Sulfasalazine, stable dose for at least 2 weeks prior to baseline and 
during the study treatment period. 
 
AND/OR 
 
− Oral corticosteroids (prednisolone ≤ 30mg/day or less or equivalent) stable dose for at 
least 2 weeks prior to baseline. This is not applicable to the subjects who have only 
exposed to 5-ASA previously as per inclusion criteria 4. 
6.   …… 
 
Rationale: Clarify the subjects deemed by the treating physician as having inadequate response, 
loss of response or intolerance to the conventional treatment include subjects with previous 
exposed to oral 5-ASA. Clarify oral corticosteroids as permitted medications during study 
treatment is not applicable to subjects with previous 5-ASA treatment only. List the detailed 
discontinuation time prior to baseline of the biological treatment according to its half life. 
4. Section 5.3 Exclusion Criteria, page 21 to 24 
Change from 
2.   …… 
 
3. Treatment naïve subjects diagnosed with ulcerative colitis (without previous exposure to 
any of the following therapies for UC treatment: corticosteroids, immune-suppressants, or 
biological treatments). 
 
…… 
 
7. Subjects receiving the following therapy: 
- 
Azathioprine/6-mercaptopurine, methotrexate, thalidomide within 7 days prior to 
baseline. 
- 
Cyclosporine, mycophenolate, tacrolimus within 4 weeks prior to baseline. 
- 
Interferon therapy within 12 weeks prior to baseline. 
- 
 
Anti-TNFα therapy/other biological therapies within 12 weeks prior to baseline. 
- 
Intravenous corticosteroids or rectally administered formulation of corticosteroids or 
5-ASA within 2 weeks prior to baseline. 
…… 


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13. Subjects with current clinically significant infections or within 6 months of baseline (eg; 
those requiring hospitalization or parenteral antimicrobial therapy or opportunistic 
infections), or those with a history of more than one episode of herpes zoster, a history 
(single episode) of disseminated zoster, a history of any infection otherwise judged by the 
investigator to have the potential for exacerbation by participation in the study or any 
infection requiring antimicrobial therapy within 2 weeks of screening. 
 
14. Subjects who may have current immunization with any live virus vaccine or history of 
immunization with any live virus vaccine within 8 weeks of baseline. 
 
15. Subjects who may have, during the 16 weeks of treatment and for 8 weeks following 
completion of study treatment, routine household contact with individuals who have 
received: 
- 
 
FluMist® (intranasal influenza vaccine) within 1 week of such contact; 
- 
 
attenuated rotavirus vaccine within 10 days of such contact; 
- 
 
varicella or attenuated typhoid fever vaccine within 4 weeks of such contact; 
or oral polio vaccine within 6 weeks of such contact. 
 
16. Subjects with a first-degree relative with a hereditary immunodeficiency. 
…… 
 
Change to 
2.   …… 
 
3. Treatment naïve subjects diagnosed with ulcerative colitis (without previous exposure to 
any of the following therapies for UC treatment: 5-ASA, corticosteroids, immune- 
suppressants, or biological treatments). 
 
…… 
 
7. Subjects receiving the following therapy: 
- 
Azathioprine/6-mercaptopurine, methotrexate, thalidomide within 7 days prior to 
baseline. 
- 
Cyclosporine, mycophenolate, tacrolimus within 4 weeks prior to baseline. 
- 
Interferon therapy within 8 weeks prior to baseline. 
- 
Intravenous corticosteroids or rectally administered formulation of corticosteroids or 
5-ASA within 2 weeks prior to baseline. 
…… 
 
13. Subjects with current clinically significant infections or within 1 month of baseline (eg; 
those requiring hospitalization or parenteral antimicrobial therapy or opportunistic 
infections), or those with a history of more than one episode of herpes zoster, a history 
(single episode) of disseminated zoster, a history of any infection otherwise judged by the 
investigator to have the potential for exacerbation by participation in the study or any 
infection requiring antimicrobial therapy within 2 weeks of screening. 


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14. Subjects who may have current immunization with any live virus vaccine or history of 
immunization with any live virus vaccine within 8 weeks of baseline. 
 
15. Subjects with a first-degree relative with a hereditary immunodeficiency. 
…… 
 
Rationale: Clarify the definition of treatment naïve patients according clinical practice. Update 
the discontinuation time prior to baseline of interferon therapy. In conjunction to the inclusion 
criteria regarding the requirement of discontinuation of biologicals, remove related requirement 
in exclusion criteria. Clarify the subjects with current clinically significant infections or within 1 
month of baseline instead of 6 months, will be excluded. Remove the requirement regarding to 
household contact with vaccinated individuals during study in exclusion criteria. 


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5. Section 5.12 Time and Event Table, page 30 
Change from 
 
 
 
 
 
 
 
 
Change to 
 
Period 
Screening 
Baseline 
Treatment Phase 
End of 
Treatment 
Phase 
Extension Phase 
End of 
Extension 
Phase 
Follow- 
up/EW11 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
-4 to -1 
0 
1 
4 
8 
9 
12 
16 
18 
Day 
-28 to -1 
0 
7± 2 days 
28± 3 days 
56± 3 days 
63± 2 days 
84± 3 days 
112± 3 days 
126± 5 days 
Procedures 
 
 
Rationale: Revise the screening period from 3 weeks to -4 days prior to baseline to 4 weeks to -1 day prior to baseline, based on the 
feasibility of the clinical procedure in each country, and keep consistent with study design diagram. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Period 
Screening 
Baseline 
Treatment Phase 
End of 
Treatment 
Phase 
Extension Phase 
End of 
Extension 
Phase 
Follow- 
up/EW11 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
-3 to -1 
0 
1 
4 
8 
9 
12 
16 
18 
Day 
-21 to -4 
0 
7± 2 days 
28± 3 days 
56± 3 days 
63± 2 days 
84± 3 days 
112± 3 days 
126± 5 days 
Procedures 


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6. Section 6.6.1 Permitted Concomitant Medications, page 36 
 
Change from 
· 
…… 
 
• Oral steroids are allowed during the study up to the dose of 30 mg/day of prednisolone or 
equivalent, providing that the dose has not been commenced or changed within 2 weeks 
of baseline and until to the end of treatment phase (Week 8). During the extension phase, 
tapering of the oral steroid dose can be commenced for subjects at investigator’s 
discretion, in accordance with the predefined tapering scheduled treatment: 
 
− Subjects receiving > 10 mg/day prednisolone or equivalent: taper dose by 5 
mg/week until a 10 mg/day dose (or equivalent) is reached, then continue tapering 
at 2.5 mg/week until 0 mg/day. 
− Subjects receiving ≤ 10 mg/day prednisolone or equivalent: taper dose by 2.5 
mg/week until 0 mg/day. 
 
If subject experiences worsening of signs or symptoms during the tapering schedule, in the 
opinion of the investigator, due to reduction in oral steroid daily dose, the daily oral steroid 
dosage for the subject could be reverted to the preceding daily dosage instructed by the 
investigator, but should not exceed Baseline dose. 
 
Change to 
· 
…… 
 
• Oral steroids are allowed during the study up to the dose of 30 mg/day of prednisolone or 
equivalent, providing that the dose has not been commenced or changed within 2 weeks 
of baseline and until to the end of treatment phase (Week 8). During the treatment 
phase, if the subject cannot tolerate the oral steroids dose or there is a significant 
safety risk associated with continued use of the steroids, the dose may be reduced at 
the discretion of the investigator and the reasons for dose reduction need to be 
documented in the medical records. During the extension phase, tapering of the oral 
steroid dose can be commenced for subjects at investigator’s discretion. Tapering 
scheduled treatment is provided as below: 
 
− Subjects receiving > 10 mg/day prednisolone or equivalent: taper dose by 5 
mg/week until a 10 mg/day dose (or equivalent) is reached, then continue tapering 
at 2.5 mg/week until 0 mg/day. 
− Subjects receiving ≤ 10 mg/day prednisolone or equivalent: taper dose by 2.5 
mg/week until 0 mg/day. 
 
If subject experiences worsening of signs or symptoms during the tapering schedule, in the 
opinion of the investigator, due to reduction in oral steroid daily dose, the daily oral steroid 
dosage for the subject could be reverted to the preceding daily dosage instructed by the 
investigator, but should not exceed Baseline dose. 


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Rationale: Clarify dose of steroids can be reduced at the discretion of the investigator if subject 
develops intolerance to the original dose or significant saftey concerns during the treatment 
phase. 
 
7. Section 7.3.10 Pregnancy, page 48 
Change from 
7.3.10 Pregnancy 
 
If the subject is found to be pregnant, the subject must be withdrawn immediately, and any 
sponsor-supplied drug (SHR0302, placebo) should be immediately discontinued. In addition, any 
pregnancies in the partner of a male subject during the study, should also be recorded following 
authorization from the subject’s partner. Any pregnancy that occurs during study participation 
must be reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy 
must be reported to Reistone Biopharma/designated CRO within 24 hours of learning of its 
occurrence. The pregnancy must be followed up to determine outcome (including premature 
termination) and status of mother and child. Pregnancy complications and elective terminations 
for medical reasons must be reported as an AE or SAE. Pregnancies will remain blinded to the 
study team. 
Change to 
7.3.10 Pregnancy 
 
If the subject is found to be pregnant, the subject must be withdrawn immediately, and any 
sponsor-supplied drug (SHR0302, placebo) should be immediately discontinued. In addition, any 
pregnancies in the partner of a male subject during the study, should also be recorded following 
authorization from the subject’s partner. Any pregnancy that occurs after the first dose of 
investigational drug must be reported using a clinical trial pregnancy form. To ensure subject 
safety, each pregnancy must be reported to Reistone Biopharma/designated CRO within 24 hours 
of learning of its occurrence. The pregnancy must be followed up to determine outcome 
(including premature termination) and status of mother and the newborn should be followed up 
to 1 month after birth. Pregnancy complications and elective terminations for medical reasons 
must be reported as an AE or SAE. Pregnancies will remain blinded to the study team. 
 
Rationale: Clarify the pregnancy occurs after first dose must be reported and the newborn 
should be followed up to 1 month after birth as pregnancy outcome. 


