Conditions: Atopic Dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 105
Healthy volunteers: no

Brief summary:
This proposed study is a randomized, double-blind, placebo-controlled, 3-arm parallel, multicenter phase II study, designed to explore the efficacy and safety of SHR0302 treatment for patients with moderate to severe atopic dermatitis.

The study will be conducted over a 12-week treatment period. Two active doses of SHR0302 will be compared to placebo and improvement in atopic dermatitis will be assessed using the Investigator's Global Score (IGA)

Detailed description:

Arms:
arm 1: Participants randomized in this arm will receive dose A of SHR0302 until end of study at week 12. arm 2: Participants randomized in this arm will receive dose B of SHR0302 until end of study at week 12. arm 3: Participants randomized in this arm will receive Placebo of SHR0302 until end of study at week 12.

Interventions: intervention 1: Drug: SHR0302
Intervention descriptions: intervention 1: The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK-1(known as a JAK-1 inhibitor).

Protocol document:
Prot_000.pdf: 
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TITLE: A Randomized, Double-Blind and Placebo-Controlled Phase II Study to 
Evaluate the Efficacy and Safety of SHR0302 in Adult Patients with Moderate to 
Severe Atopic Dermatitis 
 
 
 
 
 
 
 
 
Compound Number: SHR0302 
Compound name: 
Protocol Number： RSJ10303 
Version number: V1.1 
IND number: 
NCT number: NCT04162899 
Effective date: March 14th, 2019 
EudraCT ： 
Protocol Amendment No. ：- 
Development Staging Phase IIa/b 
Authors: Wang Beilei, Aik Han Goh, Liu Yingxue, Ma Zheyong 


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Sponsor Information 
Reistone Biopharma Co., Ltd. 
No. 800 Naxian Road, 
Building 1, Room 402-5, Zhangjiang Hi-Tech Park, 
Pudong, 201210, Shanghai, China 
Contact Tel: 00 86 (0) 21-6092 7289 
 
Sponsor Medical Monitor 
Wang Beilei 
Medical Monitor 
Reistone Biopharma 
800 Naxian Road, 
Building 1, #402-5, Zhangjiang High-tech Park, 
Pudong, 201210, Shanghai, China 
Contact telephone: 00 86 (0)21-6092 7289 
 
Back-up Medical Monitor 
Liu Lan 
Medical Monitor 
Reistone Biopharma 
800 Naxian Road, 
Building 1, #402-5, Zhangjiang High-tech Park, 
Pudong, 201210, Shanghai, China 
Contact telephone: 00 86 (0)21-6092 7289 
 
SAE reporting line 24-hour: 
COUNTRY 
Toll-Free fax Number 
Toll-Free Phone Number 
China 
Sponsor Signatory 
 
 
 
 
Project Physician 
Date 


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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
Protocol RSJ10303 
I confirm my 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 assistants, colleagues and employees assisting in the conduct of the study 
are informed of their oligations. Mechanisms are put 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  
7 
1. Protocol Summary  
9 
1.1 Study objectives and endpoints  
10 
1.2 Study Design  
12 
2. 
Introduction  
13 
2.1 Background  
13 
2.2 Rationale  
14 
2.3 Dose Selection Rationale  
16 
2.4 Risk: Benefit Assessment  
17 
3. 
Study Objectives and Endpoints  
18 
3.1 
Primary objective and primary efficacy endpoint  
18 
3.2 Secondary objectives and Secondary Endpoints  
19 
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  
21 
5.2 Inclusion criteria  
21 
5.3 Exclusion Criteria  
22 
5.4 Contraception advice  
24 
5.4.1 Female subjects of Non-Childbearing potential  
24 
5.4.2 Female subjects with childbearing potential  
24 
5.4.3 Pregnancy tests  
25 
5.4.4 Males  
25 
5.5 Randomization Criteria  
25 
5.6 Withdrawal Criteria  
26 
5.7 Pre-Screen and Screen Failure  
26 
5.8 Early Withdrawal  
27 
5.9 Stopping Criteria  
28 
5.10 Premature Study Termination  
29 
5.11 Time and Event Tables  
29 
6. 
Study Treatments  
33 
6.1 Investigational product/placebo supply  
33 
6.1.1 Study Drug Dispensing  
33 
6.1.2 Study Drug Administration  
33 


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6.2 Treatment Assignment  
33 
6.3 Blinding  
33 
6.4 Drug Storage and Accountability  
34 
6.5 Treatment Compliance  
35 
6.6 Concomitant Medications  
35 
6.6.1 Permitted Concomitant Medications  
35 
6.6.2 Prohibited Medications  
36 
6.6.3 Prohibited Medications Washout  
36 
6.6.4 Traditional Chinese Medicine and Herbal Medicines  
36 
6.7 Treatment after study completion  
37 
6.8 Study Drug Overdose Management  
37 
7. 
Study Assessments and Procedures  
37 
7.1 Critical Baseline Assessments  
37 
7.2 Efficacy Endpoint Assessment  
38 
7.2.1 Investigator’s Global Score (IGA)  
38 
7.2.2 Eczema Area and Severity Index (EASI)  
38 
7.2.3 Atopic Dermatitis Score (SCORAD)  
40 
7.2.4 Pruritus Numeric Rating Scale (NRS)  
41 
7.2.5 Skin Disease Quality of Life Index (DLQI)  
41 
7.3 Safety assessment  
41 
7.3.1 Vital Signs  
41 
7.3.2 12-lead ECG  
41 
7.3.3 QuantiFERON-TB Gold Test  
41 
7.3.5 T-SPOT.TB test  
42 
7.3.5 Clinical Laboratory Testing  
42 
7.3.6 Immunoglobulin E (IgE)  
43 
7.3.7 Lipid Profile Testing  
44 
7.3.8 Liver Biochemistry – Stopping and Follow-up Criteria  
44 
7.3.9 Pregnancy  
45 
7.3.10 Adverse Events  
45 
7.3.11 Definition of AE  
46 
7.3.13 AEs and SAEs reporting requirement and timeline  
48 
7.3.14 AE Severity Assessment  
49 
7.3.15 AE Causality Assessment  
49 
7.4   Pharmacokinetics  
49 


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8. 
Data Management (DM)  
50 
9. 
Data Analysis and Statistical Considerations  
50 
9.1 
Sample Size Determinaztion and Hypothesis  
50 
9.2 Efficacy analysis  
51 
9.2.1 Analysis of the primary efficacy endpoint  
51 
9.2.2 Analysis of the secondary efficacy endpoints  
51 
9.3 Safety Analysis  
52 
9.3.1 Analysis of adverse events  
52 
9.3.2 Other safety analyses  
53 
9.4 Pharmacokinetic analysis  
53 
9.5 Interim Analysis  
53 
10. 
Study Conduct Considerations  
54 
10.1 
Regulatory and Ethical considerations of GCP standard  
54 
10.2 Institutional Review Board (IRB)/Independent Ethics Committee (IEC)  
54 
10.3 Informed Consent Process  
54 
10.4 Study Monitoring and Quality Control  
55 
10.5 Study Site Closure  
55 
10.6 Record Retention  
55 
10.7 Independent Data Monitoring Committee (IDMC)  
56 
10.8 Provision of study results to Investigators, posting to the Clinical Trial Registry and 
Publication  
56 
11. 
Reference  
57 
12. 
Appendices  
58 
Appendix 1 Atopic Dermatitis Diagnosis -Chinese Criteria  
 58 
Appendix 2 Cockcroft-Gault calculation  
 59 
Appendix3 ECG exclusion criteria  
 60 
Appendix 4 Prohibited Concomitant Medications  
 62 
Appendix 5 Scoring Atopic Dermatitis (SCORAD)  
63 
Appendix 6 Pruritus NRS assessment  
64 
Appendix 7 DLQI Questionnaire  
65 


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List of Abbreviations 
 
 
 
AD 
Atopic Dermatitis 
AUC 
Area Under the Curve 
β-hCG 
Beta-human Chorionic Gonadotropin 
CI 
Confidence Intervals 
Cmax 
Maximal Plasma Concentration 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
DLQI 
Dermatology Life Quality Index 
EW 
Early Withdrawal 
ECG 
EMA 
Electrocardiogram 
European Drug Administration 
EASI 
Eczema Area and Severity Index 
eCRF 
FDA 
Electronic Case Report Form 
U.S. Food & Drug Administration 
FSH 
Follicle-Stimulating Hormone 
FVC 
Force Vital Capacity 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
IB 
IL 
Investigator's Brochure 
Interleukin 
IGA 
Investigator’s Global Assessment 
JAK 
Janus kinase 
IEC 
IFN-γ 
Independent Ethics Committee 
Interferon- gamma 
IgE 
Immunoglobulin E 
IgM 
Immunoglobulin M 
IND 
Investigational New Drug 
IRB 
Independent Review Board 
ITT 
Intention-to-Treat 
IVRS 
Interactive Voice Response System 
IUD 
Intra-Uterine Device 
LDH 
Lactic Dehydrogenase 
LLoQ 
Lower Limit of Quantification 
Mcg 
Micrograms 
MedRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numeric Rating Score 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PPD 
Purified Protein Derivatives 
QD 
Quaque Die （Once Daily） 
RA 
Rheumatoid Arthritis 
RAP 
Reporting and Analysis Plan 
SAE 
severe adverse event 
SAP 
Statistical Analysis Plan 


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SD 
Standard Deviation 
SPM 
Study Procedures Manual 
SCORAD 
Scoring of Atopic Dermatitis 
TCS 
Topical corticosteroids 
Tlast 
Time of last quantifiable concentration 
ULN 
Upper Limit of Normal 


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1. Protocol Summary 
Atopic Dermatitis (AD) is a common chronic inflammatory skin disease characterized by recurrent, 
pleomorphic skin lesions, dry skin, and severe pruritus. Atopic dermatitis usually begins in infancy 
or in children and is chronic, while severe cases may persist in adulthood. Meanwhile, some adult 
cases develop in adulthood. In most countries worldwide, atopic dermatitis has a prevalence of 10% 
– 20% in children and 2 – 8% in adults 1. Moderate to severe atopic dermatitis has been reported 
in about 20% of cases 2. In China, the prevalence of atopic dermatitis has also increased rapidly 
over 20 years 3. As reported in 2016, the overall prevalence of atopic dermatitis in China is 
7.8%4. As a chronic relapsing inflammatory disease, atopic dermatitis is not curable at present, 
and the treatment for moderate to severe AD is difficult. 
Janus Kinase (JAK) - Signal transducers and activators of transcription (STAT) signaling pathway 
as an important intracellular signal transduction pathway plays a critical role for signal 
transduction from cell membrane to nucleus by various cytokines such as interleukin (IL), 
interferon (IFN) and other molecules. Inflammatory mediators that depend on the JAK/STAT 
pathway are involved in the pathogenesis of many inflammatory diseases. Therefore, JAK 
inhibitors have become a research hotspot in the treatment of immune-mediated inflammatory 
diseases. There are a number of JAK inhibitors currently under investigation for the treatments of 
immune-induced disease, such as rheumatoid arthritis (RA), psoriatic arthritis, psoriasis, ulcerative 
colitis (UC), Crohn's disease (CD), ankylosing spondylitis. Meanwhile, more and more case 
reports and early Clinical studies have suggested that JAK inhibitors have also achieved good 
results in the treatment of inflammatory skin diseases such as atopic dermatitis, alopecia areata, 
psoriasis, and vitiligo. 
Compared with traditional immunosuppressants, JAK inhibitors are more targeted. As a small- 
molecular oral formulation, JAK inhibitors are more convenient and more acceptable to patients 
than biologics administered by injection. Another advantage of these JAK inhibitors is that they 
reduce the risk of inadequate responses 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. The high selectivity of SHR0302 to JAK1 
also makes it a favorable candidate from a benefit risk safety perspective. 
This proposed study is a randomized, double-blind, placebo-controlled, 3-arm parallel, multicenter 
phase II study, which designed to explore the efficacy and safety of SHR0302 treatment for patient 
with moderate to severe atopic dermatitis. This study will be conducted over a 12-week treatment 
period. Two active doses of SHR0302 will be compared to placebo and improvement in atopic 
dermatitis will be assessed using the Investigator’s Global Score (IGA). IGA response is defined 
as IGA achieving 0 (clear)/1 (almost clear) and an improvement in IGA of ≥ 2 from baseline (as 
the primary endpoint at week 12), which is widely endorsed by clinical and regulatory authorities. 
Improvement in eczema area and severity index (EASI) and scoring atopic dermatitis (SCORAD) 
are also very important and established as secondary endpoints. 


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1.1 Study objectives and endpoints 
The objective is to evaluate the efficacy and safety of SHR0302 4 mg QD and 8 mg QD treatment 
for adult subjects with moderate to severe atopic dermatitis. 