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Protocol Amendment No.03 
 
1. Section 5.3 Exclusion Criteria, page 22 
Change from 
33. Subjects with historical or current evidence of clinically significant cardiovascular, 
neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous 
system, musculoskeletal, skin, sensory, endocrine (including uncontrolled diabetes or thyroid 
disease) or hematological abnormalities that are uncontrolled. Significant is defined as any 
disease that, in the opinion of the Investigator, would put the safety of the subject at risk 
through participation, or which would affect the efficacy or safety analysis if the 
disease/condition exacerbated during the study. 
 
Change to 
 
33. Subjects with historical or current evidence of clinically significant cardiovascular, 
neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous 
system, musculoskeletal, skin, sensory, endocrine (including uncontrolled diabetes or thyroid 
disease) or hematological abnormalities that are uncontrolled. Significant is defined as any 
disease that, in the opinion of the Investigator, would put the safety of the subject at risk 
through participation, or which would affect the efficacy or safety analysis if the 
disease/condition exacerbated during the study. 
 
34. Subjects with a history thrombotic events, including deep vein thromboses (DVT), pulmonary 
embolism (PE) and those with known inherited conditions that predispose to 
hypercoagulability. 
 
Rationale: Update safety related exclusion criteria, add exclusion criteria 34 about the thrombotic 
events according to the FDA’s recommendation. 
 
2. Section 5.9 Stopping Criteria, page 29 
Change from 
The stopping safety criteria are as below: 
• Liver chemistry threshold stopping criteria have been designed to assure subject safety and to 
evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety 
guidance) Study treatment will be stopped if the liver chemistry stopping criteria is met. Refer 
to Section 7.3.9 Liver Chemistry Stopping and Follow-up Criteria. 
• A subject that meets the QTc criteria below will be withdrawn from the study. The QT 
correction formula used to determine discontinuation should be the same one used throughout 
the study. 
- 
QTc, QTcB/QTcF > 500 ms. 


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- 
Change from baseline: QTc >60 ms. 
Use the averaged QTc values of the 3 ECGs to determine whether the subject should be 
discontinued from the study. 
• An unacceptable adverse event, as determined by the Investigator and the medical monitor. 
• Any unacceptable adverse event that is thought to be related to the investigational product may 
result in the study being terminated. 
• Significant protocol deviation. The discovery that post-randomization the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health. 
If the subject is found to be pregnant, the subject must be withdrawn immediately. The procedure 
is described in Section 7.3.10. 
 
Change to 
 
The stopping safety criteria are as below: Subject who fulfil the following criteria should 
discontinue the study. 
 
• Liver chemistry threshold stopping criteria have been designed to assure subject safety and to 
evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety 
guidance) Study treatment will be stopped if the liver chemistry stopping criteria is met. Refer 
to Section 7.3.9 Liver Chemistry Stopping and Follow-up Criteria. 
• A subject that meets the QTc criteria below will be withdrawn from the study. The QT 
correction formula used to determine discontinuation should be the same one used throughout 
the study. 
- 
QTc, QTcB/QTcF > 500 ms. 
- 
Change from baseline: QTc >60 ms. 
Use the averaged QTc values of the 3 ECGs to determine whether the subject should be 
discontinued from the study. 
• Abnormal laboratory values of interests. (modified from CTCAE v5.1 criteria) 
- 
Hemoglobin (Hgb) <7.0 g/dL; or when blood transfusion is indicated. 
- 
Neutrophil count < 500/mm3. 
- 
Platelet count < 25,000/mm3. 
- 
Lymphocyte count < 200/mm3. 
- 
Leukocyte count < 2000/mm3. (Normal: 4000-10,000/mm3) 
• Subject who develops Venous Thrombosis (e.g., Deep Vein Thrombosis). 
• Subject who develops Pulmonary Embolism (PE). 
• Subject who develops Cerebrovascular Events (e.g., Thromboembolic Stroke, Transient 
Ischemic Attack (TIA), Myocardiac Infarction). 


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• An unacceptable adverse event, as determined by the Investigator and the medical monitor. 
• Any unacceptable adverse event that is thought to be related to the investigational product may 
result in the study being terminated. 
• Significant protocol deviation. The discovery that post-randomization the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health. 
If the subject is found to be pregnant, the subject must be withdrawn immediately. The procedure 
is described in Section 7.3.10. 
 
Rationale: According to the FDA’s recommendation, add the abnormal laboratory values of 
interest (e.g., at minimum, for anemia, leukopenia, neutropenia, thrombocytopenia, and abnormal 
coagulation profile). 
 
3. Section 7.3.15 Adverse Event of Special Interest (AESI), page 60 
Change from 
7.3.14 AE and SAE reporting requirement and timeline 
 
The investigator or site staff is responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE. AEs will be collected from the start of study treatment 
(Visit 2) and until the follow up contact. SAEs will be collected from the time a subject consent to 
participate in the study up to and including any follow up contact. 
 
All SAEs will be reported to Reistone Biopharma/designated CRO within 24 hours. Prompt 
notification of SAEs by the investigator to Reistone Biopharma/designated CRO is essential so 
that legal obligations and ethical responsibilities towards the safety of subjects are met. All SAEs 
will be followed up until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up. Once resolved, the SAE eCRF page will be 
updated. The investigator should report SAE/serious incident per local regulations and local EC 
requirement. The investigator will ensure that follow-up includes any supplemental investigations 
as may be indicated to elucidate the nature and/or causality of the SAE. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals. 
Reistone Biopharma/designated CRO has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation according to local regulations. Reistone Biopharma/designated CRO will comply 
with country specific regulatory requirements relating to safety reporting to the regulatory 
authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and 
investigators. 
 
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Reistone Biopharma/designated CRO policy and 
are forwarded to investigators as necessary. 


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An investigator who receives an investigator safety report describing a SAE(s) or other 
specific 
safety 
information 
(e.g., 
summary 
or 
listing 
of 
SAEs) 
from 
Reistone 
Biopharma/designated CRO will file it with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
 
Change to 
 
7.3.14 AE and SAE reporting requirement and timeline 
 
The investigator or site staff is responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE. AEs will be collected from the start of study treatment 
(Visit 2) and until the follow up contact. SAEs will be collected from the time a subject consent to 
participate in the study up to and including any follow up contact. 
 
All SAEs will be reported to Reistone Biopharma/designated CRO within 24 hours. Prompt 
notification of SAEs by the investigator to Reistone Biopharma/designated CRO is essential so 
that legal obligations and ethical responsibilities towards the safety of subjects are met. All SAEs 
will be followed up until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up. Once resolved, the SAE eCRF page will be 
updated. The investigator should report SAE/serious incident per local regulations and local EC 
requirement. The investigator will ensure that follow-up includes any supplemental investigations 
as may be indicated to elucidate the nature and/or causality of the SAE. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals. 
Reistone Biopharma/designated CRO has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation according to local regulations. Reistone Biopharma/designated CRO will comply 
with country specific regulatory requirements relating to safety reporting to the regulatory 
authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and 
investigators. 
 
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Reistone Biopharma/designated CRO policy and 
are forwarded to investigators as necessary. 
 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific 
safety 
information 
(e.g., 
summary 
or 
listing 
of 
SAEs) 
from 
Reistone 
Biopharma/designated CRO will file it with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
 
7.3.15 Adverse Event of Special Interest (AESI) 
 
The AE of special interest (AESI) (serious or non-serious) are determined based on previous 
knowledge about the disease and the mechanism of action of the investigational drug, as well as 
safety information from a similar class of drug. AESI is one of scientific and medical concern 
specific to the product or program, for which ongoing monitoring and rapid communication by the 


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investigator to the sponsor may be appropriate. Such events require heightened surveillance and 
further investigation in order to characterize and understand them. The AESI will be managed and 
follow-up according to the SAE timeline and procedure. The study’s AESI includes: 
 
• Serious infection: Serious infection is defined as any infection (viral, bacterial, and 
fungal) requiring hospitalization or parenteral antimicrobials for more than 3 days. 
 
• Thromboembolic event: Thromboembolic events are divided into two major groups 
which are venous thromboembolic events, including deep vein thrombosis (DVT) and 
pulmonary embolism (PE), and arterial thromboembolic events, including arterial 
thrombosis and cerebrovascular accident (CVA). 
 
Rationale: According to the FDA’s recommendation, add the AEs of special interest (e.g., serious 
infection associated with all JAK-inhibitors). 

SAP_001.pdf: 
 
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PROTOCOL RSJ10101 
 
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Statistical Analysis Plan 
 
 
PROTOCOL NO. RSJ10101 
A Phase II Randomized, Placebo Controlled, Double-Blind, 4 Arms Dose-Ranging 
Study to Evaluate the Efficacy and Safety of SHR0302 Compared to Placebo in 
Patients with Moderate to Severe Active Ulcerative Colitis 
 
 
 
AUTHOR: XIN WANG 
 
Version Number and Date: FINAL V 1.2, 23MAR2021 
NCT number: NCT03675477 
 


 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
 
Statistical Analysis Plan V 1.2 (Dated 23Mar2021) for Protocol RSJ10101. 
 
Name 
Signature 
Date 
Author: 
Xin Wang 
 
 
 
Position: 
Statistician 
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical 
Analysis Plan, authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
Ming-Chung Patrick 
Liu 
 
 
 
Position: 
 Statistician 
 
Company: 
Reistone Biopharma 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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PROTOCOL RSJ10101 
 
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MODIFICATION HISTORY 
 
 
Unique Identifier 
for this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
Final v1.0 
08Jan2020 
Xin Wang 
Not Applicable-First Version 
Final v1.1 
12Oct2020 
Xin Wang 
1. Reistone study statistician 
changed from Cathy Liu to 
Baoyue Li. 
2. Updated the per protocol 
set definition and added 
the reason for changes in 
the section of 3.3 changes 
to analysis from protocol . 
3. Reference for CMH 
weighted average of 
stratum specific rate 
differences and stratified 
Wald confidence interval 
was added. 
4. A listing for patients whose 
trial participation are 
impacted by COVID-19 was 
added 
 
Final v1.2 
23Mar2021 
Xin Wang 
1. Reistone study statistician 
changed from Baoyue Li to 
Ming-Chung Patrick Liu. 
 