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Primary objective 
Primary endpoint 
To evaluate the efficacy of 
SHR0302 4 mg QD, 8 mg 
QD compared to placebo in 
adult subjects with moderate 
to severe atopic dermatitis at 
Week 12 
• 
The percentage of subjects achieving IGA response at 
Week 12. IGA response is defined as IGA 0/1 
(clear/almost clear) together with IGA improvement ≥ 
2 from baseline. 
Secondary objective 
Secondary endpoints 
To evaluate safety and 
tolerability of oral SHR0302 
in subjects with moderate to 
severe atopic dermatitis 
• To assess safety and tolerability by laboratory 
parameters 
• To assess safety and tolerability by collection of 
AE/SAE incidence 
• To measure vital signs (blood pressure, heart rate, body 
temperature and respiratory rate) 
• To measure subjects’ total lipid profile, including 
triglycerides, low-density lipoprotein (LDL), and high- 
density lipoprotein (HDL) 
• To measure subjects' thyroid profile: TSH, free T4 and 
free T3 
• To evaluate liver and renal function 
• 12-lead ECG 


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To evaluate the other efficacy 
endpoints and patient 
reported outcome of 
SHR0302 in adult subjects 
with moderate to severe 
atopic dermatitis 
• Percentage of EASI change from baseline at Weeks 1, 
4, 8, and 12 
• Percentage of Subjects Achieving IGA Response at 
Weeks 1, 4, 8 
• Percentage of Subjects With ≥ 50%, 75%, and 90% 
EASI improvement from baseline (EASI50, EASI75, 
EASI90) at Weeks 1, 4, 8, and 12 
• Change from baseline in SCORAD at Weeks 1, 4, 8, 
and 12 
• Percentage of Subjects With ≥ 50%, 75%, and 90% 
SCORAD improvement from baseline (SCORAD50, 
SCORAD75, SCORAD90) at Weeks 1, 4, 8, and 12 
• Percent of pruritus numerical rating scale (NRS) change 
from baseline at Weeks 1, 4, 8, and 12 
• Percentage of Subjects Achieving Pruritus NRS 
improvement ≥3 from Baseline in at Weeks 1, 4, 8, and 
12 
• Change from baseline in Dermatology Life Quality 
Index (DLQI) at Weeks 1, 4, 8, and 12 
• Change from baseline in biomarker IgE at weeks 1, 4, 8 
and 12 
To explore Pharmacokinetic 
and dose-response properties 
of SHR0302 in subjects with 
moderate to severe atopic 
dermatitis. 
• Systemic exposure of SHR0302 at steady state in 
subjects with atopic dermatitis (ie: concentration and 
area under the curve) 
 
 
1.2 Study Design 
This is a 12-week, randomized, double-blind, placebo-controlled, 3-arm, parallel, multicenter 
clinical study, which will enroll adult subjects with moderate to severe atopic dermatitis. This 
study includes 4-week screening period and the subsequent 12-week blinded treatment period and 
2-week follow-up after last dose. The primary endpoint will be assessed at the end of the blinded 
treatment period at week 12. 


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At randomization, subjects who meet the study criteria will be randomized in a 1: 1: 1 ratio to 2 
active drug dose groups (4 mg QD and 8 mg QD) or placebo group over the 12-week treatment 
period. The total number of subjects randomized was 132. 
At Visit 1 (screening), subjects will be screened and if the subject meet all the inclusion criteria 
and do not meet any exclusion criteria, the subject can be consented and enrolled into the study 
with a subject identification number. The subjects will receive a 4-week standardized run-in period. 
At Visit 2 (Day 0), all subjects who meet all inclusion criteria and do not meet any exclusion 
criteria will be randomizaed into one of the following three treatment groups (SHR0302 4 mg QD, 
SHR0302 8 mg QD, or placebo) for 12 weeks blinded treatment. A baseline assessment will be 
performed at this visit. 
After randomization, subjects will be followed-up at Week 1, 4, 8, and 12, corresponding to Visit 
3, Visit 4, Visit 5, and Visit 6, respectively. At Visit 6 (Week 12), the primary endpoint assessment 
will be performed. 
All subjects who complete the treatment period will be followed-up for a further 2 weeks until 
Week 14 (Final Visit). Subjects who withdraw early will be followed-up for a further 2 weeks. 
The total duration of study participation (including follow-up) will be approximately 19 weeks, 7 
clinic visits. 
 
2. Introduction 
2.1 Background 
Atopic dermatitis (AD), also known as atopic eczema, is a common chronic inflammatory skin 
disease characterized by recurrent attacks, pleomorphic skin lesions, dry skin, and severe pruritus. 
Atopic dermatitis usually begins in infancy or in children and is chronic, while severe cases may 
persit in adulthood. Meanwhile, some adult cases develop in adulthood. In most countries 
worldwide, the prevalence of atopic dermatitis is 10% – 20% in children and 2 – 8% in adults 1. 
Moderate to severe atopic dermatitis has been reported in about 20% of cases 2. In recent years, a 
large number of studies have shown a progressive increase in the prevalence of atopic dermatitis 
in both children and adults 5. In China, the prevalence of atopic dermatitis has also increased 
rapidly over 20 years3. In 2016, an epidemiological study conducted in 39 tertiary hospitals in 15 
provinces showed that the overall prevalence of atopic dermatitis in China was 7.8%4. Furthermore, 
it was reported that the incidence of atopic dermatitis in China after the age of 12 is also relatively 
common 6. 
As a chronic relapsing disease, atopic dermatitis is not curable at present. The target of the 
treatment is to relieve or eliminate clinical symptoms, eliminate predisposing and/or aggravating 
factors, reduce and prevent relapses, and improve the quality of life of patients 3. Atopic dermatitis 
treatment depends on the extent and severity of the disease. Patients with mild atopic dermatitis 
may be treated with topical emollients, glucocorticoids, or calcineurin inhibitors7, patients with 


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moderate to severe disease often need to be treated with immunosuppressants or even biologics 8. 
Treatment for moderate to severe AD is difficult and often requires comprehensive therapies on 
an individualized basis. Topical glucocorticoids are considered as first-line therapy. However, they 
are not suitable for weak skin areas such as face, and long-term treatment would lead to local 
infections, atrophy, hirsutism, telangiectasia and other adverse reactions. Calcineurin inhibitors 
(such as tacrolimus, pimecrolimus cream) can be used on ace and other weak areas of the skin, but 
they also have irritation. Although systemic immunosuppressive agents (e.g., cyclosporine A, 
methotrexate, etc.) can also be used for the treatment of moderate to severe refractory AD, they 
also have many limitations. During treatment, it is necessary to monitor patient's blood pressure, 
renal function or liver function, etc. carefully9. 
Recently, with the in-depth study of the pathogenesis of atopic dermatitis, more targeted and safer 
therapeutic method have become the research and development direction of AD treatment. Anti- 
IL-4/IL-13 monoclonal antibody Dupilumab (Dupixent ® ) approved by US Drug Administration in 
March 2017 and Received European Medicines Agency ( EMA) in July 2017 provides an effective 
treatment for patients with moderate to severe atopic dermatitis in Europe and the United States 
who do not respond adequately to topical treatment or phototherapy 10, and avoids adverse effects 
of traditional hormones and immunosuppressive agents (e.g., cyclosporine A, methotrexate). 
However, a large number of studies have shown that although biologics are effective and well 
tolerated, long-term treatment may result in the absence of responses caused by immunogenicity 
in some patients. Therefore, patients may need to increase the dose and/or decrease the dosing 
interval. In addition, most patients cannot afford these higher-priced biologics. 
 
2.2 Rationale 
The pathogenesis of atopic dermatitis is complex, mainly related to genetic background, 
environmental stimuli, epidermal barrier defects and immune disorders. Disruption of the 
epidermal barrier in patients with atopic dermatitis stimulates an inflammatory response leading 
to Th2 cell activation, production cytokines such as IL-4 and IL-13, subsequently induce IgE 
produced by B cells, leading to degranulation of mast cells, basophils 11. JAK kinase (Janus Kinase) 
is a non-receptor type tyrosine kinase, and it is also an important signal transducer for many 
cytokines and interferons. When cytokines bind to cell surface receptors, they activate JAK kinases, 
which have tyrosine kinase activity and bind in pairs, and dimeric JAK can undergo spontaneous 
phosphorylation, bind to signaling and activator of transcription (STAT) proteins, phosphorylate 
STATs and translocate to the nucleus, and bind to specific promoters to increase gene expression. 
The JAK-STAT signaling pathway is implicated in the pathogenesis of inflammatory and 
autoimmune diseases and is involved in many important biological processes such as cell 
proliferation, differentiation, apoptosis, and immune regulation12. The JAK family includes four 
members, which are: JAK1, JAK2, TYK2, and JAK3. The dimer formed by JAK1 and JAK3 
mainly mediates the signal of interleukin, and JAK2 mainly mediates the signaling related to the 
development of blood cells such as erythropoietin receptor, thrombopoietin receptor, and colony- 
stimulating factor. The JAK-STAT pathway plays an important role in immune dysregulation i n  


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atopic dermatitis, including Th2 cell activation, eosinophil activation, B cell maturation, and 
suppression of regulatory T cells (Tregs). In addition, the JAK-STAT pathway activated by IL-4 
also plays a critical role in the pathogenesis of atopic dermatitis by upregulating epidermal 
chemokines, proinflammatory cytokines and proangiogenic factors, and downregulating 
antimicrobial peptides 13. Therefore, targeted blockade of the JAK/STAT pathway can inhibit the 
pathophysiological process of atopic dermatitis, thereby improving the clinical symptoms of AD 
patients and improving their quality of life. 
Several Janus kinase (JAK) inhibitors are currently under development for the treatment of 
immune-induced diseases (for example: RA, psoriatic arthritis, psoriasis, UC, CD, ankylosing 
spondylitis, and atopic dermatitis). JAK inhibitors, as small-molecule oral formulations, are more 
convenient to administer and more acceptable to patients than biologics administered by injection. 
Meanwhile, JAK inhibitors is to reduce the risk of loss of immunogenicity compared to biologics. 
It was reported that up to 50% of patients would have immunogenicity after long-term biologic 
therapy and become non-responders. Therefore, there is still an unmet medical need for these novel 
oral therapies with different mechanisms of action together with good efficacy and safety profile. 
Oral JAK1 inhibitors may fill this gap and address unmet medical needs. 
Other JAK inhibitors with different JAK selectivity profiles have shown effectiveness for RA. 
Some JAK inhibitors in atopic dermatitis are under development. Although inhibition of JAK1 
and JAK3 helps to improve the effectiveness of RA treatment, inhibition of JAK2 may also 
interfere with signaling achieved by erythropoietin, thrombopoietin, and colony-stimulating 
factors (for example: granulocyte macrophage colony-stimulating factor), and even lead to anemia 
and thrombocytopenia. 
In the world and China, some JAKs inhibitors have been investigated for phase III clinical trial, 
such as Baricitinib (JAK1/2 inhibitor) from Lilly, Upadacitinib (JAK1 inhibitor) from AbbVie, 
and PF04965842 (JAK1 inhibitor) from Pfizer. In addition, the results from completed phase II 
trials showed that the JAK inhibitors baricitinib, upadacitinib, and PF04965842 had significant 
efficacy and were well tolerated compared with placebo in the treatment of moderate to severe 
atopic dermatitis. 
SHR0302 is a highly selective JAK1 inhibitor administered through oral. An in vitro study has 
shown that its selectivity to JAK1 compared to JAK2 is about 16 times more than tofacitinib, and 
baricitinib. Selective inhibition of JAK1 would modulate multiple cytokine signaling pathways in 
AD pathogenesis, such as IL-4, IL-5, IL-13, IL-31, and IFNγ. From a safety perspective, the higher 
selectivity of SHR0302 for JAK1 also makes it a favorable candidate therapeutic agent. 
This proposed randomized, double-blind, placebo-controlled, 3-arm parallel, multicenter phase II 
study is designed to evluate the efficacy and safety of SHR0302 in subjects with moderate to severe 
AD, and to assess the optimal dose and time required for SHR0302 to induce a clinical response 
in atopic dermatitis. 


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This study will compare two active doses of SHR0302 to placebo over a 12-week treatment period. 
Improvement in clinical symptoms of atopic dermatitis will be assessed using the Investigator’s 
Global Score (IGA). Clinical response is defined as IGA achieving 0 or 1 and IGA improvement 
≥ 2 from baseline (as the primary endpoint at week 12), which is widely used in clinical trial. The 
Eczema Area and Severity Index (EASI) and the Atopic Dermatitis Score (SCORAD) are 
important parameters for reflecting disease improvement and are internationally recognized as key 
indicators for evaluating the severity of atopic dermatitis and are therefore chosen as secondary 
endpoints. In addition, regulators are increasingly focusing on patient-reported outcomes because 
patient-reported outcomes (PROs) are more able to reflect patients' symptoms, disease progression, 
and severity. Therefore, two PROs, the Dermatology Life Quality Index (DLQI) and the Subject 
Pruritus Numerical Rating Scale (NRS), are included in the secondary endpoints. 
The use of placebo as a comparator drug is the gold standard for assessing absolute efficacy and 
safety in new drug development. Placebo is particularly important for assessing placebo response, 
as it is well-known that placebo may demonstrate significant improvement in clinical trials. 
Therefore, inclusion of the placebo group in this study is extremely necessary to evaluate the 
efficacy and safety of SHR0302 in AD patients. Subjects in the placebo group may continue to 
receive some of their original basic treatment as allowed by the protocol. 
 
2.3 Dose Selection Rationale 
In this phase II study, enrolled subjects will be randomized to receive 2 different daily active doses 
of SHR0302 (4 mg QD, 8 mg QD) or placebo for the treatment period. The choice of the doses is 
based on efficacy, tolerability, and safety data obtained in three completed phase I studies as well 
as in one ongoing phase II study in patients with active rheumatoid arthritis. 
Phase I single ascending dose (SAD) study investigated the oral dose range from 1 mg to 100 mg 
in healthy volunteers. Sixty-four 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, where16 (25%) subjects reported adverse events (AEs), of 
which majority of cases were grade 1 to 2 AEs with neutrophils and lymphocytes reduction, 
except for one case of grade 3 neutrophils reduction in in the 100 mg group. All the AEs resolved, 
and all patients have recovered. There were 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 eg 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 


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randomized into this study, 20 subjects (55.6%) reported AEs. All were regarded as grade 1 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 this information, the aim of this 12-week phase II study in AD subjects is to investigate 
the 4 mg QD and 8 mg QD dose regimens. This phase II study will further validate the efficacy 
and safety of SHR0302 in inducing clinical responses in patients with moderate to severe atopic 
dermatitis. The dose interval with increment of a fold should enable enough exposure variability 
to distinguish efficacy differences between the treatment groups. 
SHR0302 with a half-life of approximately 8-9 hours will enable JAK1 inhibition over a 24-hour 
peroid and enable a once daily dosing regimen. This was supported by PD evidence from the SAD 
study where pSTAT3 inhibition could be sustained for 24 hours after once daily dosing. This phase 
II proof-of-concept and dose-ranging study in AD patients aims to evaluate the efficacy of 
SHR0302 in clinical practice providing further clinical evidence to support the dose selection. 
The selection of 12 weeks as study duration was based on the reported clinical trial experience 
where 8-12 weeks is enough to observe clinical benefit in the treatment for atopic dermatitis. This 
was demonstrated in similar class of medicine, where baricitinib and upadacitinib selected 16 
weeks and PF04965842 selected 12 weeks to demonstrate their effectiveness in treating AD. 
Therefore, it is reasonable to choose a treatment period of 12 weeks. 
In conclusion, Reistone believes that a large body of scientific evidence on JAK/STAT 
involvement in atopic dermatitis, and data from similar class of new drugs, and current early phase 
data on SHR0302 will support the rationale to proceed with phase II clinical study to evaluate the 
efficacy and safety of SHR0302 in patients with moderate to severe atopic dermatitis. 
 