 
 
 
 


 
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LIST OF ABBREVIATIONS AND RELEVANT TERMS 
 
Initials/Abbreviations 
Terms 
ACS 
Abnormal Clinically Significant 
AE 
Adverse Event  
ANCOVA 
Analysis of Covariance 
ANCS 
Abnormal Not Clinically Significant 
ATC 
Anatomical Therapeutic Chemical 
BD 
Twice Daily 
β-hCG 
Beta‐human Chorionic Gonadotropin 
BLQ 
Below the Lower Limit of Quantification 
BMI 
Body Mass Index 
BOCF 
Baseline Observation Carried Forward 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ENR 
Enrolled Set 
FAS 
Full Analysis Set 
IP 
Investigational Product 
JAK 
Janus Kinase 
LOCF 
Last Observation Carried Forward 
LS Mean 
Least Square Mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
 
Milligram 
NCF 
Non-completers Considered Failure 
PPS 
Per Protocol Analysis Set 
PT 
Preferred Term 
PGA 
Physician Global Assessment 
QD 
Once a Day 


 
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RND 
                                           Randomized Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SS 
Safety Analysis Set 
TEAE 
Treatment Emergent Adverse Event 
ULQ 
Upper Limit of Quantification 
UC 
Ulcerative Colitis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 


 
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1. INTRODUCTION ................................................................................................................................ 9 
2. STUDY OBJECTIVES ......................................................................................................................... 9 
2.1 Primary Objective..............................................................................................................................................9 
2.2 Secondary Objectives ........................................................................................................................................9 
3. STUDY DESIGN ............................................................................................................................... 10 
3.1 General Description ........................................................................................................................................ 10 
3.2 Schedule of Events .......................................................................................................................................... 12 
3.3 Changes to Analysis from Protocol .................................................................................................................. 12 
4. PLANNED ANALYSES .................................................................................................................... 13 
4.1 Data Monitoring Committee (DMC) ................................................................................................................ 13 
4.2 Interim Analysis .............................................................................................................................................. 13 
4.3 Final Analysis................................................................................................................................................... 14 
5. ANALYSIS SETS .............................................................................................................................. 14 
5.1 All Patients Enrolled Set [ENR] ........................................................................................................................ 14 
5.2 All Patients Randomized Set [RND] ................................................................................................................. 14 
5.3 Full Analysis Set [FAS] ..................................................................................................................................... 14 
5.4 Per Protocol Analysis Set [PPS] ........................................................................................................................ 15 
5.5 Safety Analysis Set [SS] ................................................................................................................................... 15 
6. GENERAL CONSIDERATIONS ..................................................................................................... 15 
6.1 Reference Start Date and Study Day................................................................................................................ 15 
6.2 Baseline ........................................................................................................................................................... 16 


 
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6.3 Derived Timepoints ......................................................................................................................................... 16 
6.4 Unscheduled Visits, Retests and Early Termination Data ................................................................................. 16 
6.5 Windowing Conventions ................................................................................................................................. 16 
6.6 Statistical Tests ............................................................................................................................................... 16 
6.7 Common Calculations ...................................................................................................................................... 17 
6.8 Software Version ............................................................................................................................................. 17 
7. STATISTICAL CONSIDERATIONS ............................................................................................. 17 
7.1 Multicentre Studies ......................................................................................................................................... 17 
7.2 Missing Data ................................................................................................................................................... 17 
7.3 Examination of Subgroups............................................................................................................................... 18 
8. OUTPUT PRESENTATIONS ......................................................................................................... 19 
9. DISPOSITION AND WITHDRAWALS ....................................................................................... 19 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .......................................... 20 
10.1 Derivations .................................................................................................................................................... 21 
11. MEDICAL HISTORY ....................................................................................................................... 21 
12. MEDICATIONS AND PROCEDURES .......................................................................................... 22 
13. STUDY MEDICATION EXPOSURE ............................................................................................. 22 
13.1 Derivations .................................................................................................................................................... 23 
14. STUDY MEDICATION COMPLIANCE ........................................................................................ 24 
14.1 Derivations .................................................................................................................................................... 25 
15. EFFICACY ENDPOINTS ................................................................................................................. 25 


 
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15.1 Primary Endpoint .......................................................................................................................................... 25 
15.2 Secondary Endpoints ..................................................................................................................................... 28 
16. SAFETY ENDPOINTS ..................................................................................................................... 31 
16.1 Adverse Events (AEs) ..................................................................................................................................... 31 
16.2 Deaths ........................................................................................................................................................... 34 
16.3 Laboratory Evaluations .................................................................................................................................. 35 
16.4 Electrocardiogram (ECG) EVALUATIONS ........................................................................................................ 35 
16.4.1 ECG Markedly Abnormal Criteria ................................................................................................................ 36 
16.5 Vital Signs ...................................................................................................................................................... 37 
16.6 Physical Examination ..................................................................................................................................... 38 
16.7 Other Safety Assessments ............................................................................................................................. 38 
APPENDIX 1. Programming Conventions for Outputs ............................................................................................ 40 
APPENDIX 2. Partial Date Conventions .................................................................................................................. 43 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and 
analysis of efficacy and safety data for Protocol RSJ10101. It describes the data to be 
summarized and analyzed, including specifics of the statistical analyses to be performed.  
 
This Statistical Analysis Plan (SAP) is based on protocol version 3.0, dated July 31, 2019.  
Pharmacokinetic analysis is not in IQVIA Bios work scope and analysis method for 
pharmacokinetic analysis is not included in this SAP. 
2. STUDY OBJECTIVES 
2.1 PRIMARY OBJECTIVE 
The primary objective is: 
 
• The primary objective is to evaluate the efficacy of SHR0302 at 4mg once a day (QD), 
8mg QD, and 4mg twice a day (BD) given orally compared to placebo in inducing 
clinical response in adult patients with moderate to severe active Ulcerative Colitis 
(UC) at Week 8. 
 
2.2 SECONDARY OBJECTIVES 
The secondary objectives are: 
 
• To evaluate the safety and tolerability of oral SHR0302 in patients with moderate to 
severe ulcerative colitis. 
 
• To evaluate the efficacy of oral SHR0302 in inducing clinical remission in patients with 
moderate to severe ulcerative colitis. 
 
• To evaluate the efficacy of oral SHR0302 in inducing mucosal healing in patients with 
moderate to severe ulcerative colitis. 
 
• To evaluate the change from baseline in the following biomarkers; CRP, fecal 
calprotectin. 
 


 
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• To further evaluate the efficacy of SHR0302 in maintaining remission. 
 
• To characterize the pharmacokinetics of SHR0302 in moderate to severe active 
Ulcerative Colitis patients, and explore the correlation of exposure-response. 
3. STUDY DESIGN 
3.1 GENERAL DESCRIPTION 
Ulcerative Colitis is a debilitating disease resulting in high morbidity and severely affect 
patients’ quality of life. Patients with UC will experience periods of remission and flare up. It is 
a disease affecting the colon, characterized by altered bowel habit, bloody diarrhea, 
abdominal pain, weight loss and anaemia. 
 
The understanding of cytokines and intracellular messenger pathway in UC has led to the 
discovery of Janus Kinase (JAK) enzymes. There are a number of Janus kinase inhibitors 
currently under investigation for the treatments of immune-induced diseases, such as 
Rheumatoid Arthritis, Psoriatic Arthritis, Psoriasis, Ulcerative Colitis, Crohn’s Disease, and 
Ankylosing Spondylitis. These JAK inhibitors can be given orally, which could be an advantage 
compared to the intravenously given biological treatments. There is also an advantage of not 
having the risk of developing loss of response due to immunogenicity. 
 
SHR0302 is a highly selective JAK1 inhibitor. An in vitro study has demonstrated that its 
selectivity to JAK1 compared to JAK2 is about 16 times more than tofacitinib, and baricitinib, 
while 10 times more than filgotinib. In an animal model study, SHR0302 significantly 
attenuated gross bleeding and stool consistency while also relieved body weight loss in DSS-
induced Colitis mice. Meanwhile the study has also demonstrated SHR0302’s ability in 
reducing colon inflammation score by reducing crypt score and inflammation score in these 
mice to the extent comparable to tofacitinib, an active comparator. These in vitro and animal 
studies have demonstrated the potential efficacy of SHR0302 in addressing colon 
inflammation, hence the potential for the treatment of inflammatory Bowel Disease. The high 
selectivity of SHR0302 to JAK1 also makes it a favourable candidate from a benefit risk safety 
perspective. 
 
The proposed study is a multi-national, multi-center, double-blind, randomized, placebo 
controlled phase II dose- ranging study to include 152 patients with moderate to severe active 
ulcerative colitis. The study consists of an 8-week blinded treatment phase, followed by an 8-
week active arms extension phase. All patient have the option not enrolling into the extension 


 
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phase after first 8 weeks of treatment. All patients in the extension phase are followed-up for 
further 2 weeks until week 18. Patients who have completed the first 8-week of treatment 
phase, but decided not entering into extension phase are required to attend the 2-week 
follow-up visit. Early withdrawn patients during the first 8-week treatment phase cannot enter 
the extension phase. Early withdrawal visit should be done within 2 weeks after last 
dose/decision of withdrawal. The total duration of the study participation, including extension 
and follow-up, will be approximately 18 weeks. 
 
At the baseline visit, patients with moderate-to-severe active ulcerative colitis, with a 
modified 9-point Mayo score of 5 to 9 points and endoscopic subscore of 2 to 3, and fulfilling 
all the inclusion/exclusion criteria will be randomized into one of the four treatment arms for 
the treatment phase: 4mg QD, 8mg QD, 4mg BD of SHR0302 or placebo. All the patients will 
be stratified according to whether they have previously exposed to anti-TNFα/biological 
treatment. Patients randomized into placebo in treatment phase will also have a pre-assigned 
randomized treatment sequence for extension phase, which are 3 active groups (placebo -> 
4mg QD, placebo -> 4mg BD, and placebo -> 8mg QD) in a 1:1:1 ratio. Patients randomized to 
the active arms for treatment phase will remain in the same dose group in the extension 
phase. 
 