2.4 Risk: Benefit Assessment 
At present, there is no curable treatment for atopic dermatitis. The goal of treatment is to relieve 
or eliminate clinical symptoms, recover skin lesions to the greatest extent, eliminate predisposing 
and/or aggravating factors, reduce and prevent relapses, and improve the quality of patients’ life. 
To strike a balance between AD maintaining remission with conventional hormones and 
immunosuppressants and preventing the side effects of these treatments has always been a 
challenge for clinicians. Therefore, identification of new effective and safe therapies is an 
important area of research. 


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In the phase I studies to date, SHR0302 has been well tolerated without any reported SAEs or 
deaths. 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 they 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 4 mg QD and 8 mg QD are selected for investigation in this proposed study. 
It is recognized 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 minimized 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 are selected for which the predicted exposure is supported by previous 
safety and tolerability data in phase I healthy volunteers and patients and allows for appropriate 
safety margin below the NOAEL limits in toxicology studies. The duration of 12 weeks study has 
also been covered by the long-term repeated-dose toxicology study. 
The efficacy, safety, tolerability, and anti-inflammatory data obtained in this proposed phase II 
study will be critical for assessing the potential of this promising, novel small molecule targeted 
agent as a therapeutic for moderate to severe atopic dermatitis, and one or two doses can be selected 
to progress into further phase III 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. Study Objectives and Endpoints 
3.1 Primary objective and primary efficacy endpoint 
 
Primary objective 
Primary efficacy endpoint 
To evaluate the efficacy of SHR0302 4 
mg QD, 8 mg QD compared to placebo in 
adult subjects with moderate to severe 
atopic dermatitis at Week 12 
• The percentage of subjects achieving IGA 
response at Week 12. IGA responsed is 
defined as IGA 0/1 (clear/almost clear) 
together with IGA improvement ≥ 2 from 
baseline 


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3.2 Secondary objectives and Secondary Endpoints 
 
Secondary objectives 
Secondary endpoints 
To evaluate safety and tolerability of oral 
SHR0302 in subjects with moderate to 
severe atopic dermatitis 
• To assess safety and tolerability by 
laboratory parameters 
• To assess safety and tolerability by 
collection of AE/SAE incidence 
• To measure vital signs (blood pressure, 
heart 
rate, 
body 
temperature 
and 
respiratory rate) 
• To measure subjects’ total lipid profile, 
including 
triglycerides, 
low-density 
lipoprotein 
(LDL), 
and 
high-density 
lipoprotein (HDL) 
• To measure subjects' thyroid profile: TSH, 
free T4 and free T3 
• To evaluate liver and renal function 
• 12-lead ECG 
To evaluate the other efficacy endpoint 
and patient reported outcome of SHR0302 
in adult subjects with moderate to severe 
atopic dermatitis 
• Percentage of EASI change from baseline 
at Weeks 1, 4, 8, and 12 
• Percentage of Subjects Achieving IGA 
Response at Weeks 1, 4, 8 
• Percentage of Subjects With ≥ 50%, 75%, 
and 90% EASI improvement from 
baseline (EASI50, EASI75, EASI90) at 
Weeks 1, 4, 8, and 12 
• Mean change from baseline in SCORAD 
at Weeks 1, 4, 8, and 12 
• Percentage of Subjects With ≥ 50%, 75%, 
and 90% SCORAD improvement from 
baseline 
(SCORAD50, 
SCORAD75, 
SCORAD90) at Weeks 1, 4, 8, and 12 


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Secondary objectives 
Secondary endpoints 
• Percent of pruritus numerical rating scale 
(NRS) change from baseline at Weeks 1, 
4, 8, and 12 
• Percentage of Subjects Achieving Pruritus 
NRS improvement ≥3 from Baseline in at 
Weeks 1, 4, 8, and 12 
• Change from baseline in Dermatology Life 
Quality Index (DLQI) at Weeks 1, 4, 8, 
and 12 
• Change from baseline in biomarker IgE at 
weeks 1, 4, 8 and 12 
To explore Pharmacokinetic and dose- 
response properties of SHR0302 in 
subjects with moderate to severe atopic 
dermatitis. 
• Systemic exposure of SHR0302 at steady 
state in subjects with atopic dermatitis (ie: 
concentration and area under the curve) 
 
4. Investigational Plan 
4.1 Study Design 
 
See  Figure 1 . 
 
 
 
Figure 1. Study Design Diagram 


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4.2 Discussion of the design 
This is a randomized, double-blind, placebo-controlled, multicenter phase II study that will enroll 
132 subjects with moderate to severe atopic dermatitis. This study consists of a 4-week screening 
period followed by a 12-week blinded treatment period and 2-week follow-up after last dose. At 
baseline visit, subjects with moderate to severe atopic dermatitis who meet all inclusion criteria/do 
not meet any of the exclusion criteria will be randomized in a 1: 1: 1 ratio during the treatment 
period to one of 3 study groups (2 active drug dose groups (4 mg QD, 8 mg QD) and placebo 
group) . 
All subjects will be followed-up for further 2 weeks until Week 14 (Final Visit). Subjects who 
withdraw early will be followed for an additional 2 weeks. 
The end of study is defined as the date of last subject's last visit or actual date of follow-up, 
whichever is later. 
 
5. Subject Selection and Withdrawal Criteria 
5.1 Number of Subjects 
132 eligible subjects will undergo randomization to achieve the estimated evaluable subjects in the 
study. The following criteria are designed to select subjects suitable for treatment according to the 
protocol. All relevant medical and non-medical conditions should be considered when deciding 
whether a subject is suitable for participation in this study. Subjects' eligibility should be reviewed 
and documented by a qualified appropriate member of the investigator's study team prior to subject 
enrollment in the study. Subjects must be able to voluntarily provide informed consent for 
participation in this study. 
 
5.2 Inclusion criteria 
Subjects must meet all the following inclusion criteria to be eligible for enrollment into the study: 
1. Subjects between 18-75 years of age (inclusive), male or female, at the time of informed 
consent 
2. Moderate to severe atopic dermatitis, as determined by all of the following: 
o Have a clinical diagnosis of AD for at least 1 year before Visit 1 (Chinese Criteria of 
AD refer to Appendix 1) 
o EASI ≥ 12, BSA ≥ 10%, and IGA ≥ 3 at the Screening and Baseline Visits 
o In the judgment of the investigator, subjects who have inadequate response and/or 
cannot be tolerable, to one or more of the below treatments for at least 4 weeks 
▪ Topical therapy (topical corticosteroids and/or topical calcineurin inhibitors) 
▪ Systemic steroids and/or phototherapy 


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▪ Cyclosporine 
and/or 
other 
immunomodulators 
(e.g., 
methotrexate, 
mycophenolate mofetil, and azathioprine, etc.) 
3. Capable of providing a signed and dated informed consent form indicating the subject 
has been informed of all pertinent aspect of the study 
4. 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) 
o Male subjects with a female partner of childbearing potential must be willing to use 
condom in addition to a highly effective contraceptive method. 
5. Subjects who are willing and able to comply with the scheduled visits and treatment plan, 
laboratory testing and other study procedure 
6. Subjects receiving non-prohibited concomitant medications for any reason must maintain 
a stable dosing regimen, defined as no administration of a new drug or no change in dose 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study drug 
 
5.3 Exclusion Criteria 
Subjects presenting with any of the following criteria will not be enrolled in this study: 
1. 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 
2. Subject has a current diagnosis of other active skin disease (e.g., psoriasis or lupus 
erythematosus) or skin infection (bacterial, fungal, or viral) that may affect the evaluation 
of atopic dermatitis 
3. Subject has a severe comorbidity that may require systemic steroids therapy or other 
interventions or requires active frequent monitoring (e.g., unstable chronic asthma) 
4. Subjects with evidence of hematopoietic disorders: 
o Hemoglobin level < 9.0 g/dL or hematocrit < 30% at screening visit or within 3 months 
prior to baseline 
o Absolute white blood cell (WBC) count <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. 


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o 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. 
5. 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. 
6. Subjects with eGFR ≤ 60 ml/min based on Cockcroft-Gault calculation (Appendix2), or 
patients currently undergoes regular hemodialysis 
7. Subjects with current clinically significant infections or within 6 months 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 
8. Subjects may have evidence of active, latent, or inadequately treated infection with 
Mycobacterium tuberculosis (i.e., tuberculosis [TB]), as defined by the following: 
o Negative QuantiFERON TB Gold (QFT Gold test) /or T-Spot test performed within 
the 3 months prior to/within screening; 
OR 
o Subjects have a chest radiograph, taken within the 3 months prior to/within screening, 
and showing no change suggestive of active TB infection 
OR 
o Subjects have history of either untreated or inadequately treated latent or active TB 
infection 
9. Subjects have received systemic corticosteroids, cyclosporin or other immunosuppressants 
(e.g., methotrexate, mycophenolate mofetil and azathioprine) or PDE4 inhibitor or 
phototherapy (e.g., UVB) treatment within 4 weeks of first dose of study drug 
10. Subjects have received topical treatment (which may affect AD, e.g., topical corticosteroids, 
topical calcineurin inhibitor, antibiotic compound cream and topical herbal) within 2 weeks 
of firs dose of study drug 
11. 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 
12. Women who are pregnant or lactating or planning pregnancy while enrolled in the study 
13. History of alcohol or drug abuse with less than 6 months of abstinence prior to baseline 
14. 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 ) 
15. Subjects with temperature ≥ 38 ° C at screening or baseline 
16. Subjects with malignancies or a history of malignancies except for adequately treated or 
excised non-metastatic basal cell or squamous cell carcinoma of the skin 


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17. Subjects with positive human immunodeficiency virus (HIV) or hepatitis B virus or 
hepatitis C virus-related laboratory tests 
18. Subjects who currently have thyroid disorders (including hyperthyroidism, hypothyroidism, 
or are currently receiving thyroid replacement therapy. Subjects with abnormal TSH, fT4, 
and fT3 values on blood tests at screening must be excluded 
19. Subjects who have previously been treated with JAK inhibitors (for example: tofacitinib, 
baricitinib, upadacitinib, PF04965842, etc.) 
20. Subjects who have previously been treated with biologics (Dupilumab, etc.) 
21. Subjects receiving or are expected to receive prohibited concomitant medication(s) within 
4 weeks prior to the first dose of study drug (see Appendix 4 ) 
22. Subjects who have received herbal treatment of unknown nature or known efficacy 
within 4 weeks prior to the first dose of study drug 
23. Subjects who, in the opinion of the investigator, will be uncooperative or unable to comply 
with the study procedures 
24. Any other condition which in the opinion of the investigator would make the subject 
unsuitable for inclusion in the study. 
 
5.4 Contraception advice 
Contraceptive measures for both male and female subjects with childbearing potential should be 
documented in the original document. 
 
5.4.1 Female subjects of non-Childbearing potential 
Female subjects of non-childbearing potential must meet at least one of the following criteria: 
o Postmenopausal female who are at least 45 years of age with amenorrhea for at least 2 years. 
To confirm the postmenopausal status (FSH level > 30 IU/L), FSH testing should be performed 
for women within 5 years from their last menses; 
OR 
o Female subjects with physician documented hysterectomy, bilateral salpingectomy and/or 
bilateral oophorectomy 
All other female subjects (including women with tubal ligations) will be considered as of 
childbearing potential. 
 
5.4.2 Female subjects with childbearing potential 
Female subjects with childbearing potential and their male partners must use at least one of the 
following highly effective methods of contraception: 
a. Combined (oestrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or transdermal). 


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b. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, or implantable). 
c. Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS) 
d. Documented bilateral tube occlusion at least 4 weeks before screening 
e. Vasectomized partner with medical confirmation of absence of sperm in the ejaculate 
at least 4 weeks before screening. 
Female subjects and their heterosexual 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 tests 
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 
At randomization visit (Visit 2), subjects who meet all inclusion criteria and do not meet any 
exclusion criteria will be randomized in a 1: 1: 1 allocation ratio to SHR0302 4 mg QD, SHR0302 
8 mg QD, or placebo. Subjects will be assigned to treatment groups using a computer-generated 
randomization table. Subjects will be assigned subject numbers in the order in which they consent 
to participate in the study. This identification number will be kept throughout the study. 


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5.6 Withdrawal Criteria 
Subjects may withdraw from the study at any time on their own request, or subjects 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 been stable. 
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 7.3.10. 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. 
 
5.7 Pre-Screen and Screen Failure 
Subjects will be assigned a subject number after they have signed a written informed consent and 
completed at least one additional study procedure (study procedures do not include washout of any 
medication). 
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: 
• 
Screening Visit Date 


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• 
Subject Number 
• 
Demographic information, including race, age, and gender 
• 
Inclusion/Exclusion Criteria 
• 
Reasons for screening failure 
• 
Primary method of subject recruitment 
• 
Serious adverse event (SAE) information 
In most circumstances, subjects who failed screening could not be re-screened. In rare instance, 
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. 
 
5.8 Early Withdrawal 
The definition of an early 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 6 
procedure (Week 12). 
Subjects 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 
• 
Physical examination (documented in original document only) 
• 
Vital signs 
• 
Collect and review patient questionnaires (pruritus NRS, DLQI) 
• 
Collect used study medication (blinded study medication) 
• 
Topical triamcinolone used was collected and weighed 
• 
Assess compliance with study medication 
• 
12-lead ECG 
• 
Laboratory evaluations (including biochemistry, hematology, pregnancy test for female 
subjects of childbearing potential and routine urinalysis) 
• 
Call IVRS to report the subject's early withdrawal from the study 
• 
Investigator’s Global Score (IGA) 
• 
Eczema Area and Severity Index (EASI) 
• 
Scoring atopic dermatitis (SCORAD) 


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Subjects who withdraw from the study after randomization to treatment cannot be re-screened and 
will not be replaced. If a subject withdraws from the study, and withdraws consent for further 
disclosure, no further assessments will be performed and no additional data will be collected. 
The sponsor may retain and continue to use any data collected prior to such withdrawal of 
consent. 
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 follows: 
• 
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 7.3.8 Liver Chemistry Stopping and Follow-up Criteria. 
• 
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 > 500ms 
− Change from baseline: QTc > 60ms 
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. 
• 
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 should be withdrawn immediately. The 
procedure is detailed in Section 7.3.10 


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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. 
 