Primary endpoint assessment will be conducted at week 8. 9-point modified Mayo score is the 
Mayo score excluding physician global assessment (PGA) subscore. 9-point modified Mayo 
score will be collected as the primary endpoint. This has been advised by the US FDA 
according to FDA guidance on ulcerative colitis trial. At the completion of the first 8-week 
treatment period, all patients, responders or non-responders, have the option to enter a 
blinded active arms 8-week extension phase according to the group they were randomized to 
for the extension phase. The end-of-study is defined as the date of the last patient’s last visit 
or the actual date of follow-up visit/contact, whichever is later. The study design diagram is 
provided in below figure (Figure 1).  
 
The efficacy, safety, tolerability, and anti-inflammatory data generated by this proposed phase 
II study will be essential for evaluating the potential of this promising, novel anti-inflammatory 
agent as a treatment for moderate to severe active ulcerative colitis so that one or two doses 
can be selected to progress into further clinical development. 
 
 
 
Figure 1: Study Design Diagram 
 
 


 
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The sample size calculation is based on pairwise comparison of clinical response at week 8 
among SHR0302 8mg, 4mg BD, 4mg QD dose group and placebo group at the 2-sided 0.1 
significance level. 57%, 57%, 50%, 30% clinical response are assumed for 8mg QD, 4mg BD and 
4mg QD dose group, placebo group at week 8 respectively. The planned sample size of 35 
evaluable patients per treatment group will provide 80% global power to detect at least 1 
dose group is different from placebo group by using Hochberg’s step-p test. The total sample 
size is 152 randomized patients with consideration of 8% drop out rate. 152 eligible patients 
will be randomized to achieve an estimated 140 evaluable patients in the study. 
 
3.2 SCHEDULE OF EVENTS 
Schedule of events can be found in Section 5.12 Time and Event Table of the protocol. 
 
3.3 CHANGES TO ANALYSIS FROM PROTOCOL 
• Two new analysis sets which are all patients enrolled set and all patients randomized 
set have been added in this SAP. The reason for these changes is to summarize patient 
disposition clearly. 
• In protocol, per protocol set is defined as all patients from FAS who do not have 
significant protocol violation. Based on the data before the interim database lock, 
there are some subjects who do not have primary efficacy results at week 8. In order 
to assess the primary efficacy results based on observed results without non-
completers considered failure (NCF) imputation, these subjects without week 8 
efficacy results will be excluded from PP set. 


 
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4. PLANNED ANALYSES 
The following analyses will be performed for this study: 
• Two Analyses for Safety Review Committee (SRC) Meetings 
• Interim Analysis 
• Final Analysis 
 
4.1 DATA MONITORING COMMITTEE (DMC)  
A data monitoring committee for efficacy is not required for this study.  
 
A safety review committee will be established in this study to assess overall safety data and 
early safety signal in order to protect the ethical and safety interests of the patients recruited 
into the study, while maintaining, as far as possible, the scientific validity of the study. The SRC 
is independent of the study team and will comprise of at least one external independent 
statistician and an external independent physician. 
 
During the study, the SRC will convene at least twice to review the safety and tolerability data 
after the study recruited the 50th and 100th patient treated for first 8 weeks of treatment 
phase. Based on the safety information, the SRC has the discretion to make recommendation 
to the study team based on predefined SRC Charter. 
 
4.2 INTERIM ANALYSIS  
One interim analysis will take place for this study. The primary analysis of primary endpoint 
will occur after all patients have the opportunity to complete the 8-week treatment phase 
study visit. The results will be based on unblinded treatment groups. 
 
Primary comparison:  
SHR0302 8mg QD versus placebo, Week 8;  
SHR0302 4mg BD versus placebo, Week 8;  
SHR0302 4mg QD versus placebo, Week 8. 
 
The list of outputs provided with the full set of output templates (planned for the final 
analysis) will highlight which of these outputs will be provided for the interim analysis. 
 
The IQVIA study team, including those responsible for creating the programs to produce the 


 
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outputs for the Interim Analysis, will remain blinded. Once the programs have been produced 
by the IQVIA blinded study team in Beijing, these programs will be sent to the IQVIA unblinded 
statistician, who will apply the randomization schedule and provide the Reistone unblinded 
team with a set of unblinded outputs. 
 
4.3 FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics 
following sponsor authorization of this Statistical Analysis Plan, Database Lock, Sponsor 
Authorization of Analysis Sets and Unblinding of Treatment. 
5. ANALYSIS SETS 
Agreement and authorization of patients included/ excluded from each analysis set will be 
conducted prior to the unblinding of the study. 
 
5.1 ALL PATIENTS ENROLLED SET [ENR] 
The all patients enrolled set will contain all patients who provide informed consent for this 
study.  
 
5.2 ALL PATIENTS RANDOMIZED SET [RND] 
The all patients randomized set will contain all patients in the ENR set who were randomized 
to study medication. 
 
For analyses and displays based on RND, patients will be classified according to randomized 
treatment. 
 
5.3 FULL ANALYSIS SET [FAS] 
Full analysis set will comprise of all randomized patients who have received any amount of 
investigational product (IP) and have observed analysis data in at least one valid Mayo related 
score. All summaries of baseline and demographic data and all listings will be produced for the 
FAS population. In the full analysis set, patients will be analyzed according to randomized 
treatment, regardless of the treatment received. 


 
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5.4 PER PROTOCOL ANALYSIS SET [PPS] 
Per protocol set is defined as all patients from FAS who have week 8 efficacy data and do not 
have significant protocol violation. 
 
5.5 SAFETY ANALYSIS SET [SS] 
The Safety analysis set will comprise all patients who received any amount of investigational 
product and will be based on the actual treatment received, if this differs from that to which 
the patient was randomized to. The Safety analysis set will be used for all summaries of safety 
data. 
 
If there is any doubt whether a patient was treated or not, they will be assumed treated for 
the purposes of analysis. 
6. GENERAL CONSIDERATIONS 
6.1 REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/ stop 
day of assessments and events.  
 
Reference start date is defined as the day of the first dose of investigational product (Day 0 is 
the day of the first dose of investigational product) and Study Day will appear in every listing 
where an assessment date or event date appears.  
 
• If the date of the event is on or after the reference date, then:  
   
  Study Day = (date of event – reference date) . 
 
• If the date of the event is prior to the reference date, then:  
  
  Study Day = (date of event – reference date). 
 
In the situation where the event date is partial or missing, Study Day, and any corresponding 
durations will appear partial or missing in the listings. 
 


 
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6.2 BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement 
(including unscheduled assessments) taken prior to first dose on or before Day 0. In the case 
where the last non-missing measurement and the reference start date coincide, that 
measurement will be considered pre-baseline. However, Adverse Events (AEs) and 
medications commencing on the first dose date will be considered as post-baseline. For the 
related assessments such as systolic blood pressure (SBP) and diastolic blood pressure (DBP), 
it is desirable that both baseline values come from the same measurement and not from 
different dates/visits in case one value is missing. 
 
6.3 DERIVED TIMEPOINTS 
For some endpoints, Last-observation-carried-forward (LOCF) or Baseline-observation-carred-
forward (BOCF) approach will be applied for subscore other than endoscopy of Mayo score. In 
the by-visit summary, “LOCF imputation” or “BOCF imputation” will be used to make it clear 
what is being shown in the outputs. 
 
6.4 UNSCHEDULED VISITS, RETESTS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. 
Unscheduled measurements will not be included in by-visit summaries but will contribute 
best/ worst case value where required .  
 
In the case of a retest (same visit number assigned), the latest available measurement for that 
visit will be used for by-visit summaries.  
 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
 
6.5 WINDOWING CONVENTIONS 
 No visit windowing will be performed in the statistics for this study. 
  
6.6 STATISTICAL TESTS 
The default significant level will be 2-sided 0.1; confidence intervals (CI) will be 90% and 


 
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statistical tests will be two-sided, unless otherwise specified in the description of the analyses. 
 
6.7 COMMON CALCULATIONS 
• For quantitative measurements, change from baseline will be calculated as: 
  Change from baseline =Test Value at Visit X – Baseline Value 
 
• For quantitative measurements, percent change from baseline will be calculated as: 
  Percent change from baseline= ((Test Value at Visit X – Baseline Value) /Baseline    
Value)*100 
 
6.8 SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher. 
7. STATISTICAL CONSIDERATIONS 
7.1 MULTICENTRE STUDIES 
This study will be conducted by multiple investigators at multiple centers internationally.  
 
7.2 MISSING DATA 
In general, missing values will not be imputed for descriptive statistics.   
 
Unless otherwise specified, all analysis will be based on the number of observations in the 
relative population, i.e. patients with missing information will be included in the denominator 
when calculating percentages. 
 
Missing efficacy data will be handled as described in section 15.1 and 15.2.2 of this analysis 
plan.  
 
Missing or incomplete data will not be imputed unless indicated otherwise. 
 


 
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7.3 EXAMINATION OF SUBGROUPS 
Subgroup analyses for primary endpoint will be conducted as exploratory analysis. It should 
be noted that the study was not designed to detect response differences with high statistical 
power within subgroups. Forest plots will be used to display differences in clinical response 
rate across subgroups in each SHR0302 dose level compared to placebo group. 
 
The following subgroups will be assessed and described: 
 
• Age (years) 
 
o < 45 years 
o ≥ 45 years 
 
• Sex 
 
o Male 
o Female 
  
• Country  
 
o USA 
o Ukraine 
o Poland 
o China 
 
• Ethnicity Origin 
 
o Not Hispanic or Latino 
o Hispanic or Latino 
o Not reported or Unknown 
 
• Duration of UC (years) 
 
o < 5 
o ≥ 5 
 
• Overall Compliance before Week 8 


 
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o Yes (≥ 80% compliance) 
o No (< 80% compliance) 
 
•  Previous exposure to anti-TNFα/biological treatment 
 
o Yes 
o No 
          
• Baseline total Mayo score 
 
o ≤10 
o >10 
8. OUTPUT PRESENTATIONS 
Appendix 1 of the analysis plan shows conventions for presentation of data in outputs. 
  
The templates provided with this SAP describe the presentations for this study and therefore 
the format and content of the summary tables, figures and listings to be provided by IQVIA 
Biostatistics. 
 
Continuous variables will be summarized using descriptive statistics, i.e., non-missing 
observations, mean, median, standard deviation (SD), minimum, and maximum.  
 
Categorical variables will be summarized by counts and percentages. Unless otherwise stated, 
the calculation of proportions will be based on the population of interest. Counts of missing 
observations will be included in the denominator, unless specified. 
9. DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study.  
 
Patient disposition and withdrawals will be presented for the enrolled population. The 
breakdown of patients into the analysis sets (ENR, RND, FAS, SS, and PPS) will be presented. 
 
Follow up time (days) is time between a specified event (death, end of the study or the cut-off 


 
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date for dry run or SRC analysis, whichever occurred first) and the date of randomization. 
Follow up time will be summarized for RND. 
 
• 
Follow-up time (days) = the date of event-the date of randomization +1 
 
Number and percentage of patients allocated to treatment will be presented by previous 
exposure to TNFα/biological treatment for RND. 
 
Number and percentage of patients allocated to treatment in each country and site will be 
presented by treatment group for RND. 
 
A listing of inclusion/exclusion criteria deviations and reason for screen failure will be 
provided for screen failure patients.  
 
Additionally, any protocol deviations identified during the course of the study will be listed 
and the number and percentage of patients in each type of protocol deviations will be 
summarized for the randomized population. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
The demographic and other baseline characteristics will be presented for the FAS. The 
following demographic and other baseline characteristics will be reported for this study.  
 
• 
Age (years)─RAVE age function  
• 
Age groups (< 45 years/≥45 years) 
• 
Sex 
• 
Race  
• 
Ethnicity 
• 
Weight (kg) 
• 
Height (cm) 
• 
BMI (kg/m2) 
• 
Cigarette Use 
• 
Alcohol Use 
• 
Previous exposure to anti-TNFα/biological treatment 
• 
UC disease duration 
• 
Location and extent of patient's UC 
• 
Baseline total Mayo score (≤10/>10) 


 
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Descriptive statistics will be used for summarizing the patients’ characteristics in each treatment 
group and overall. No statistical testing will be carried out for demographic or other baseline 
characteristics. 
10.1 DERIVATIONS  
• 
BMI (kg/ m2) = weight (kg)/ height (m)2 
• 
Age (years) = Year of informed consent (IC) – Year of birth, if month of IC is later than month of 
birth, or if month of IC is equal to month of birth but day of informed consent is later than or 
equal to day of birth; 
 Age (years) = Year of informed consent – Year of birth – 1, otherwise. 
In this case, if one patient is more than 45 years old but less than 46 years old, then this patient 
will be presented as age 45.  
• 
UC disease duration (years) = (Date of informed consent – Date of Diagnosis +1)/365.25, 
presented to 1 decimal place. 
For partially missing dates, the UC disease duration (years) will be based on imputed values. If 
the date part is missing while year and month present, 15th of the month will be used for 
imputation. If both date and month part are missing while year presents, July 1st will be used 
for imputation. 
11. MEDICAL HISTORY 
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 21.1 or higher version. Data captured on the Medical History page of the CRF will be 
presented by body system description (SOC) and Preferred Term (PT) for FAS. 
 
Number and percentage of patients with at least one medical history or one complication of 
UC will be presented by treatment group for FAS. 
 
Detailed information of medical history including medical history term, year diagnosed, 
ongoing or not, and whether this conditions or events is a complication of Ulcerative Colitis 
will be listed for FAS. 


 
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12. MEDICATIONS AND PROCEDURES 
Prior medications are those medications that were stopped prior to first study treatment. 
Concomitant medications are medications taken at least once after first study treatment. 
Medications stopped on the same day as first study treatment will be considered as prior 
medication only. 
 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO Drug Global 01Sep2018_B3). The PT and Anatomical Therapeutic Chemical 
(ATC) Classification System level 2 will be used for tabulation. The summary tables will show 
the number and percentage of patients by PT and ATC level 2, for each treatment group and 
overall. Only concomitant medications will be summarized. The descriptive summaries for 
concomitant medications will be presented for the SS. Missing or partial dates for medications 
will be handled according to Appendix 2 of this analysis plan. In the case where it is not 
possible to define a medication as prior or concomitant, the medication will be classified by 
the worst case; i.e. concomitant. For the summaries of concomitant medications, patients 
who take the same medication (in terms of the PT), more than once will only be counted once 
for that medication. Prior medications will be listed only. 
 
The detailed information of prior and concomitant medication use including medication 
name, start date, end date, ongoing or not, primary reason for use, total daily dose, frequency 
and route of administration, etc. will be listed. Prior and concomitant medications will be 
listed separately. 
 
The detailed information of procedures will be collected on the “Procedures” form of 
Electronic Case Report Form (eCRF) including procedure name, start date, end date, ongoing 
or not, and primary reason for use. Procedure name will be coded using Medical Dictionary 
for Regulatory Activities Version 21.1 or higher version. Procedures information be will be 
listed. 
13. STUDY MEDICATION EXPOSURE 
Exposure to study medication will be presented for SS by treatment group. 
 
The date of first study medication administration will be taken from eCRF “Noncompliance 
with study treatment ” form if available (Site will check medical chart and make the first dose 
record on this eCRF form). In case of not available, the first dose date from the diary data will 
be used. The date of last study medication will be taken from the eCRF “End of Treatment” 


 
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form. In the case of missing data on the eCRF, the last dose date from diary data will be used 
 
The study medication intake for each day will be taken from the diary “Time of Dosing” and “# 
Tablets Taken” items. The following information will be summarized for each treatment group 
in treatment phase, extension phase and overall: 
• 
Duration of Exposure (days) 
• 
Planned number of study drug tablets 
• 
Actual number of study drug tablets 
• 
Number of Dosing Days 
• 
Cumulative Dose (mg) 
• 
Average Daily Dose (mg/day) 
13.1 DERIVATIONS 
• 
Duration of exposure(days)= Last date of exposure in corresponding phase– First dose date in 
corresponding phase +1 
 
When the start or stop date is missing, then the exposure will be treated as missing. 
Interruptions, compliance, and dose changes are not taken into account for duration of 
exposure. 
 
• 
Planned number of tablets 
 
The investigational product taken during the 16-week treatment period will be double blind. In 
order to preserve blinding and ensure patients compliance, all arms are administered under 
twice daily dosing regime and placebo is used according to the schedule in table 1. At each 
dosing time (morning, am or afternoon, pm), patient will be taking two tablets. The treatments 
are given twice daily and it is assumed that the patient should take medication from the 
morning of the visit day at which their medication is initially dispensed to the afternoon of their 
last visit date.  At each dosing time (morning, am or afternoon, pm), patient will be taking two 
tablets. In one day, a patient will take a total of four tablets, two tablets in the morning and two 
tablets in the afternoon. For example, if the initial dispense date is Day 1 and the last visit date 
is Day 10, then the patient should have taken 2 tablets at am on Days 1 to 10; hence, the total 
number of planned tablets at am would be 10×2 =20. 
 


 
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• 
Actual number of tablets=Sum of tablets captured on Patient Diary 
 
• 
Number of dosing days= Last date of exposure in corresponding phase – First dose date in 
corresponding phase +1(-off drug period) 
 
Number of dosing days is the number of days with non-zero tablets. 
 
• 
Cumulative dose (mg)= Sum of SHR0302 dose based on Patient Diary.  
 
In one day, a patient will take a total of four tablets, two tablets in the morning and two tablets 
in the afternoon.  According to treatment arm and the time of dosing, the average dose of 
SHR0302 per tablet are calculated and listed in below table (Table 1). 
 
According to the actual treatment group of a patient, SHR0302 dose per day will be calculated 
by the following formula: 
 
SHR0302 dose per day=number of tablets taken at am* average SHR0302 dose per tablet (am) 
+number of tablets taken at pm* average SHR0302 dose per tablet (pm) 
 
Cumulative dose will be sum of SHR0302 dose per day based on Patient Diary.  
 
Table 1: Study drug packaging design and average dose per tablet 
 
Study Arms-all 
BID 
Dose 1(am) 
Average dose per tablet 
(am) 
Dose 2 (pm) 
Average dose per 
tablet(pm) 
4mg QD 
4mg+placebo 
SHR0302 2mg per tablet 
Placebo+placebo 
SHR0302 0mg per tablet 
8mg QD 
4mg+4mg 
SHR0302 4mg per tablet 
Placebo+placebo 
SHR0302 0mg per tablet 
4mg BD 
4mg+placebo 
SHR0302 2mg per tablet 
4mg+placebo 
SHR0302 2mg per tablet 
Placebo 
Placebo+placebo 
SHR0302 0mg per tablet 
Placebo+placebo 
SHR0302 0mg per tablet 
 
• 
Average daily dose(mg/day) = Cumulative dose (mg)/ Number of dosing days (days) 
14. STUDY MEDICATION COMPLIANCE  
Compliance to investigational product will be presented for the SS. Compliance with 
investigational product is derived from data recorded on the eCRF “Drug Accountability” and 
“Noncompliance With Study Treatment” pages. Compliance will be calculated as the number 
of tablets taken (amount dispensed-amount returned-amount lost) divided by the planned 
number of tablets to be taken. The compliance rate will be categorized as <80 , ≥80 to ≤100 
and >100.  Compliance in treatment phase and extension phase will be summarized and 


 
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presented. Furthermore, Compliance will be calculated for kits dispensed at baseline, Week 4, 
Week 8, Week 12, other visits, unscheduled visit and overall. Overall Compliance before Week 
8 used in subgroup analysis in section 7.3 is defined as taking more than or equal to 80% of 
study drug products before Week 8. Overall Compliance before Week 8 will be calculated as 
the total number of tablets taken before Week 8 divided by the planned number of tablets to 
be taken before Week 8.  
 
In addition, the following information will be summarized: 
 
• 
Overall non-compliance  
     
Overall non-compliance is defined as taking less than 80% of study drug products as directed 
by the dosing instructions. 
 
• 
Reason for non-compliance with study treatment  
 
A by-patient listing will include any reasons for noncompliance with study treatment. 
 