5.11 Time and Event Tables 
 
See details in Table 1 . 


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Table 1. Time and Event Table 
 
Period 
Screening 
Baseline 
Treatment period 
Follow-up/ 
EW 12 
Visit 
1 
2 
3 
4 
5 
6 
7 
Study Week 
-4 to -1 
0 
1 
4 
8 
12 
14 
Study Day 
-28to -1 
0 
7 ± 2 days 
28 ± 3 days 
56 ± 3 days 
84 ± 3 days 
98 ± 3 days 
Procedures 
Written Informed Consent 1 
x 
Demography/Medical 
History 2 
x 
Physical Examination 
x 
x 
x 
x 
x 
x 
x 
Height 
x 
Weight 
x 
x 
Chest X-ray3 
x 
Inclusion/Exclusion Criteria 
x 
Randomization criteria 
x 
Study Drug Dispensing 
x 
x 
x 
Study Drug Accountability 
x 
x 
x 
x 13 
Enrollment Visit in IVRS 4 
x 
x 
x 
x 
x 
x 
x 13 
Assessment of effectiveness 
Investigator’s Global 
Assessment (IGA) 
x 
x 
x 
x 
x 
x 
x 13 
Eczema Area and Severity 
Index (EASI) 
x 
x 
x 
x 
x 
x 
x 13 
Scoring Atopic Dermatitis 
(SCORAD) 
x 
x 
x 
x 
x 
x 
x 13 
Pruritus numeric rating scale 
(NRS) 
x 
x 
x 
x 
x 
x 
x 13 
Dermatology quality of life 
index (DLQI) 
x 
x 
x 
x 
x 
x 
x 13 
Photography5 
x 
x 
x 
x 
x 
x 
x13 
safety assessment 
12-lead ECG 
x 
x 
x 
x 
x 
x 
x 


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Vital signs (blood pressure, 
heart rate, temperature and 
respiratory rate) 6 
x 
x 
x 
x 
x 
x 
x 
Adverse Event Assessment 7 
x 
x 
x 
x 
x 
x 
Laboratory Evaluation 
Hematological and 
biochemical tests 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
Lipid Profile (fasting) 
x 
x 
x 
x 
x 
x 
TSH, fT3, fT4 
x 
x 
x 
x 
x 
x 
x 
QuantiFERON-TB Gold or 
T-SPOT.TB test 
x 
Hepatitis B surface antigen, 
Hep C Ab, HIV test 
x 
Immunoglobulin E (IgE) 
x 
x 
x 
x 
x 
x 
x13 
Urine Pregnancy Test 8 
x 
x 
x 
x 
x 
x 
β-HCG (blood) 9 
x 
PK Sampling 
X10 
x11 
Medication 
Concomitant Medication 
Assessment 
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. Atopic Dermatitis Disease History includes collection of details of AD: AD diagnosis, the use of topical treatments, systemic treatments and other 
treatments for AD. 
3. Only to be performed if there is no chest X-ray or CT scan available within 3 months of Visit 1. 
4. IVRS is a randomization system used to record all patient visits. 
5. Subjects will be photographed at a distance of 1m by a fixed investigator at each visit (the principle of photography is to reflect the characteristics of 
AD skin lesion to the greatest extent). When photographed, face and private part will be well covered. 
6. Vital signs include resting blood pressure, heart rate, body temperature and respiratory rate. It is advised to measure them before any procedures 
or questionnaires. 
7. Adverse events and serious adverse events will be collected from the start of study drug treatment (Visit 2) to the telephone follow-up period. 
However, any serious adverse events will be recorded from the time of consent. 
8. Urine pregnancy test to be done in females of childbearing potential only at scheduled visit 
9. 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. 


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10. At week 8, pre-dose PK blood samples will be collected prior to medication. Post-dose PK blood samples will be collected at any time point from 1 
to 2 hours after medication. Subjects will take the study drug at the center site. The time of medication and the time of blood collection after 
medication need to be recorded in the eCRF. 
11. At week 12, pre-dose PK blood samples will be collected prior to medication. Post-dose PK blood samples will be collected at any time point from 
2 to 8 hours after medication. Subjects will take the study drug at the center site. The time of medication and the time of blood collection after 
medication need to be recorded in the eCRF. 
12. The early withdrawal visit should be done 2 weeks after the last dose/decision of withdrawal. 
13. Only to be conducted in the early withdrawal subjects. 


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6. Study Treatments 
6.1 Investigational product/placebo supply 
SHR0302 tablets and matching placebo tablets will be dispensed for subjects to take orally during 
the treatment period. During the treatment period, subjects will be randomized in a ratio of 1: 1: 1 
to 4 mg QD, 8 mg QD, or placebo. 
SHR0302 will be provided as combination of 4 mg tablets, including the matching placebo by the 
sponsor. At study visit on Day 0, Week 4 and Week 8, sufficient trial medication will be dispensed 
to complete dosing for 4 weeks. 
At the Week 12 visit or follow-up visit (if the patient withdraws), the subject must return all trial 
medication and the amount of medication returned will be recorded. 
 
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 completion of the 12-week treatment period, all subjects will be followed for an additional 
2 weeks. 
 
6.1.2 Study Drug Administration 
Study drug will be self-administered by the subject once daily orally in the morning. 
However, the first dose will be administered at the clinic at baseline (Day 0). Subjects should take 
their oral dose at the clinic at the Week 4, Week 8, and Week 12 visits. Study drug may be taken 
with or without food. 
6.2 Treatment Assignment 
Subjects who meet all inclusion criteria and do not meet any of the exclusion criteria will be 
randomized in a 1: 1: 1 allocation ratio to SHR0302 4 mg QD, SHR0302 8 mg QD, or placebo 
during the treatment period. 
6.3 Blinding 
Investigational product taken during the 12-week treatment period will remain double-blind. 
Neither the subject nor the study physician will know which study medication the subject is 
receiving. 
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 


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oncedaily (QD) dosing regime and placebo is used according to the schedule in the table below. 
(Table 2) 
Table 2. Study drug package design for treatment group 
Study Group 
Dose (QD) 
Day 0 to Day 84 
4mg SHR0302 
4mg tablet + placebo tablet 
8mg SHR0302 
4mg tablet + 4mg tablet 
placebo 
Placebo tablet + placebo tablet 
At each dosing time (morning), subjects will take two tablets. 
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 (e.g., 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 of the treatment period or at follow-up (if the subject withdraws). 


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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 study center at each clinic visit 
following 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. 
Previous treatment 
All treatment for atopic dermatitis including systemic steroids after the first diagnosis of 
atopic dermatitis (as determined by medical history or by medical inquiry) and all treatment 
performed within 4 weeks prior to screening must be documented in the eCRF. Reasons for 
discontinuing these medications should be recorded as: 
• 
Never achieved a satisfactory response 
• 
A satisfactory response was initially achieved, but later became ineffective 
• 
Treatment discontinuation due to intolerance/side effects 
• 
Other (detailed description) 
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. At screen visit (Visit 1), subjects will be provided with 
non-medicated study emollient. Subjects will start the emollient twice daily 2 weeks prior to the 
baseline visit (Visit 2). The non-medicated study emollient is the only topical products permitted 
to be used on atopic dermatitis skin during the study. If a subject has a history of intolerability or 
currently does not tolerate the non-medicated study emollient, the investigator should contact 
Reistone for approval to use an alternative topical treatment; the approved alternative non- 
medicated emollient should be documented in study records. 
At the same time, all subjects will also be asked about other co-medications at each clinic visit and 
recorded in the co-medications section of the CRF. Other concomitant medications allowed if 
needed during the study are as follows: 


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o Over-the-counter shower gel 
o Oral antihistamines 
o Nonsteroidal anti-inflammatory drugs 
In addition, the investigator or appropriate study staff should be consulted before the subject 
starts a new combined treatment regimen during the study. 
6.6.2 Prohibited Medications 
The following medications are prohibited throughout the duration of the study: 
o Topical treatment for AD (including but not limited to topical corticosteroids, calcineurin 
inhibitor, herbal, etc.) 
o Phototherapy 
o Cyclosporin and other immunosuppressant (e.g., methotrexate, mycophenolate mofetil and 
azathioprine, etc.) 
o Systemic corticosteroids 
o Biologics 
In addition, concomitant administration of CYP3A inducers and moderate to potent CYP3A 
inhibitors with systemic effects should be avoided during 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 lase dose of study medication. 
 
6.6.3 Prohibited Medications Washout 
Subjects who have received systemic corticosteroids, cyclosporin and other immunosuppressant 
(e.g., methotrexate, mycophenolate mofetil and azathioprine, etc.) 、PDE4 inhibitor as well as 
phototherapy treatment should washout at least 4 weeks prior to first dose of study drug. Subjects 
who have topical treatment for AD (e.g., topical corticosteroids, calcineurin inhibitor and herbal, 
etc.) should washout at least 2 weeks prior to first dose of study drug. 
 
6.6.4 Traditional Chinese Medicine and Herbal Medicines 
 
The following categories of traditional Chinese medicine or herbal medicine are prohibited 
during the study: 
o 
Traditional Chinese medicine or herbal medicine used for the treatment of AD, including those 
which may contain corticosteroids according to investigator’s judgment. 
o 
Traditional Chinese medicine or herbal medicine known effects on platelets and that increase 
bleeding tendency. 


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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 nor not Reistione Biopharma/designated CRO is 
providing specific post study treatment after week 12. Reistione Biopharma/designated CRO has 
provided a 12-week double-blind treatment period and will not provide treatment after the end of 
the 12-week treatment period. Post-treatment AD 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. 
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 key baseline assessments will be performed at Visit 1: 
• Demographic history (including gender, ethnic origin, date of birth, height, and weight) 
• Medical history of atopic dermatitis, including date of diagnosis (year of diagnosis is 
acceptable) and previous and/or current medical conditions 
• Physical examination 
• Heart rate, blood pressure, respiratory rate and temperature measurement 
• 12-lead ECG 
• Chest X-ray (or previous CT scan results obtained within 3 months of Screening (Visit 1)) 
• Clinical laboratory evaluation (including biochemistry, hematology, urine pregnancy test) 
• IGA (Investigator’s Global Assessment) 
• EASI (Eczema Area and Severity Index) 
• SCORAD (Scoring Atopic Dermatitis) 
• Pruritus numerical rating scale (NRS) 
• Dermatology Life Quality Index (DLQI) 


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7.2 Efficacy Endpoint Assessment 
 
7.2.1 Investigator’s Global Score (IGA) 
 
Primary Efficacy Endpoint: the treatment response rate based on Investigator's Global 
Assessment (IGA). The IGA score is a very simple and convenient assessment method, which is 
commonly used in clinical research as a gold-standard clinical assessment tool14. 
The IGA score will be assessed at each visit by the investigator using clinical characteristics of 
erythema, infiltration, papulation, oozing, and crusting as guidelines for the overall severity 
assessment. The IGA consists of a 6-point severity scale from clear to very severe disease (See 
Table 3 ). The assessment will be static evaluation without regards to the score at a previous 
visit. 
 
Table 3. Investigator’s Global Score (IGA) 
 
Score 
Category 
Description 
0 
Clear 
Atopic dermatitis is cleared, except for any residual 
discoloration 
1 
Almost clear 
Only just perceptible erythema and perceptible 
papules/infiltrates or edema 
2 
Mild 
Mild erythema, and mild papules/infiltrates or edema 
3 
Moderate 
Moderate erythema, and moderate papules/infiltrates or edema 
4 
Severe 
Severe erythema, and severe papules/infiltrates or edema 
5 
Very Severe 
Very severe skin lesions, severe erythema, and severe 
papules/infiltrates or edema with exudation/crusting. 
 
 
7.2.2 Eczema Area and Severity Index (EASI) 
The EASI score is the sum of the skin lesion severity scores and the integral and coefficient product 
of the area affected by the skin lesions in the four parts of the body: head and neck, trunk, upper 
limbs, and lower limbs. The specific calculation methods are as follows: ①The clinical 
manifestations of the severity of skin lesions are divided into four items, namely erythema (E), 
infiltration (edema) or papules (induration (edema)/papulation, I), epidermal exfoliation 
(excoriation, Ex), lichenification (lichenification, L). The severity of each clinical manifestation 
was scored on a 0 – 3 scale: 0 = none, 1 = mild, 2 = moderate, and 3 = severe (for details see Table 
4 ). Half of the scores, and 0. 5, can be recorded between symptom scores. ②Lesion area size 
score: The whole body was divided into four parts, namely, head and neck (H), trunk (T), upper 
limb (UL), lower limb (LL). Using the patient's palm as an estimate of 1%, the four-part lesion 
area was converted into a proportion of the site scored on a scale of 0 to 6: 0 for no rash, 1 for < 
10%, 2 for 10% to 29%, 3 for 30% to 49%, 4 for 50% to 69%, 5 for 70% to 89%, and 6 for 90% 


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to 100%. 3 Then according to the proportion of body parts in the whole body (see details Table 5 ), 
each part was multiplied by the corresponding percentage coefficient, and the score of each part 
was added as the total score of EASI skin lesion symptom severity, which was calculated by the 
following formula, and the total score was 0-72 15. 
EASI = 0.1Ah (Eh + Ih + Exh + Lh) + 0.2Au (Eu + Iu + ExU + Lu) + 0.3At (Et + It + Ext + Lt) + 
0.4Al (El + Il + Exl + Ll) 
A = area score; E = erythema; I = infiltration/papulation; Ex = excoriation; L = lichenification; H 
= head/neck; U = upper limbs; T = trunk; L = lower limbs. 
The EASI score ranges from 0.0 to 72.0, can be varied in increments of 0.1, Higher scores indicate 
greater severity. 
Table 4.  Clinical severity scoring criteria for the Eczema Area and Severity Index (EASI) 
Score 
Description 
Erythema (E) 
0 
Absent 
None; may have residual discoloration 
1 
Mild 
Light pink to light red 
2 
Moderate 
Red 
3 
Severe 
Deep, dark red 
Infiltration/Papulation(I) 
0 
Absent 
None 
1 
Mild 
Barely palpable to slight, but definite hard thickened skin and/or 
papules 
2 
Moderate 
Easily palpable moderate hard thickened skin and/or papules 
3 
Severe 
Severe hard thickened skin and/or papules 
Excoriation (Ex) 
0 
Absent 
None 
1 
Mild 
Slight, but definite linear or picked scratch marks or penetrating 
surface injur 
2 
Moderate 
Moderate linear or picked scratch marks or penetrating surface 
injury 
3 
Severe 
Severe linear or picked scratch marks or penetrating surface 
injury 
Lichenification (L) 