14.1 DERIVATIONS 
• 
Compliance (%)= (Amount Dispensed-Amount Returned-Amount Lost) *100/ (Planned number 
of tablets to be taken) 
15. EFFICACY ENDPOINTS  
15.1 PRIMARY ENDPOINT 
Mayo score is an instrument designed to measure disease activity of ulcerative colitis. Mayo 
score ranges from 0 to 12 points. It consists of 4 subscores, each graded from 0 to 3 with 
higher scores indicating more severe disease. The four subscores are listed below.  
 
• Stool frequency (0-3)  
• Rectal bleeding (0-3) 
• Findings of colonoscopy (0-3) 
• Physician global assessment (0-3) 
 
The Physician global assessment (PGA) is a clinician-reported assessment that reflects “the 
patient’s recorded symptoms, the proctoscopic appearance of the rectosigmoid mucosa, and 


 
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other pertinent clinical indexes, such as physical findings and the patient’s performance 
status.  
 
9-point modified Mayo score is the Mayo score excluding PGA subscore, hence the maximum 
is 9 points and minimum 0 point. By removing the PGA, it removes the subjective 
view/assessment from the physicians hence reducing bias. It is also a recommended 
assessment by the regulators. 9-point modified Mayo score will be collected as a primary 
endpoint at week 8. 
 
The primary endpoint is the percentage of patient achieving clinical response at week 8 which 
is defined as decrease from baseline in 9-point modified Mayo score of at least 2 points and at 
least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 
point or absolute subscore for rectal bleeding of 0 or 1. 
 
15.1.1 Primary Analysis of Primary Efficacy Endpoint 
The primary objective of the study will be evaluated for SHR0302 dose groups (8mg QD, 4mg 
BD, 4mg QD) compared to placebo group with respect to the percentage of patients with 
clinical response at week 8. The aim of the study is to detect at lease 1 dose group different 
from placebo group by using Hochberg’s step up test. The primary analysis will be based on 
the FAS population.  
 
Hochberg's step-up method for multiple testing was developed in 1988 to control the 
familywise error rate.The familywise error rate is the probability of a coming to at least one 
false conclusion in a series of hypothesis tests . In other words, it's the probability of making 
at least one Type I Error. Hochberg's method is thought of as a step-up version of the 
Bonferroni test. 
 
The Hochberg method will be used to maintain the 2-sided study-wise Type I error rate at 0.1. 
The null and alternative hypothesis for the primary endpoint that will be tested are:  
 
• H01: The percentage of patients with clinical response at week 8 in SHR0302 8mg group 
– the percentage of patients with clinical response at week 8 in placebo group = 0;  
• H11: The percentage of patients with clinical response at week 8 in SHR0302 8mg group 
– the percentage of patients with clinical response at week 8 in placebo group ≠ 0.  
 
• H02: The percentage of patients with clinical response at week 8 in SHR0302 4mg BD 
group – the percentage of patients with clinical response at week 8 in placebo group = 


 
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0;  
• H12: The percentage of patients with clinical response at week 8 in SHR0302 4mg BD 
group – the percentage of patients with clinical response at week 8 in placebo group ≠ 
0.  
 
• H03: The percentage of patients with clinical response at week 8 in SHR0302 4mg QD 
group – the percentage of patients with clinical response at week 8 in placebo group = 
0;  
• H13: The percentage of patients with clinical response at week 8 in SHR0302 4mg QD 
group – the percentage of patients with clinical response at week 8 in placebo group ≠ 
0. 
 
 
Figure 2. The decision rules of hyopthesis 
 
For clinical response at week 8, the comparisons of the percentage of patients achieving 
clinical response in each treatment versus placebo will be made using a stratified Cochran-
Mantel-Haenszel (CMH) test with stratification according to prior anti-TNFα/biological 
treatment (with or without). The CMH method is a technique that generates an estimate after 
adjusting for or taking into account stratification. Strata-adjusted proportion difference 
between each SHR0302 dose group and placebo group will be obtained by CMH method [1]. 
 
Missing data will be imputed as NCF. If a patient is missing one or more Mayo subscores at the 
visit where the endpoint is being assessed, the patient would be considered a treatment 
failure.  
 
Two-sided p-values for the treatment group differences will be provided for all comparisons. 
Thus, 3 p-values will be gained. Order the three p values as (p(3), p(2), p(1)), where p(3) ≥ p(2) ≥ 
p(1). The decision rules are provided in Figure 2.  Note that in Figure 2, H(01) is the 


 
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corresponding null hypothesis of the smallest p value p(1), H(02) is the corresponding null 
hypothesis of the second smallest p value p(2), and H(03) is the corresponding null hypothesis of 
the largest p value p(3). Therefore, H(01) and H01 may not be the same null hypothesis, H(02) and 
H02 may not be the same null hypothesis, H(03) and H03 may not be the same null hypothesis, 
either. 
 
15.1.2 Sensitivity Analysis of Primary Efficacy Endpoint 
Sensitivity analyses for the primary endpoint include:  
 
• Sensitivity to analysis set 
  
The same analysis will use the per-protocol analysis set  
 
• Sensitivity to missing data assumptions 
The same analysis will use LOCF imputation for subscore other than endoscopy of 
Mayo score.  For missing endoscopy subscore, BOCF imputation will be used  .  
 
15.2 SECONDARY ENDPOINTS 
The secondary endpoints are as follows: 
 
• The percentage of patients with clinical remission (per 9-point modified Mayo score) 
at week 8;  
• The percentage of patients with clinical remission (per total Mayo score) at week 8 
• The percentage of patients achieve endoscopic remission at week 8 
• Change from baseline in 9-point modified Mayo score at week 8 
• Change from baseline in total Mayo score at week 8  
• Changes from baseline in partial Mayo score (Mayo score without endoscopy) at week 
1, 4, 8, 9, 12 and 16. 
•  Change from baseline in the level of biomarkers CRP, fecal calprotectin 
 
15.2.1 Analysis Methods for Secondary Efficacy Endpoints 
All secondary endpoint analyses will be performed on the full analysis set. 
 
Dichotomized Secondary Efficacy Endpoints 
 
Clinical remission per 9-point modified Mayo score is calculated by using 9-point modified 


 
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Mayo score where stool frequency subscore ≤1, rectal bleeding subscore of 0, and endoscopic 
subscore ≤ 1. In addition, Clinical remission per total Mayo score is defined as a total Mayo 
score of 2 points or lower than 2, with no individual subscore exceeding 1 point. The 
percentage of patients achieve clinical remission per 9-point modified Mayo score or per total 
Mayo score will be presented at Week 8. The 90% CI for unadjusted rate will be calculated 
using the Clopper-Pearson method. Adjusted difference between each SHR0302 dose group 
and placebo group in clinical remission rate and 90% CI will be provided by CMH method after 
adjusting for prior anti- TNFα treatment/biological treatment. The adjusted effect will be 
obtained by CMH weighted average of stratum specific rate differences. Stratified Wald 
confidence interval will be provided [1].  
 
A shift table will be used to evaluate changes from baseline in Stool Frequency, Rectal 
Bleeding, Endoscopy and Physician’s global assessment subscores of total Mayo score and 
compare these changes of each of the subscores between the treatment arms. 
 
The percentage of patients achieving clinical response or remission (per 9-point modified 
Mayo score or total Mayo score) and 90% CI will be presented for each treatment group in a 
figure. 
 
Endoscopy examination will be required at baseline and Week 8 in order to establish Mayo 
endoscopic subscore. 
 
Endoscopic remission is defined as the findings of colonoscopy subscore of the Mayo score 
equals 0. The percentage of patients achieve endoscopic remission will be presented at Week 
8. Adjusted difference between each SHR0302 dose group and placebo group in endoscopic 
remission rate and 90% CI will be provided by CMH method after adjusting for prior anti- 
TNFα treatment/biological treatment. CMH weighted difference in percentages and 
confidence interval will be caculated [1]. 
 
Continuous Secondary Efficacy Endpoints 
 
Change from baseline in 9 point modified Mayo score or total Mayo score at Week 8 will be 
summarized in each treatment group and overall. Descriptive statistics will be presented. An 
analysis of covariance (ANCOVA) model will be used to evaluate whether the means of change 
from baseline are equal across treatment groups, while statistically controlling for the effects 
of baseline value and previous exposure to anti-TNFα treatment/other biological treatments. 
The model will include treatment group, baseline value, with/without previous exposure to 
anti-TNFα treatment/biological treatment as main effects. Least square mean (LS Mean) and 
90% CI for each treatment group will be provided at Week 8. 


 
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A partial Mayo score is the Mayo score without endoscopy component. Hence the maximum 
is 9 points and minimum 0 point. A partial Mayo score will be assessed at baseline, Week 1, 
Week 4, Week 8, Week 9, Week 12, Week 16 , Week 18, early withdrawal visit and follow up 
visit, as secondary endpoints. 
 
Changes from baseline in partial Mayo score at Weeks 1, 4, 8, 9, 12 and 16 will be summarized 
descriptively. For each visit, the change from baseline in partial Mayo score will be calculated. 
For the change from baseline value at each visit, ANCOVA model including treatment group, 
baseline value, with/without previous exposure to anti-TNFα treatment as main effects will be 
used to assess the treatment effect in partial Mayo score. LS Mean and 90% CI for each 
treatment group will be provided at Week 1, 4, and 8.  
 
A figure will be used to present mean and 90% CI of the partial Mayo score at each visit in 
each treatment group.  
 
C-reactive protein is considered an acute-phase protein which provides an objective criterion 
of inflammatory activity. CRP measurements will be collected at screening, baseline, Weeks 1, 
4, 8, 9, 12, 16, early withdrawal visit and follow up visit and will be analyzed by a central 
laboratory. 
 
Change from baseline in the level of biomarker CRP at Weeks 1,4, and 8 will be summarized by 
using ANCOVA model including treatment group, baseline value, with/without previous 
exposure to anti-TNFα treatment/biological treatment as main effects.  
A figure will be used to present mean and 90% CI of the CRP level at each visit in each 
treatment group.  
 
Fecal calprotectin is a 36kDa calcium and zinc binding protein which is neutrophil derived 
and it represents 60% of cytosolic proteins in granulocytes. It is considered as a measurement 
of neutrophil migration to the gastrointestinal tract. Fecal calprotectin is a very stable marker 
(stable for one week at room temperature). There is a growing body of evidence that fecal 
calprotectin correlates well with disease activity and making it a useful tool in monitoring 
disease and treatment. Fecal calprotectin measurements will be collected at baseline, Weeks 
4,  8, and 16 and will be analyzed by a central laboratory. 
 
Change from baseline in the level of biomarker fecal calprotectin at Weeks 4 and 8 will be 
summarized in a similar way as change from baseline in the level of biomarker CRP. 
 
 


 
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15.2.2 Missing Data for Secondary Efficacy Endpoints 
For dichotomized endpoints, missing data will be imputed as non-completers considered 
failure; if a patient is missing one or more Mayo subscores at the visit where the endpoint is 
being assessed, the patient would be considered a treatment failure.  
 
For continuous endpoints, missing data will be imputed by using LOCF approach for results 
other than endoscopy of Mayo score. For missing endoscopy subscore, BOCF approach will be 
used. 
16. SAFETY ENDPOINTS 
Summaries of safety data will be based on the safety analysis set. There will be no statistical 
comparisons between the treatment groups for safety data, unless otherwise specified with 
the relevant section.  
 
16.1 ADVERSE EVENTS (AES) 
AE is any untoward medical occurrence in a patient or clinical investigation patient, 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. 
 
Adverse events will be collected from the start of the study drug until the Follow-Up contact. 
Serious adverse events will be recorded from the time of consent up to and including any 
follow up contact. 
 
Adverse Events will be coded using MEDDRA 21.1 or higher version. 
 
Treatment emergent Adverse Events (TEAEs) are defined as AEs which commence on or after 
the time of start of IP administration. Adverse events without an onset date or time or AEs 
with an onset date of the date of IP administration but without an onset time will be defined 
as treatment emergent, except if an incomplete date (e.g., month and year) clearly indicates 
that the event started before administration of IP or if the AE stop date indicates that the 
event stopped before administration of IP. 
 
See Appendix 2 of the SAP for handling of partial dates for AEs.   
 
Listings will include all AEs (TEAEs and Non-TEAEs). 


 
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Summaries of the incidence of AEs within each of the categories described below, will be 
provided. 
 
16.1.1 All TEAEs   
An overall summary of TEAEs in treatment phase will be provided. The number and 
percentage of patients experiencing AEs and the number of TEAEs will be tabulated. 
 
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) 
and summarized in treatment phase for each SHR0302 dose level , placebo and overall.  
 
All TEAEs during the whole study period will also be summarized for the following groups 
similarly. 
• 8 mg QD total: 8mg QD during the whole study period+ Placebo->8mg QD group after 
treatment phase 
• 4 mg BD total: 4 mg BD during the whole study period + Placebo->4mg BD group after 
treatment phase 
• 4 mg QD total: 4 mg QD during the whole study period + Placebo->4mg QD group after 
treatment phase 
• Placebo only: Placebo group during treatment phase 
 
Incidence of TEAEs will also be broken down further as shown in the following sections. 
 
16.1.1.1 Relationship to IP 
 
Relationship, as indicated by the Investigator, is classified into 5 grades: related, probably 
related, possibly related, unlikely to be related, and unrelated. A “related” TEAE is defined as 
a TEAE with a relationship to study medication as “related”, “probably related”, “possibly 
related” or “unlikely to be related” to study medication.If a patient reports the same AE more 
than once within that SOC/ PT, the AE with the worst case relationship to study medication 
will be used in the corresponding relationship summaries. All TEAEs in treatment phase will be 
summarized by SOC, PT and by relationship for each SHR-0302 dose level , placebo and 
overall. All TEAEs will also be summarized similarly for 8 mg QD total, 4 mg BD total, 4 mg QD 
total, Placebo only and overall during the whole study period. 
 
16.1.1.2 Severity 
 


 
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The severity of TEAE will be collected as mild, moderate and severe. All TEAEs in treatment 
phase will be summarized by SOC, PT, and severity for each SHR-0302 dose level and placebo. 
If a patient reports a TEAE more than once within that SOC/ PT, the AE with the worst case 
severity will be used in the corresponding severity summaries. All TEAEs will also be 
summarized similarly for 8 mg QD total, 4 mg BD total, 4 mg QD total, placebo only and overall 
during the whole study period. 
 
16.1.2 TEAEs of Serious Infection 
A serious infection during the study is defined as any infection (viral, bacterial, and fungal) 
requiring hospitalization or parenteral antimicrobials. The patient must be discontinued from 
the study. Serious infection will be identified as those records with a response of “Yes” to the 
item “Is this a serious infection defined in protocol?” on the “Adverse Events” form of the 
eCRF. Serious Infection in treatment phase will be summarized by SOC and PT for each 
SHR0302 dose level , placebo and overall. The number of patients with at least one serious 
infection will be presented and 95% CI will be calculated using the Clopper-Pearson method. 
TEAEs of serious infection will also be summarized similarly for 8 mg QD total, 4 mg BD total, 4 
mg QD total, Placebo only and overall during the whole study period.  
16.1.3 TEAEs Leading to Study Discontinuation  
TEAEs leading to study discontinuation will be identified as those records with a response of 
“Yes” to the item “Did the adverse event cause the patient to be discontinued from the 
study?” on the “Adverse Events” form of the eCRF. Summaries of patients (frequencies and 
percentages) with TEAEs leading to study discontinuation and summaries of incidence rates 
(frequencies) in treatment phase by SOC and PT will be prepared for each SHR0302 dose level, 
placebo and overall. TEAEs leading to study discontinuation will also be summarized similarly 
for 8 mg QD total, 4 mg BD total, 4 mg QD total, Placebo only and overall during the whole 
study period. 
 
A listing will be prepared for TEAEs leading to study discontinuation.  
 
16.1.4 Serious Adverse Events (SAEs) 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
c. 
Requires hospitalization or prolongation of existing hospitalization 
d. 
Results in disability/incapacity, or 
e. 
Is a congenital anomaly/birth defect 


 
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f. 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
g. 
All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT ≥ 
3xULN and bilirubin ≥ 2xULN (>35% direct) (or ALT ≥ 3xULN and INR>1.5, if INR 
measured) termed ‘Hy’s Law’ events (INR measurement is not required and the 
threshold value stated will not apply to patients receiving anticoagulants). 
 
On the Adverse Events page of the eCRF, serious adverse events are those events respond as 
“Yes” for item “Serious Criteria”. 
 
Summaries of all serious TEAEs and serious TEAEs Related to study medication in treatment 
phase by SOC and PT for each SHR0302 dose level , placebo and overall will be prepared. All 
serious TEAEs and serious TEAEs related to study medication will also be summarized similarly 
for 8 mg QD total, 4 mg BD total, 4 mg QD total, Placebo only and overall during the whole 
study period. Patients with missing relationship will be treated as probably related. 
 
Listings will include all SAEs (serious TEAEs and serious Non-TEAEs).Listings for SAEs will 
include the start date, end date, severity, severity, relationship to study drug, action taken, 
outcome, SAE criteria, and a liver event or not, etc. 
 
16.1.5 TEAEs Leading to Death 
TEAEs leading to Death are those TEAEs which are recorded as “Fatal” on the Adverse Events 
page of the eCRF. A summary of TEAEs leading to death in treatment phase by SOC and PT will 
be prepared for each SHR0302 dose level , placebo and overall. TEAEs leading to death will 
also be summarized similarly for 8 mg QD total, 4 mg BD total, 4 mg QD total, Placebo only 
and overall during the whole study period.A listing will be prepared for TEAEs leading to 
death. 
 
16.2 DEATHS 
If patients die during the study as recorded on the” Death Details” page of the eCRF, the 
information will be presented in a in a summary table for each SHR0302 dose level , placebo 


 
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and overall. Death information will also be summarized similarly for 8 mg QD total, 4 mg BD 
total, 4 mg QD total, Placebo only and overall during the whole study period. Death 
information will be presented in a data listing for SS. 
 
16.3 LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for 
Hematology, Chemistry, Urinalysis and Others. All laboratory assessments will be listed in the 
outputs. 
 
Presentations will use SI Units. All laboratory data will be summarized and listed for all 
patients in the SS set by visits where data are collected. 
 
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
quantification (BLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will be 
converted to X for the purpose of quantitative summaries, but will be presented as recorded, 
i.e. as “< X” or “> X” in the listings. 
 
Quantitative laboratory measurements will be compared with the relevant laboratory 
reference ranges in SI units and categorized as: 
• Low: Below the lower limit of the laboratory reference range.  
• Normal: Within the laboratory reference range (upper and lower limit included). 
• High: Above the upper limit of the laboratory reference range. 
 
 
The following summaries will be provided for laboratory data: 
• Actual and change from baseline by visit (for quantitative measurements) 
• Incidence of abnormal values according to normal range criteria 
• Shift tables representing categorical change of laboratory evaluation results from 
baseline to each post baseline  
• Listing of patients with laboratory results 
 
16.4 ELECTROCARDIOGRAM (ECG) EVALUATIONS 
12-lead ECGs will be recorded in triplicate at the scheduled time points. The three values of 
each ECG parameter at each visit will be averaged to determine time-specific parameter for a 
patient and used in summaries. The three values of each ECG parameter at each visit will be 


 
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included in listings.  
 