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0 
Absent 
None 
1 
Mild 
Barely perceptible to slight, but definite thickened skin, fine skin 
markings and lichenoid scal 
2 
Moderate 
Moderate thickened skin, coarse skin markings, and coarse 
lichenoid scale 
3 
Severe 
Severe thickened skin with very coarse skin markings and 
lichenoid scale 
 
 
Table 5. Body Region Surface Area (BSA) 
Body region 
The proportion of each part 
Head/neck 
0.1 
Upper limbs 
0.2 
Trunk 
0.3 
Lower limb 
0.4 
 
7.2.3 Atopic Dermatitis Score (SCORAD) 
SCORAD is a scoring standard proposed by the European Atopic Dermatitis Research Group 
(ETFAD) in 1993. It integrates the observational assessment of physicians and patients and is 
recognized by the Harmonizing Outcome Measures for Eczema (HOME) as an effective 
assessment method that can be used in clinical research and clinical practice 14. 
The scoring scale consists of three major sections: the objective signs section includes lesion area 
(A) and lesion severity (B), and the subjective symptoms include the degree of itching and sleep 
effects (C), as detailed in Appendix 5 . 
A. Lesion area: In adults, the lesion area was estimated according to the "rule of nine": head and 
neck 9%, double upper limbs 18%, trunk back 36%, lower limbs 36%, perineum 1%. Taking 
1% of the area as 1 point, the total area score is A (maximum score 100). 
B. Lesion severity: Overall assessment of six clinical features including erythema, papular (or) 
edema, exudation (or) crusting, epidermal exfoliation, lichenification, and dry skin 
(uninvolved skin only). According to the severity of skin lesions, each item was rated as 0-3 
points on a four-grade scale, and six parts were summed as B (maximum score 18). 
C. Itching and sleeplessness: The evaluation was performed using a visual analogue scale (VAS) 
method, with 0 – 10 points for each item (itching 0 = no itching, itching 10 = very itchy; sleep 
0 = no impact, sleep 10 = severely affected), taking the sum of the mean scores of itch and 
sleep impact in the last 3 days as C (maximum score 20). 


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SCORAD total score = A/5 + 7B/2 + C with a score of 0-103. 
 
7.2.4 Pruritus Numeric Rating Scale (NRS) 
Pruritus Rating: At each visit, the degree of pruritus/scratching was assessed by the subject on an 
11-grade rating scale from 0 (no pruritus/scratching) - 10 (severe pruritus/scratching) for the first 
24 h of the visit (see details in Appendix 5 ). 
 
7.2.5 Skin Disease Quality of Life Index (DLQI) 
The DLQI is a commonly used dermatology-related questionnaire that allows subjects to assess 
the impact of skin disease on quality of life through 10 questions (see details in Appendix 6 ), 
widely used in clinical studies of AD. 
Subjects should complete questionnaires prior to all other study-related procedures at each visit. 
The DLQI questionnaire will be checked by the study center staff before the subject leaves the 
study center. All completed DLQI questionnaires will have CRA returned and sent to the sponsor 
for transcription into the EDC system. 
 
7.3 Safety assessment 
 
7.3.1 Vital Signs 
Vital signs measurements will include heart rate as well as systolic and diastolic blood pressure 
and body temperature, and height and weight. Vital signs will be obtained after subjects have rested 
for approximately 5 minutes and before performing ECG. A sigle set of values will be collected. 
Vital signs will be performed using equipment provided by sites and will be obtained at visits and 
time points as detailed in Section 5.11 - Time and Event Tables . 
 
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 5.11 – 
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. 
 
7.3.3 QuantiFERON-TB Gold Test 
QuantiFERON-TB Gold ® ™ test may be used at the discretion of the investigator based on the 
implement ability of the local test. The mechanism of QuantiFERON-TB Gold Test is that this 
enzyme-linked immunosorbent assay (ELISA) assay detects interferon-gamma (IFN-γ) release in 


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sensitized humans when fresh heparinized whole blood is co-incubated with a synthetic peptide 
mixture mimicking two proteins in M. tuberculosis, early secretory antigen target protein-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. Since all Bacillus Calmette-Guérin (BCG) vaccine 
strains and common non-tuberculous mycobacteria (except M. kansasii, M. stephensi and 
M.mainum) neither of these proteins are present, so the QuantiFERON-TB Gold assay is more 
specific for M. tuberculosis than the test in which tuberculin purified protein derivative (PPD) is 
used as antigen. 
 
7.3.5 T-SPOT.TB test 
T-SPOT may be used at the discretion of the investigator based on the implement ability of the 
local test. The mechanism of T-SPOT TB assay is that tuberculosis-specific antigen stimulation 
of activated effector T cells (secreting gamma interferon) can be detected by this enzyme-linked 
immunospot (ELISPOT) assay when peripheral blood mononuclear cells are co-incubated with a 
synthetic peptide mixture mimicking both proteins in M. tuberculosis (early secretory antigen 
target protein-6 (ESAT-6) and culture filtrate protein-10 (CFP-10)). Each spot represents a gamma 
interferon-secreting T cell, and the number of spots is counted to obtain the number of tuberculosis- 
primed T cells in the peripheral blood. Similar to the QuantiFERON-TB Gold assay, compared to 
the PPD assay, T-SPOT.TB test is more specific for M. tuberculosis. 
 
7.3.5 Clinical Laboratory Testing 
Routine, non-fasting clinical laboratory (hematology and chemistry and urinalysis) tests will be 
performed as detailed in Section 5.11 –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 childbearing potential as detailed in 
Table 6. 
The study clinical laboratory tests including analytes for clinical chemistry and hematology are 
shown below in Table 6. 
 
Table 6. Clinical Laboratory Testing Lists 


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Biochemistry 
Hematology 
Urinalysis 
Other 
Albumin 
Hemoglobin 
pH 
Hepatitis B surface antigen 1 
Alkaline phosphatase 
Hematocrit 
Protein 
Hepatitis C virus antibody 1 
Alanine 
aminotransferase 
(ALT or SGPT) 
Platelet count 
Glucose 
HIV tests 1 
Aspartate 
amino- 
transferase (AST or 
SGOT) 
WBC count 
Bilirubin and 
White Cell 
Count 
Urine 
pregnancy 
test 
(performed in clinic) 2 
Bilirubin, direct 
RBC count 
FSH 3 
Bilirubin, indirect 
Neutrophils, absolute 
β-HCG blood test 4 
Bilirubin, total 
Neutrophils, segs (%) 
Lipid check item (fasting) total 
cholesterol, 
low density lipoprotein (LDL) 
high density lipoprotein (HDL) 
triglyceride 
Calcium 
Neutrophils, bands (%) 
Thyroid 
function 
tests, 
including TSH, free T4, and 
free T3 
Chloride 
Basophils (%) 
total IgE 
CO2 
content/Bicarbonate 
Eosinophils (%) 
PK sampling5 
Creatinine 
Eosinophils, absolute 
Creatine 
phosphokinase 
(CPK), total 
Lymphocytes (%) 
Gamma 
glutamyl 
transferase (GGT) 
Monocytes (%) 
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 for confirmation of postmenopausal status at screening visit only 
4 Only for females of child-bearing potential at screening, and if urine pregnancy test positive 
5 Only done as per Section 7.4 Pharmacokinetics 
 
 
7.3.6 Immunoglobulin E (IgE) 
Atopic dermatitis is divided into endogenous and exogenous types. In adult AD patients, 
exogenous AD accounts for approximately 80% and endogenous AD for 20%. Patients with 
exogenous AD usually present with elevated serum total IgE 16. Blood samples will be collected 
for detection of IgE levels at screening, baseline, week 1, week 4, week 8, and week 12. 


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7.3.7 Lipid Profile Testing 
A fasting lipid profile blood collection, as per Section 5.11 –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. 
 
7.3.8 Liver Biochemistry – Stopping and Follow-up Criteria 
Phase II Liver Biochemistry Stopping and Follow-up Criteria have been designed to ensure subject 
safety and to assess liver event etiology (consistent with FDA premarketing clinical liver safety 
guidance). If any of the following conditions occur at any time during the study drug treatment 
period, the study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests until the subject's laboratory values return to normal or return to 
baseline condition): 
− ALT or AST > 8 x ULN, or 
− ALT or AST > 5 x ULN and retest 5 x ULN, or 
− ALT or AST > 3 x ULN with elevated total bilirubin > 2 x ULN, or international normalized 
ratio > 1.5, or 
− ALT or AST > 3 x ULN associated with fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash. 
For one of above criteria, make every effort to carry out the liver event follow-up assessment of 
described below ： 
• Viral hepatitis serology including: 
• Hepatitis A IgM antibody; 
• Hepatitis B surface antigen and Hepatitis B core antibody (IgM); 
• Hepatitis C virus RNA; 
• Cytomegalovirus IgM antibody; 
• Epstein-Barr viral capsid antigen IgM antibody (if not available, 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 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) 


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• 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 
 
7.3.9 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. 
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 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. 
 
7.3.10 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. 


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7.3.11 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. 
Events that do not meet the definition of an AE include: 
• Medical or surgical procedures (e.g., endoscopy, appendectomy): the disease 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 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 
• Serious 


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• 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 
 
7.3.12 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 outpatient 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 
baseline is not considered an AE. 
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. 


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g. All events of possible drug-induced liver injury with hyperbilirubinemia 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). 
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 
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. 
 
7.3.13 AEs and SAEs 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 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. 
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. 


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7.3.14 AE Severity Assessment 
The investigator will grade the severity of each adverse event using the following definitions: 
• 
Mild 
Adverse events are transient and easily tolerated by subjects 
• 
Moderate 
Adverse events cause discomfort to the subject or affect the subject's 
daily 
activities 
• 
Severe 
Adverse events have a great impact on the subject's daily activities and may 
cause disability or risk and life 
 
7.3.15 AE Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs. The investigator will 
use the following definitions to assess the causal relationship between adverse events and 
investigational product: 
• 
Not Related 
There is no correlation between adverse events and investigational 
product 
• 
Unlikely to be related 
Adverse events are more likely to be related to other factors 
• 
Possibly related 
Adverse events may be caused by investigational product, but other 
factors cannot be excluded 
• 
Probably Related 
Adverse events may be caused by the study drug 
• 
Related 
Adverse events can be confirmed as adverse reaction of 
investigational product, and cannot be explained by other reasons 
7.4  Pharmacokinetics 
Blood samples for pharmacokinetics exposure-response analysis of SHR0302 will be collected 
from randomized subjects at the following time points ( Table 7 ). If not, please address the reason. 
 
Table 7. Pharmacokinetic Sampling Schedule 
 
Week 8 (Visit 5) 
Week 12 (Visit 6) 
In all subjects: 
− One pre-dose PK blood sample 
(within 1 hour prior to dosing) 
− One post-dose PK blood sample (1-2 
hours post dose) 
In all subjects: 
− One pre-dose PK blood sample 
(within 1 hour prior to dosing) 
− One post-dose PK blood sample (at 
any time between 2 to 8 hours post 
dose) 
 
For 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 in the original document and in the 
eCRF. The exact time and date of blood sample collection should also be recorded in the eCRF. 
For details regarding PK blood samples collection, processing and transport are described in the 
laboratory manual. For pharmacokinetic evaluation of SHR0302, the following windows for 
blood sample collection are allowed: 
• At Week 8 (Visit 5): a sample within 1 hour prior to dosing and a sample between 1 to 2 
hours post dose 
• At Week 12 (Visit 6): a sample within 1 hour prior to dosing and a sample at any time 
between 2 to 8 hours post dose 


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On the days of PK sampling at Weeks 8 and 12, subjects will take their dose of study medication 
for that day at the study site. 
Blood samples will be analyzed using validated analytical methods. Only samples from subjects 
who have received active drug (i.e., SHR0302) will be measured for the analysis (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 (DM) 
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 
Detailed summary and statistical analysis of the data collected in this study will be recorded in the 
Statistical Analysis Plan (SAP) and maintained by Reistione Biopharma/Designated CRO. The 
document may provide a revision of the plan in the protocol; however, any major revision of the 
definition of the primary endpoint and/or its analytical approach should be reflected in the protocol 
amendments. 
9.1 Sample Size Determination and Hypothesis 
This study is planned to enroll 132 subjects, 44 in each group (assuming 9% dropout rate, 120 
completers, 40 completers in each group), and provide approximately 81% power to detect 20% 
difference in the primary endpoint between SHR0302 and placebo assuming placebo response rate 
is approximately 10% and response rates of SHR0302 4 mg QD, 8 mg QD are around 30%. By 
using the Hochberg incremental procedure, the type I error for the primary endpoint was controlled 
at a level of 0.1 bilaterally. 
The null and alternative hypotheses to be tested are: 
o H01: Percentage of subjects achieving an IGA response in the SHR0302 8 mg QD dose group 
at Week 12 - Percentage of subjects achieving an IGA response in the placebo group at Week 
12 = 0; 


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H11: Percentage of subjects achieving an IGA response at Week 12 in the SHR0302 8 mg QD 
dose group - Percentage of subjects achieving an IGA response at Week 12 in the placebo 
group ≠ 0. 
o H02: Percentage of subjects achieving IGA response in the SHR0302 4 mg QD dose group at 
Week 12 - Percentage of subjects achieving IGA response in the placebo group at Week 12 
= 0; 
H12: SHR0302 Percentage of Subjects Achieving IGA Response at Week 12 in the 4 mg QD 
Dose Group - Percentage of Subjects Achieving IGA Response at Week 12 in the Placebo 
Group ≠ 0. 
Two 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 two p values as (p (2), p(1)), where p(2) ≥ p(1). 
The decision rules are provided in below figure (Figure 2 ). 
 