The following ECG parameters will be reported for this study: 
• Heart Rate (Beats/min) 
• PR Interval (msec) 
• RR Interval (msec) 
• QRS interval (msec) 
• QT Interval (msec) 
• QTc(F) Interval (msec) 
• Overall assessment of ECG 
o 
Normal 
o 
Abnormal Not Clinically Significant (ANCS)  
o 
Abnormal Clinically Significant (ACS) 
The following summaries will be provided for ECG data: 
• Actual and change from baseline by visit (for quantitative measurements) 
• Incidence of abnormal and clinically significant values 
• A shift analysis table showing shift in overall ECG interpretation from baseline to each 
time point  
 
16.4.1 ECG MARKEDLY ABNORMAL CRITERIA 
For all patients in the safety analysis population, the maximum QTcF interval will be 
summarized using frequency tables for each SHR0302 dose level , placebo and overall in 
treatment phase  for values of clinical importance using the range criteria below. 
• 
Absolute values for post baseline QTcF interval will be classified as: 
Cumulative Category: 
o 
≤ 450 msec 
o 
> 450 msec  
o 
> 480 msec  
o 
> 500 msec 
 
  Interval Category: 
 
o 
≤ 450 msec 
o 
> 450 to ≤  480 msec 
o 
> 480 to ≤  500 msec 
o 
> 500 msec 


 
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• 
Change from Baseline for QTcF interval will be classified as: 
Cumulative Category: 
o 
<0 msec increase from baseline 
o 
≥ 0 msec increase from baseline 
o 
>30 msec increase from baseline 
o 
>60 msec increase from baseline 
 
 Interval Category: 
 
o 
<0 msec increase from baseline 
o 
≥ 0 to ≤  30 msec increase from baseline 
o 
> 30 to ≤  60 msec increase from baseline 
o 
>60 msec increase from baseline 
 
The maximum QTcF interval will also be summarized similarly for 8 mg QD total, 4 mg BD total, 4 
mg QD total, Placebo only and overall during the whole study period. 
 
16.5 VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
• Systolic Blood Pressure (mmHg) 
• Diastolic Blood Pressure (mmHg) 
• Heart Rate (beats/min) 
• Temperature (⁰C) 
• Weight 
• Height  
 
The following summaries will be provided for vital signs data: 
• Actual and change from baseline by visit  
• Incidence of abnormal values according to markedly abnormal criteria 
• Listing of patients with vital signs measurements  
 
16.5.1 Vital Signs Markedly Abnormal Criteria 
Markedly abnormal quantitative Vital Signs measurements will be identified in accordance 
with the following predefined markedly abnormal criteria detailed in below table: 
 


 
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Variable 
Unit 
Low 
High 
SBP 
mmHg 
≤ 90 mmHg AND  
change from baseline 
≤ -20 mmHg 
≥ 180 mmHg AND 
change from baseline 
≥ 20 mmHg 
DBP 
mmHg 
≤ 50 mmHg AND 
change from baseline ≤ -15 
mmHg 
≥ 105 mmHg AND 
change from baseline 
≥ 15 mmHg 
Heart Rate  
Bpm 
≤ 50 bpm AND 
change from baseline ≤ -15 
bpm 
≥ 120 bpm AND 
change from baseline 
≥ 15 bpm 
Body 
temperature 
˚C 
NA 
≥ 38.3 ˚C AND 
change from baseline ≥ 1.1 
˚C 
Weight 
Kg 
percentage change from 
baseline ≤ -7.0 % 
percentage change from 
baseline ≥ 7.0 % 
16.6 PHYSICAL EXAMINATION 
Physical examination data will be listed only. 
 
16.7 OTHER SAFETY ASSESSMENTS 
Female patients of childbearing potential will be tested for serum beta-human chorionic 
gonadotropin (β-hCG) at screening visit. In addition, urine β-hCG test will be done at 
baseline and at each study visit until the end of follow-up period. If at any point there is a case 
of a positive urine β-hCG test, and this is confirmed by serum β-hCG, the patient will be 
withdrawn from the study and all the necessary follow up will be conducted. Urine pregnancy 
test will be done in females of childbearing potential only. Pregnancy tests data will be listed. 
 
Phase II liver chemistry stopping and follow up criteria have been designed to assure 
patient safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance). Please refer to section 7.3.9 of the protocol for details. Liver 
Event Follow up Assessments and Liver Event Alcohol intake will be listed.  
 
Supplemental lab data will be listed 
 
Microscopy data, if available, will be listed.  
 


 
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A listing will be provided for patients whose trial participation are impacted by COVID-19, 
including patient number and site number together with a description of the impact. These 
protocol deviations are documented in IQVIA clinical trial management system. 
17. REFERENCES 
[1] KIM Y，WON S．Adjusted proportion difference and confidence interval in stratified 
randomized trials[R]．Chicago，2013． 
 


 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA Output Conventions 
Outputs will be presented according to the IQVIA general guidelines and template for outputs 
conventions. 
 
Dates & Times 
Depending on data available, dates and times will take the form DDMMMYYYY hh:mm:ss. 
 
Significant Digits of Summary Statistics 
1 Summary statistics are displayed with the following digits. 
Description 
Characteristic 
Number of decimal places 
Count 
n 
0 
Count corresponding to the 
number of patients for a 
treatment group 
N 
0 
Mean 
Mean 
As in source + 1 
Standard Deviation 
SD 
As in source + 1 
Confidence Interval 
CI 
As in source + 1 
Minimum 
Min  
As in source 
Median 
Median 
As in source + 1 
Maximum 
Max 
As in source 
Percentage 
% 
1 * 
P-value 
P-value 
3 decimal places.  
If the value is less than 0.001,  
then it will be shown as 
"<0.001".  
If P-value cannot be calculated, 
"-" is shown.  
If test is not performed, nothing 
is shown.  
*   Number of decimal places can be two, if necessary. 
2 If the source has more than 5 significant digits, the above would be replaced with the 
corresponding number of significant digits. 
 
Spelling Format 
English US.  
 


 
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Presentation of Treatment Groups 
 
For outputs, treatment groups will be represented as followsand in that order: 
Treatment Group 
For Tables, Listings and Graphs 
SHR0302 8mg QD during the 
whole study period 
8mg QD 
SHR0302 4mg BD during the 
whole study period 
4mg BD 
SHR0302 4mg QD during the 
whole study period 
4mg QD 
Initially randomized to Placebo  
Placebo 
Placebo during the treatment 
phase and SHR0302 8mg QD 
after treatment phase 
Placebo->8mg QD 
Placebo during the treatment 
phase and SHR0302 4mg BD after 
treatment phase 
Placebo->4mg BD 
Placebo during the treatment 
phase and SHR0302 4mg QD 
after treatment phase 
Placebo->4mg QD 
Screen failure 
Screen failure 
 
For some tables related to TEAE and ECG markedly abnormal criteria, treatment group will 
be presented as follows. 
 
Treatment Group 
For TEAE and ECG Markedly Abnormal Criteria Tables 
SHR0302 8mg QD during the 
whole study period+ 
Placebo->8mg QD group after 
treatment phase 
8mg QD total 
SHR0302 4mg BD during the 
whole study period + 
Placebo->4mg BD group after 
treatment phase 
4mg BD  total 
SHR0302 4mg QD during the 
whole study period + 
Placebo->4mg BD group after 
treatment phase 
4mg QD total 


 
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Treatment Group 
For Tables, Listings and Graphs 
Placebo group during treatment 
phase 
Placebo only 
 
Presentation of Visits 
CRF visits (visits as recorded in the eCRF) will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Screening  
Scr  
Baseline 
BL 
Week 1 
W1 
Week 4 
W4 
Week 8 
W8 
Week 9 
W9 
Week 12 
W12 
Week 16 
W16 
Early Withdrawal 
EW 
Follow Up 
FU 
Unscheduled Visit 
US 
 
CRF visits will be displayed in the listings.  Analysis baseline defined in SAP will be flagged and 
will be identified in the listings as needed.  
 
Analysis visits will be displayed in the tables.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
 
Algorithm for Treatment Emergence of Adverse Events: 
START DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not 
TEAE 
If start date >= study med start date, then TEAE 
 
Partial 
If start date < study med start date, then not 
TEAE 
If start date >= study med start date, then TEAE 
 
Missing 
If start date < study med start date, then not 
TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, but known 
components show that 
it cannot be on or after 
study med start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or 
after study med start 
date 
Known 
If stop date < study med start date, then not 
TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last 
day of month if day unknown or 31st December 
if day and month are unknown), then: 
If stop date < study med start date, then not 
TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not 
TEAE 
If stop date >= study med start date, then TEAE 


 
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START DATE 
STOP 
DATE 
ACTION 
 
Partial 
Impute stop date as latest possible date (i.e. last 
day of month if day unknown or 31st December 
if day and month are unknown), then: 
If stop date < study med start date, then not 
TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Algorithm for TEAEs by Study Phase for Onset  
TEAE START DATE 
ACTION 
Known 
If start date <week 8 visit date, then TEAE in treatment phase 
If week 16 visit date≥start date ≥week 8 visit date, then TEAE in 
extension phase 
If start date>week 16 visit date, then TEAE in follow up phase 
Partial, but known 
components can 
determine the 
phase 
If start date <week 8 visit date, then TEAE in treatment phase 
If week 16 visit date≥start date ≥week 8 visit date, then TEAE in 
extension phase 
If start date>week 16 visit date, then TEAE in follow up phase 
Partial and known 
components can 
not determine the  
phase 
Missing day - Impute the 1st of the month unless month is same as 
month of first dose of study drug then impute first dose date  
Missing day and month – impute 1st January unless year is the same 
as first dose date then impute first dose date 
 
If the imputed start date <week 8 visit date, then TEAE in treatment 
phase 
If week 16 visit date≥imputed start date ≥week 8 visit date, then 
TEAE in extension phase 
If imputed start date>week 16 visit date, then TEAE in follow up 
phase 
Other missing 
status 
impute first dose date and treat the onset of TEAE as in treatment 
phase 
 
 
 


 
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Algorithm for Prior / Concomitant Medications:  
START 
DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If stop date <= study med start date, assign as prior  
If stop date >study med start date, assign as concomitant  
 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date <= study med start date, assign as prior 
If stop date > study med start date, assign as concomitant  
 
Missing 
If stop date is missing could never be assumed a prior 
medication , assign as concomitant 
 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown), then: 
If stop date <=study med start date, assign as prior 
If stop date >study med start date, assign as concomitant 
 
 
Partial 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown) and impute stop date as latest possible date (i.e. 
last day of month if day unknown or 31st December if day and 
month are unknown), then: 
If stop date <= study med start date, assign as prior 
If stop date > study med start date, assign as concomitant 
 
 
Missing 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown), then: 
If stop date is missing could never be assumed a prior 
medication, assign as concomitant 
 
 
 
 
 


 
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START 
DATE 
STOP 
DATE 
ACTION 
Missing 
Known 
If stop date <= study med start date, assign as prior 
If stop date > study med start date, assign as concomitant 
 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date <= study med start date, assign as prior 
If stop date >study med start date, assign as concomitant 
 
 
Missing 
Assign as concomitant