 
 
 
 
 
Figure 2. The decision rules of hypothesis 
NOTE: H(01) is the corresponding null hypothesis of the smallest p value p(1) 
 
9.2 Efficacy analysis 
Efficacy analysis will be based on all subjects who are randomized and administered with study 
medication. Subjects will be analyzed according to randomization, irrespective of the treatment 
received. A descriptive statistical summary of all efficacy endpoints will be provided. 
9.2.1 Analysis of the primary efficacy endpoint 
For the primary endpoint, the method of normal approximation will be used to test whether each 
drug group is superior to the placebo group. Subjects who early withdraw from the study for any 
reason will be considered as non-responders. 
Other analyses for the primary endpoint will be described in the statistical analysis plan (SAP). 
9.2.2 Analysis of the secondary efficacy endpoints 
All secondary endpoints for each drug group and placebo control will also be analyzed. 
No
Reject H (01) 
and stop 
 
None of 
Yes 
hypotheses were 
No
Reject all null 
hypotheses and stop 
p (2) > 0.1 
Yes 
Test if p (1) > 0.05 


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For dichotomous secondary endpoints (percentage of subjects achieving IGA response at other 
follow-up time points except Week 12; percentage of subjects achieving ≥ 50%, 75%, and 90% 
improvement from baseline in EASI scores at Weeks 1, 4, 8, and 12 (EASI50, EASI75, EASI90); 
percentage of subjects achieving ≥ 50%, 75%, and 90% improvement from baseline in SCORAD 
at Weeks 1, 4, 8, and 12 (SCORAD50, SCORAD75, SCORAD90); percentage of subjects 
achieving ≥ 3 points improvement from baseline in pruritus NRS at Weeks 1, 4, 8, and 12), the 
method of normal approximation will be used for analysis. 
For continuous secondary endpoints (percent change from baseline in EASI scores at Weeks 1, 4, 
8, and 12; change from baseline in SCORAD at Weeks 1, 4, 8, and 12; percent change from 
baseline in pruritus numeric rating scale (NRS) at Weeks 1, 4, 8, and 12; change from baseline in 
Dermatology Life Quality Index (DLQI) at Weeks 1, 4, 8, and 12; and change from baseline in 
biomarkers hsCRP and Ig E at Weeks 1, 4, 8, and 12.), a mixed-effects repeated measures model 
(MMRM) will be used for analysis. Fixed effects in the model were treatment group, baseline 
value, visit, and treatment-by-visit interaction, with random effects for subject. 
9.3 Safety Analysis 
Safety analysis will be based on all subjects who have taken study medication. Subjects will be 
analyzed by actual treatment group. Safety data will be summarized using descriptive statistics. 
9.3.1 Analysis of adverse events 
Adverse events will be classified according to the Pharmaceutical Affairs Management Standard 
Medical Terminology Set (MedDRA), System Organ Classification (SOC) and Preferred Terms 
(PT) and summarized by actual treatment. Treatment-emergent adverse events (TEAEs) are 
defined as AEs which commence on or after the time of start of investigational product 
administration. Adverse events without an onset date or time or AEs with an onset 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 indicate that the event started before administration 
of investigational product or if the AE stop date indicates that the event stopped before 
administration of investigational product. 
Treatment emergent AEs will be summarized for each SHR-0302 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 reported: 
• 
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 investigational product 
• 
Serious AEs by SOC and PT 
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9.3.2 Other safety analyses 
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. 
9.4 Pharmacokinetic analysis 
Plasma concentrations of SHR0302 will be summarized according to 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 different biomarkers (e.g., 
hsCRP and Ig E), 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. 
9.5 Interim Analysis 
 
There is no interim analysis planned for this study. 


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10. Study Conduct Considerations 
10.1 Regulatory and Ethical considerations of 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) reviewed 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, e.g., 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. 
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 follow ICH GCP, local 
regulatory requirements, and legal requirements. The informed consent form used in this study, 
and any changes made during the study, must be prospectively approved by both the IRB/IEC and 
Reistone/designated CRO before use. 


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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 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 Biopharma /designated 
CRO, the investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, e.g., CRFs and hospital records), all original signed 
informed consent forms, copies of all CRFs, serious adverse event forms, source documents, and   
detailed 


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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 (e.g., 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 continuously conducted by the Sponsor study team. or Reistone Biopharma /designated 
CRO will hold regular data monitoring meetings to review the data in order to ensure data accuracy 
and protocol compliance. Safety data will also be continuously reviewed to detect early signals 
and identify risk. 
 
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. 
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. 


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11.Reference 
1. 
Wollenberg A, Barbarot S, Bieber T, et al. Consensus-based European guidelines for 
treatment of atopic eczema (atopic dermatitis) in adults and children: part I. J Eur Acad 
Dermatol Venereol. 2018;32(5):657-682. 
2. 
Hamilton JD, Suarez-Farinas M, Dhingra N, et al. Dupilumab improves the molecular 
signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin 
Immunol. 2014;134(6):1293-1300. 
3. 
Hen Gu JZ. Guidelines for the diagnosis and treatment of atopic dermatitis in China. Chin 
J Dermatol. 2014;47(7):4. 
4. 
Wang X, Li LF, Zhao DY, Shen YW. Prevalence and Clinical Features of Atopic 
Dermatitis in China. Biomed Res Int. 2016;2016:2568301. 
5. 
Garmhausen D, Hagemann T, Bieber T, et al. Characterization of different courses of 
atopic dermatitis in adolescent and adult patients. Allergy. 2013;68(4):498-506. 
6. 
Ping Liu YZ, Jianzhong Zhang. Clinical Features of Adult/Adolescent Atopic Dermatitis 
and Chinese Criteria for Atopic Dermatitis. Chinese Medical Journal. 2016;129(7):6. 
7. 
Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of 
atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical 
therapies. J Am Acad Dermatol. 2014;71(1):116-132. 
8. 
Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic 
dermatitis: section 3. Management and treatment with phototherapy and systemic agents. 
J Am Acad Dermatol. 2014;71(2):327-349. 
9. 
Irvine AD JA, Beattie P A randomised controlled trial protocol assessing the effectiveness, 
safety and cost-effectiveness of methotrexate versus ciclosporin in the treatment of severe 
atopic eczema in children: the treatment of severe Atopic eczema Trial (TREAT). Br J 
Dermatol. 2018. 
10. 
Giavina-Bianchi M, Giavina-Bianchi P. Systemic Treatment for Severe Atopic Dermatitis. 
Arch Immunol Ther Exp (Warsz). 2018. 
11. 
Paller AS, Kabashima K, Bieber T. Therapeutic pipeline for atopic dermatitis: End of the 
drought? J Allergy Clin Immunol. 2017;140(3):633-643. 
12. 
Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT Signaling as a Target 
for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs. 
2017;77(5):521-546. 
13. 
Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in 
chronic inflammatory skin disease atopic dermatitis. JAKSTAT. 2013;2(3):e24137. 
14. 
Gooderham MJ, Bissonnette R, Grewal P, Lansang P, Papp KA, Hong CH. Approach to 
the Assessment and Management of Adult Patients With Atopic Dermatitis: A Consensus 
Document. Section II: Tools for Assessing the Severity of Atopic Dermatitis. J Cutan Med 
Surg. 2018;22(1_suppl):10S-16S. 
15. 
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and 
severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. 
Exp Dermatol. 2001;10(1):11-18. 
16. 
Mansouri Y, Guttman-Yassky E. Immune Pathways in Atopic Dermatitis, and Definition 
of Biomarkers through Broad and Targeted Therapeutics. J Clin Med. 2015;4(5):858-873. 


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12.Appendices 
Appendix 1 Atopic Dermatitis Diagnosis -Chinese Criteria 
 
In 2016, Profession Zhang et al. reported Chinese Criterial for atopic dermatitis diagnosis. There 
are 3 criteria, subjects who meet the first criterion together with one of the 2nd or 3rd criterion can 
be diagnosed as atopic dermatitis: 
1. Symmetrical eczema (dermatitis) for more than 6 months 
2. Personal and/or family history of atopic diseases 
3. Elevated total serum Ig E level and/or positive allergen-specific Ig E and/or eosinophilia 


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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)] × Weight (kg) × coefficient a) 
(72 × Serum Creatinine [mg/dL]) 
a Coefficients is equal to 0.85 in females and 1.00 in males 


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Appendix3 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 ≥ 110 bpm 
NOTE: sinus tachycardia 
110bpm should be confirmed by two additional readings at least 
5 minutes apart 
• Sinus bradycardia < 45 bpm 
NOTE: Sinus bradycardia <45bpm should be confirmed by two additional readings at least 5 
minutes apart 
• Multifocal atrial tachycardia 
• Junctional tachycardia (heart rate > 100 bpm) 
• Junctional escape complexes 
• Supraventricular tachycardia (> 100 bpm) 
• Ventricular tachycardia (sustained, polymorphic or monomorphic) 
• Atrial fibrillation with rapid ventricular response (heart rate > 100 bpm) 
• Atrial flutter 
• Evidence of bigeminy, trigeminy or multifocal premature ventricular complexes 
• Ventricular flutter 
• Ventrucular fibrillation 
• Torsades de pointes 
• R-on-T phenomenon 
• Wide QRS tachycardia (diagnosis unknown) 
• Electrical alternans 
• Pacemaker 
• Idioventricular rhythm - heart rate < 100 bpm 
• 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) ≥ 450 msec or ECG 
not suitable for QT measurement (e.g., poor defined termination of the T wave). 


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• For subjects with complete right bundle branch block: QTc(F) 
480msec 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 ago) 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 agents such as ketoconazole cream and grapefruit juice are not contraindicated. 
 
CYP3A INHIBITORS 
CYP3A INDUCER 
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 
Erythromycin 
Fluconazole 
Diltiazem 


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Appendix 5 Scoring Atopic Dermatitis (SCORAD) 
 
 
 
ITEMS OF SCORAD 
SYSTEM 
DESCRIPTION 
SCORE 
TOTAL 
SCORE 
A.  Lesional area 
9% were in the head and neck, 18% in both 
upper limbs, 36% in the anteroposterior aspect 
of the trunk, 36% in both lower limbs, and 1% 
in the perineum 
(1% of body surface area is 1 point) 
B. Severity of skin 
lesions (evaluation of 
six clinical features) 
Erythema (reddening) 
0 = none; 1 = mild; 2 = moderate; 3 = severe 
Edema (swelling) 
0 = none; 1 = mild; 2 = moderate; 3 = severe 
Oozing/crusting 
0 = none; 1 = mild; 2 = moderate; 3 = severe 
Excoriation (scratch marks) 
0 = none; 1 = mild; 2 = moderate; 3 = severe 
Skin thickening (lichenification) 
0 = none; 1 = mild; 2 = moderate; 3 = severe 
Xerosis (dryness) 
0 = none; 1 = mild; 2 = moderate; 3 = severe 
C. 
Itching 
and 
sleeplessness (using a 
visual analogue scale) 
Itching (0-10) (average degree of itching over 
the past 3 days) 
0 = no itching, 10 = very itching 
Sleeplessness 
(0-10) (average degree of 
sleeplessness affected in the past 3 days) 
0 = no impact, 10 = severe impact 
SCORAD total score 
A/5 + 7B/2 + C 


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Appendix 6 Pruritus NRS assessment 
 
 
 
Pruritus Rating: Selet the number that best describes your itching due to Atopic Dermatitis 
over the past 24 hours (check one number only) 
 
 
 
 
 


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Appendix 7 DLQI Questionnaire 
 
Dermatology Life Quality Index (DLQI) – Example, sample only 
 
The purpose of this questionnaire is to measure how much your skin problem has affected 
your life over the last week, please tick "√" on one box for each question 
 
Question 
Response 
1. Over the last week, how itchy, 
sore, painful or 
stinging has your skin been? 
Very much 
□ 
A lot 
□ 
A little 
□ 
Not at all 
□ 
2. Over the last week, how 
embarrassed or self-conscious 
have you been because of your 
skin? 
Very much 
□ 
A lot 
□ 
A little 
□ 
Not at all 
□ 
3.   Over the last week, how much 
has your skin interfered with you 
going shopping or looking after 
your home or garden? 
Very much 
□ 
A lot 
□ 
A little 
□ 
Not at all 
□ 
4. Over the last week, how much 
has your skin influenced the 
clothes you wear?? 
Very much 
□ 
A lot 
□ 
A little 
□ 
Not at all 
□ 
5.  Over the last week, how much 
has your skin affected any social 
or leisure activities? 
Very much 
□ 
A lot 
□ 
A little 
□ 
Not at all 
□ 
6.   Over the last week, how much 
has your skin made it difficult for 
you to do any sport? 
Very much 
□ 
A lot 
□ 
A little 
□ 
Not at all 
□ 
7. Over the last week, has your skin 
prevented you from working or 
studying? 
Yes 
□ 
No 
A lot 
□ 


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If you choose "no," over the last 
week how much has your skin 
been a problem at work or studying? 
A little 
□ 
Not at all 
□ 
8. Over the last week, how much 
has your skin created problems 
with your partner or any of your 
close friends or relatives? 
Very much 
□ 
A lot 
□ 
A little 
□ 
Not at all 
□ 
9. Over the last week, how much 
has your skin caused any sexual 
difficulties? 
Very much 
□ 
A lot 
□ 
A little 
□ 
Not at all 
□ 
10. Over the last week, how much of 
a problem has the treatment for 
your skin been, for example by 
making your home messy, or by 
taking up time? 
Very much 
□ 
A lot 
□ 
A little 
□ 
Not at all 
□ 
 
 
 
Please check that you have answered EVERY question.  Thank you. 

SAP_001.pdf: 
 
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Statistical Analysis Plan                           
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1 
 
 
Statistical Analysis Plan  
Study Title:  
A Randomized, Double-Blind, Placebo-Controlled Phase II Study 
to Evaluate the Efficacy and Safety of SHR0302 in Adult Patients 
with Moderate to Severe Atopic Dermatitis 
 
 
Protocol No.:  
RSJ10303  
Compound No.:  
SHR0302  
NCT number： 
NCT04162899 
 
 
 
Identification/Version No.: Final 1.0  
Effective Date: 24Sep2020  
 
Description:  
The purpose of this Statistical Analysis Plan (SAP) is to describe the analyses planned for Protocol 
RSJ10303 and the information to be provided in the Statistical Analysis Report (SAR) and Clinical 
Study Report (CSR).  
This SAP will elaborate the statistical analysis planned for the study from the aspects of efficacy 
and safety of multiple doses of the drug based on the study objectives. The study team members 
will have access to this document to understand what is included in the statistical analysis of the 
deliverables.  
 
Topics:  
SHR0302, Adult Patients with Moderate to Severe Atopic Dermatitis, Efficacy and Safety  
 
Name and Affiliation of Author(s):  
Feng (Crystal) 
Cheng 
Senior Principal Statistician 
dMed Biopharmaceutical Co., Ltd.  
Wengang He 
Statistician 
dMed Biopharmaceutical Co., Ltd.  
 


 
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Signature Page for Review and Approval of Statistical Analysis Plan 
 
Biostatistics, dMed Biopharmaceutical Co., Ltd. 
Name and Title  
Signature  
Date (mm-dd-yyyy)  
Jie (Jack) Li 
Executive Director, Biostatistics 
 
 
 
 
Sponsor: Reistone Biopharma Company Limited  
Name and Title  
Signature  
Date (mm-dd-yyyy)  
Baoyue Li 
Director, Biostatistics 
 
 
 
 
Copyright © 2020 Reistone Biopharma Company Limited. All rights reserved. Unauthorized 
reproduction or use of this information is prohibited.  
 
 


 
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TABLE OF CONTENTS  
 
Introduction ........................................................................................................................ 9 
 
Discrepancies between statistical analysis plan and protocol ............................................ 9 
 
Study objectives and endpoints .......................................................................................... 9 
3.1 
Study objectives ................................................................................................................. 9 
3.1.1 
Primary objective ............................................................................................................... 9 
3.1.2 
Secondary objectives .......................................................................................................... 9 
3.2 
Study endpoints ................................................................................................................ 10 
3.2.1 
Primary endpoint .............................................................................................................. 10 
3.2.2 
Secondary endpoints ........................................................................................................ 10 
3.2.2.1 Safety endpoints ............................................................................................................... 10 
3.2.2.2 Efficacy endpoints ............................................................................................................ 10 
3.2.2.3 Pharmacokinetics endpoints ............................................................................................. 11 
 
Study design ..................................................................................................................... 11 
4.1 
Overall study design ......................................................................................................... 11 
4.2 
Dosage regimen ................................................................................................................ 11 
 
Planned analyses .............................................................................................................. 12 
5.1 
Interim analysis ................................................................................................................ 12 
5.2 
Final analysis .................................................................................................................... 13 
 
Sample size considerations .............................................................................................. 13 
 
Statistical analysis set ....................................................................................................... 13 
 
Statistical hypothesis and multiplicity comparison .......................................................... 13 
 
Description of treatment groups ....................................................................................... 14 
 
Considerations for data analysis and data dealing conventions ....................................... 14 
10.1 
General rules for statistical description ............................................................................ 14 
10.2 
Statistical result reporting rules ........................................................................................ 14 
 
Derived and transformed Data ......................................................................................... 15 
11.1 
Baseline definition and change from baseline ................................................................. 15 
11.2 
Study day .......................................................................................................................... 15 
11.3 
Multiple measurements at the same timepoint ................................................................. 15 
11.4 
Early withdrawa ............................................................................................................... 16 
11.5 
Missing data ..................................................................................................................... 16 


 
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Data source ....................................................................................................................... 16 
 
Study population analysis ................................................................................................ 17 
13.1 
Disposition of subjects ..................................................................................................... 17 
13.2 
Protocol violation ............................................................................................................. 17 
13.3 
Demographic and baseline characteristics ....................................................................... 17 
13.4 
Medical history ................................................................................................................. 18 
13.5 
Treatment of atopic dermatitis ......................................................................................... 18 
13.6 
Prior and concomitant medications/non-drug treatments ................................................ 18 
 
Efficacy analysis .............................................................................................................. 19 
14.1 
Overview of efficacy analyses ......................................................................................... 19 
14.2 
Primary efficacy analysis ................................................................................................. 19 
14.3 
Secondary efficacy analyses ............................................................................................ 20 
14.3.1 Percentage of subjects achieving IGA response at Week 1, Week 4, Week 8 ................ 21 
14.3.2 Percentage of EASI change from baseline at Weeks 1, 4, 8, and 12 ............................... 21 
14.3.3 Percentage of subjects with ≥ 50%, 75%, and 90% EASI improvement from baseline 
(EASI50, EASI75, EASI90) at Weeks 1, 4, 8, and 12 ..................................................... 22 
14.3.4 Change from baseline in SCORAD at Week 1, Week 4, Week 8, and Week 12 ............ 22 
14.3.6 Percent of pruritus numerical Rating scale (NRS) change from baseline at Weeks 1, 4, 8, 
and 12 ............................................................................................................................... 22 
15.1 
Study Drug Exposure and treatment Compliance ............................................................ 25 
15.2 
Adverse events ................................................................................................................. 26 
15.2.1 All adverse events ............................................................................................................ 27 
15.2.2 Serious adverse event ....................................................................................................... 27 
15.2.3 Death ................................................................................................................................ 27 
15.2.4 Adverse events affecting administration of study drug or leading to study withdrawal .. 27 
15.3 
Clinical laboratory evaluations ........................................................................................ 27 
15.4 
Vital signs ......................................................................................................................... 28 
15.5 
Electrocardiogram (ECG) ................................................................................................ 28 
15.6 
Physical examination ....................................................................................................... 29 
 
References ........................................................................................................................ 30 
 
Appendices ....................................................................................................................... 31 
17.1 
Time and event table ........................................................................................................ 31 


 
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17.2 
Statistical tables, figures and listings ............................................................................... 32 
 


 
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Table 1. 
Abbreviations 
Abbreviation 
Definition 
AD  
Atopic dermatitis  
AUC  
Area under the curve  
BMI  
Body mass index  
Β-hCG  
β-human chorionic gonadotropin  
CI  
Confidence interval  
Cmax  
Maximum plasma concentration  
CRF  
Case Report Form  
CRP  
C-reactive protein  
DLQI  
Dermatology life quality index  
EW  
Early withdrawal  
ECG  
Electrocardiogram  
EMA  
European Medicines Agency  
EASI  
Eczema area and severity index  
ECRF  
Electronic Case Report Form  
FAS  
Full analysis set  
FDA  
U.S. Food and Drug Administration  
FSH  
Follicle stimulating hormone  
FVC  
Forced vital capacity  
GCP  
Good Clinical Practice  
GFR  
Glomerular filtration rate  
IB  
Investigator's Brochure  
IL  
Interleukin  
IGA  
Investigator’s global assessment 
JAK  
Janus kinase  
IEC  
Independent Ethics Committee  
IFN-γ  
Interferon-γ  
IgE  
Immunoglobulin E  
IgM  
Immunoglobulin M  
IND  
Investigational new drug  
IRB  
Institutional Review Board  
ITT  
Intention-to-treat  
IVRS  
Interactive voice response system  
IUD  
Intrauterine device  
LDH  
Lactate dehydrogenase  
LLoQ  
Lower limit of quantitation  
Mcg  
Microgram  
MedDRA  
Medical dictionary for regulatory activities  
NRS  
Pruritus numerical rating scale  
PK  
Pharmacokinetics  


 
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Abbreviation 
Definition 
PP  
Per-Protocol  
PPD  
Purified protein derivative  
PT  
Preferred term  
QD  
Once daily  
RA  
Rheumatoid arthritis  
RAP  
Reporting and Analysis Plan  
SAE  
Serious adverse event  
SAP  
Statistical Analysis Plan  
SAR  
Statistical Analysis Report  
SD  
Standard deviation  
SOC  
System organ class  
SPM  
Study Procedures Manual  
SCORAD  
Atopic dermatitis score  
SS  
Safety set  
TCS  
Topical corticosteroids  
TSH  
Thyroid stimulating hormone  
ULN  
Upper limit of normal  
 
 
 
 
 
 
 
 
 
 
 


 
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Trademark Information  
Trademark(s) 
of 
Reistone 
Biopharma 
Company Limited  
 
Trademarks that do not belong to Reistone 
Biopharma Company Limited  
 
 
SAS  
 
 
MedDRA  
 
 
WHODrug  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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 INTRODUCTION  
The purpose of this Statistical Analysis Plan (SAP) is to describe the analyses to be included in the 
Clinical Study Report for Protocol RSJ10303 V2.0 (Dec. 31, 2019).  
All decisions regarding the final analysis (as defined in this SAP) will be made before all subjects 
have completed study drug administration and follow-up, and database freeze. In case of any 
change in the analysis described in this SAP, such change will be recorded in the Clinical Study 
Report together with the reasons.  
 DISCREPANCIES BETWEEN STATISTICAL ANALYSIS PLAN AND 
PROTOCOL  
The changed contents in SAP relative to the analysis contents specified in the protocol and reasons 
are shown in Table 2.  
Table 2. 
Discrepancies between Statistical Analysis Plan and Protocol  
Protocol  
Statistical Analysis Plan  
Reasons to Change  
Prior medications 
are defined as 
medications that 
were stopped prior to 
first study treatment.  
Prior medications are defined as drugs 
used before the first study treatment.  
The drugs used before the first 
administration of study drug 
until after the first 
administration of study drug 
will be classified into the prior 
and concomitant medications, 
both.  
 
The analyses of secondary efficacy 
endpoint, change from baseline and 
related analyses about absolute 
eosinophil counts are added.  
The absolute eosinophil 
counts could be used as a 
secondary endpoint reflecting 
the efficacy.  
 STUDY OBJECTIVES AND ENDPOINTS  
3.1 
STUDY OBJECTIVES  
3.1.1 Primary objective  
• 
To evaluate the efficacy of oral administration of SHR0302 at doses of 4 mg and 8 mg, QD vs. 
Placebo in adult subjects with moderate to severe atopic dermatitis at week 12.  
3.1.2 Secondary objectives  
• 
To evaluate the safety and tolerability of oral SHR0302 in subjects with moderate to severe 
atopic dermatitis.  
• 
To evaluate the impact of oral SHR0302 on other efficacy endpoints in subjects with moderate 
to severe atopic dermatitis and on the reported outcomes of subjects.  


 
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• 
To investigate the pharmacokinetic (PK) characteristics of SHR0302 in subjects with moderate 
to severe atopic dermatitis, and to explore the exposure-effect relationship.  
3.2 
STUDY ENDPOINTS  
3.2.1 Primary endpoint  
• 
The percentage of subjects who achieve IGA response at week 12. IGA response is defined as 
IGA score of 0/1 (complete or almost complete clearance of skin lesions) with an improvement 
in IGA score by ≥ 2 from baseline.  
3.2.2 Secondary endpoints  
3.2.2.1 
Safety endpoints  
• 
Laboratory parameters will be used to evaluate safety and tolerability.  
• 
Incidences of adverse events (AEs)/serious adverse events (SAEs) will be used to evaluate 
safety and tolerability.  
• 
Measurements of vital signs (blood pressure, heart rate, body temperature, and respiratory rate).  
• 
Assessment of total lipids, including triglycerides, low density lipoproteins (LDL), and high-
density lipoproteins (HDL).  
• 
Assessment of thyroid functions: TSH, free T4, and free T3.  
• 
Assessment of liver and kidney functions.  
• 
12-Lead ECG.  
3.2.2.2 
Efficacy endpoints  
• 
The percentage change in EASI score from baseline at weeks 1, 4, 8, and 12.  
• 
The percentage of subjects who achieve IGA response at weeks 1, 4, and 8.  
• 
The percentage of subjects whose EASI scores improve by ≥ 50%, 75%, and 90% (EASI50, 
EASI75, EASI90) from baseline at weeks 1, 4, 8, and 12.  
• 
Changes in scoring atopic dermatitis (SCORAD) from baseline at weeks 1, 4, 8, and 12.  
• 
The percentage of subjects whose SCORAD improve by ≥ 50%, 75%, and 90% 
(SCORAD50, SCORAD75, SCORAD90) from baseline at weeks 1, 4, 8, and 12.  
• 
The percentage change in Pruritus Numerical Rating Scale (NRS) from baseline at weeks 1, 4, 
8, and 12.  
• 
The percentage of subjects whose NRS improve by ≥ 3 points from baseline (NRS-3) at 
weeks 1, 4, 8, and 12.  
• 
Changes in Dermatology Life Quality Index (DLQI) from baseline at weeks 1, 4, 8, and 12.  
• 
Changes in biomarker immunoglobulin E (IgE) from baseline at weeks 1, 4, 8, and 12.  
• 
Changes in absolute eosinophil count from baseline at weeks 1, 4, 8, and 12.  


 
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3.2.2.3 
Pharmacokinetics endpoints 
• 
Systemic exposure (i.e., concentration and area under the curve) of SHR0302 at steady state in 
subjects with atopic dermatitis.  
 STUDY DESIGN  
4.1 
OVERALL STUDY DESIGN  
This 12-week, randomized, double-blind, placebo-controlled, 3-arm parallel, multi-center clinical 
study will enroll adult patients with moderate to severe atopic dermatitis. This study includes a 4-
week screening period, followed by a 12-week blind treatment period, and a 2-week follow-up 
period after the last dose of the study drug. Primary endpoint will be evaluated at the end of the 12-
week blind treatment.  
At randomization, subjects who meet the study criteria will be randomly assigned to one of three 
study groups on a 1:1:1 basis: 2 active drug dose groups (SHR0302 4 mg QD and SHR0302 8 mg 
QD) and 1 placebo group, to receive blind treatment for 12 weeks. A total of 105 subjects will 
undergo randomization.  
All subjects who complete the treatment period will undergo a 2-week follow-up period until week 
14 (last visit). In the event of early withdrawal or discontinuation, subjects will also undergo a 2-
week follow-up period.  
A total of 7 outpatient visits will be conducted during this study as detailed in Figure 1.  
 
Figure 1. 
Study design diagram 
4.2 
DOSAGE REGIMEN  
The study drug will be taken orally by subjects themselves in the morning, QD.  


 
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However, the outpatient dosing will be performed at the time of the first dose at baseline (Day 0) 
and at visits at weeks 4, 8, and 12. The study drug may be taken with or without food.  
4.3 
RANDOMIZATION AND BLINDING  
This proposed study is a randomized, double-blind, placebo-controlled, 3-arm parallel, multi-center 
phase 2 study. At the randomized visit (Visit 2), if the subjects are in line with the inclusion 
criteria/not in line with any exclusion criteria, they would be randomized to the SHR0302 4 mg 
QD group, the SHR0302 8 mg QD group, or the placebo group at a ratio of 1:1:1. A computer-
generated randomization table will be used to assign subjects to each study group via an electronic 
randomization system at the baseline visit. Subjects will be assigned with the subject numbers 
based on the order in which subjects are enrolled to participate in the study and will be told to keep 
their ID numbers throughout the study.  
The double-blind method will be adopted regarding the study drugs taken during the 12-week 
treatment period. Neither subjects nor the study doctor will be aware of the study drugs taken by 
subjects.  
The packages of the study drugs have been carefully considered and designed, so as to maintain 
the blindness and ensure the compliance of the subjects throughout the study. In all groups, the 
study drugs will be taken QD, and the following arrangements will be implemented for the dosage 
regimen and placebo (Table 3).  
Table 3. 
Packaging design of study drugs in the treatment group 
Study group  
Dose from Day 0 to 84 (QD) 
4 mg SHR0302  
one 4 mg tablet + one placebo tablet  
8 mg SHR0302  
one 4 mg tablet + one 4 mg tablet  
Placebo  
one placebo tablet + one placebo tablet 
At each dose time point (morning), subjects will swallow 2 tablets.  
The investigator or the attending doctor could unblind the treatment assignments of the subject only 
in case of emergency (i.e., when it is necessary to know the study treatment in order to implement 
appropriate clinical treatment or for the sake of the health of subjects).  
After the clinical database is locked, the statistician responsible for this project will complete the 
"Application Form for Randomization Code Release". All subjects will be unblinded once after the 
approval by the sponsor. The treatment allocation of unblinded subjects will be submitted to the 
SAS programmer for import into the analysis database for analysis.  
 PLANNED ANALYSES  
5.1 
INTERIM ANALYSIS  
There is no formal interim analysis plan for this study.  


 
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5.2 
FINAL ANALYSIS  
The PK statistical analysis plan will not be included here as it will be described in a separate 
document.  
The final analysis specified in this SAP will be performed after the database locked and the data 
released.  
 SAMPLE SIZE CONSIDERATIONS  
This study is planned to enroll 105 subjects, 35 in each group, and provide approximately 82% 
power to test differences in primary endpoint between at least one active group and the placebo 
group, assuming the response rates in the 4 mg QD group, the 8 mg QD group and the placebo 
group are 26%, 26%, and 6%, respectively. By using the Hochberg incremental procedure, the type 
I error for the primary endpoint is controlled at the level of 0.1 bilaterally.  
 STATISTICAL ANALYSIS SET  
The analysis sets for this study include full analysis set (FAS), per protocol analysis set (PPS), 
Efficacy sensitivity set (ESS) and safety set (SS). 
• 
FAS: Includes all subjects who are randomized and received at least one time of the study drug 
administration. In FAS, subjects will be analyzed according to randomization, regardless of 
the actual treatment received. 
• 
PPS: PPS is a subset of FAS, including subjects who have not experienced the major protocol 
deviations that significantly affect the efficacy evaluation, and have obtained primary efficacy 
evaluation endpoints (excluding remote visit results). Subjects excluded from the PPS will be 
identified and recorded before the study unblinding. 
• 
ESS: ESS is a subset of FAS, including subjects who have not experienced the major protocol 
deviations that significantly affect the efficacy evaluation, and excluding subjects who have 
obtained the primary efficacy endpoints through remote visits. Subjects excluded from the ESS 
will be identified and recorded before the study unblinding. 
• 
SS: Included all subjects who have received at least one dose of the study drug. The analysis 
set will be analyzed according to the actual treatment groups. 
SS will be used for demographic and baseline characteristics analysis; FAS, PPS and ESS will be 
used for efficacy analysis, with FAS as the main analysis set and PPS and ESS as the supportive 
analysis sets; SS will be used for safety analysis. FAS, PPS, and ESS will be analyzed based on 
randomization groups, and SS will be analyzed based on the actual treatment groups.  
Prior to treatment group unblinding and database release, data from all subjects will be assessed to 
determine the classification of each statistical analysis set.  
 STATISTICAL HYPOTHESIS AND MULTIPLICITY COMPARISON  
In this study, there are multiple comparisons in the primary analysis. The hypothesis test will be 
performed for the primary efficacy endpoint, i.e., the comparison of 4 mg QD and 8 mg QD groups 
with placebo, respectively. The type I error of the primary endpoint will be controlled at the level 


 
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of 0.1 bilaterally by using the Hochberg incremental procedure1. The statistical hypotheses are 
detailed in the efficacy analysis section.  
Unless otherwise specified, the significance level for other analyses will also be set to 0.1 bilaterally.  
 DESCRIPTION OF TREATMENT GROUPS  
Unless otherwise specified, the statistical description and summary will be presented according to 
below treatment groups as follows. 
Table 4  Description of Treatment Groups 
Treatment Description  
Final Data Display  
4 mg tablet + placebo tablet  
4 mg QD SHR0302  
4 mg tablet + 4 mg tablet  
8 mg QD SHR0302  
Active drug total 
Treatment Total  
Placebo tablets + placebo tablets  
Placebo  
Total  
Total  
 CONSIDERATIONS FOR DATA ANALYSIS AND DATA DEALING 
CONVENTIONS 
10.1 
GENERAL RULES FOR STATISTICAL DESCRIPTION  
Unless otherwise specified, descriptive statistics appropriate to the type of variable will be provided.    
Continuous variables will be presented with the number of non-missing values (n), mean, standard 
deviation (SD), median, minimum, and maximum values. If less than 3 observations, only n, 
minimum and maximum values will be presented. 
Categorical variables will be presented as frequencies and percentages. 
10.2 
STATISTICAL RESULT REPORTING RULES  
Analyses will be performed using SAS® version 9.4 or higher.  
All analysis outcomes will be presented by statistical tables and/or figures. And the original data 
listings corresponding to the tables or figures will be provided, including important derivation 
variables and study endpoints, and unscheduled visit data. The general rule for sorting variable in 
listings is by study site, dose group/treatment group, subject ID, demographic characteristics, 
visit/treatment cycle, date and time, test/assessment, original results (unit), standard/derived results 
or study endpoints, explanation for results, reason and other information. The variable sort could 
be adjusted according to original data, data characteristics or requirement from report. Please refer 
to the mock shells for each listing, as not all of which will be specified in this analysis plan. 
The decimal places are specified as below. 
Table 5    Basic Descriptive Statistics 
Name 
Illustration 
Decimal Places（dp） 
N  
Number of subjects in analysis set 
Always present 0 dp 
n  
Number of non-missing observations  
Always present 0 dp 
% 
Percentage 
Categorical data 1 dp 


 
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Mean 
Arithmetic Mean 
1 more dp than original data 
SD 
Standard Deviation 
2 more dp than original data 
Median 
Median 
1 more dp than original data 
Min. 
Minimum value 
Same with original data 
Max. 
Maximum value 
Same with original data 
 
Table 6   Derived Data Or Statistics of Estimated Parameters  
名称 
说明 
小数位数（dp） 
SE 
Standard Error 
1 more dp than derived data or parameter 
95% CI 
95% Confidence Interval 
1 more dp than derived data or parameter 
p value 
P value 
Present 3 dp, or < 0.001 
The derived data and its statistics will be 1 more decimal place than the original data or the 
corresponding statistics.  
Reasonable decimal places will be adjusted for proper presentation and interpretation. 
 DERIVED AND TRANSFORMED DATA  
11.1 
BASELINE DEFINITION AND CHANGE FROM BASELINE  
Unless otherwise specified, the baseline value for a parameter of interest is the latest non-missing 
value prior to date of the first administration of study drug.  
Change from baseline and percentage from baseline will be derived as follows: 
• 
Change from baseline = the post-baseline value - the baseline value of a parameter of interest 
for a subject. 
• 
Percentage change from baseline =  (post-baseline value - the baseline value)/ baseline value 
of a parameter of interest for a subject. 
If either the baseline or the post-baseline value is missing, then the change or percentage change 
will be set to missing. 
11.2 
STUDY DAY  
 
Day 1 = Date of the first administration of study drug for a subject 
Study Day  
= Calendar Date – date of the first administration of study drug + 1 if the calendar date is on or 
after the date of the first administration of study drug, or  
= Calendar Date - date of the first administration of study drug if the calendar date is before the 
first administration of study drug 
11.3 
MULTIPLE MEASUREMENTS AT THE SAME TIMEPOINT  
If there are multiple measurement results at a timepoint, unless otherwise specified, use the mean 
of these measurements to summarize and derive. If there is unscheduled measurement, consider the 


 
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scheduled data firstly, if missing at the scheduled visit, then impute with closest non-missing per-
protocol data within the visit window to make analysis. 
11.4 
EARLY WITHDRAWA  
All subjects who early withdraw/discontinue study drug administration will be documented, and 
the reasons will also be recorded in the final clinical study report. All available data will be included 
in each applicable analysis set for summarization and analysis. The definition of each analysis set 
is detailed in Section 7.  
If the study is terminated early, all available data will be listed and the study team will review these 
data to evaluate which statistical analysis will be still applicable.  
11.5 
MISSING DATA  
In general, missing data will not be included in descriptive statistics analysis.  
Missing efficacy data will be handled as specified in section of efficacy analysis. 
For safety data, if there is “< x”, “<= x”, “> x”, or “>= x” value in the quantitative safety data, the 
“x” will be used for derivation or summary. But the final handling and analysis will be based on 
medical opinion. 
If the dates used for derivation or calculation are not complete or missing, the following rules will 
be considered. 
• 
If the onset date of an AE is missing or incomplete, it is assumed to have occurred during 
the study treatment phase, except if the stop date indicates that the event happened before the study 
treatment. 
• 
If the phase of a concomitant medication used cannot be identified, due to missing or 
incomplete onset/end date, it will be assumed to have occurred during both screening and study 
treatment phase, except if partial dates indicate that the medication is not administrated in one of 
the study phases. 
• 
When calculating the age of subject, if birth date is missing or not complete, the age 
collected in CRF will be used, else impute with the first date of the month or the first day (01January) 
of the year. 
 DATA SOURCE  
Detailed sources of all types of data that will be analyzed in this SAP are described as below.  
Table 7  Data source 
Data type  
Origin  
Data format  
Responsible Party  
Subject Demographics, 
Baseline Characteristics, 
Efficacy, Safety  
eCRF  
The SAS dataset (. 
sas7dat)  
dMed Biopharmaseutical 
Co. Ltd 


 
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 STUDY POPULATION ANALYSIS  
13.1 
DISPOSITION OF SUBJECTS  
In all screened subjects, the number and percentage of subjects screened, screen failure, screened 
successfully and randomized, screened successfully and but not randomized will be summarized 
as well as the reasons. 
In all enrolled subjects, the number and percentage will be summarized of subjects enrolled, 
randomized, with at least one dose of assigned drug, with week 12 remote visit, with week 12 
prolonged visit and those who have completed study or discontinue from treatment or study along 
with reasons. The flow chart of subject disposition will be provided in a separate file. 
The number of subjects in different analysis sets by treatment group will be summarized in enrolled 
subjects. 
13.2 
PROTOCOL VIOLATION  
Major protocol deviations (including informed consent deviations, deviation of inclusion/exclusion 
criteria, deviation of termination/withdrawal criteria, study medication deviation, use of prohibited 
medications, trial procedures/procedures, and any other deviation deemed likely to have a 
significant impact on study results) will be summarized.  
All major protocol deviations will be discussed and identified at the data review meeting and the 
impact on each analysis set will be assessed.  
13.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS  
The following demographic and baseline characteristic will be summarized. Continuous variables 
will use statistics including mean, standard deviation and so on, Number of non-missing values (n) 
and corresponding percentage (%) will be presented for descriptive presentation of categorical data. 
• 
Continuous variables: age, height, weight, body mass index (BMI) 
• 
Categorical variables: gender, ethnic group, race 
Age = INT((date of informed consent - date of birth)/365.25);  
Body mass index (BMI) = weight (kg)/height (m2).  
Baseline characteristics includes tobacco use (summary of smoking status and frequency. Smoking 
status includes never smoke, previous smoke and current smoke), alcohol use (summary of use 
status and frequency. Use status includes never use, previous use and current use), virology test 
(hepatitis B surface antigen, hepatitis C antibody, human immunodeficiency virus antibody), 
tuberculosis infection test (summary of both tests types and results), and primary diagnosis of 
atopic dermatitis (disease duration), atopic dermatitis disease activity (Eczema Area and Severity 
Index (EASI), BSA, Investigator's Global Assessment (IGA) and Pruritus Numerical Rating Scale 
(NRS). Atopic dermatitis disease activity will be summarized using baseline results.  
Duration of atopic dermatitis = (date of initial dose of IMP– date of diagnosis of atopic dermatitis 
+ 1)/365.25 in years. When the date of primary diagnosis for atopic dermatitis recorded in the eCRF 
is incomplete or missing, the following rules will be applied for imputation:  


 
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o 
If day is missing then 15th of the current month will be imputed, and if month is missing 
then July of the current year will be imputed;  
o 
If duration of atopic dermatitis is less than 1 year due to the imputation, then 1st day will 
be used for missing days, and January will be used for missing months;  
o 
Missing year will not be imputed;  
o 
Listings of missing dates will be presented as collected on the eCRF.  
Baseline results for other safety endpoints will be summarized in safety analysis part. Other 
efficacy endpoints will be summarized in the efficacy analysis part.  
13.4 
MEDICAL HISTORY  
Medical history and concomitant illness will be presented for the safety analysis set.  
Medical history and concomitant illness will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by system organ class (SOC) and preferred term (PT). 
Medical history is defined as those conditions ended prior to the date of the first administration of 
study drug; concomitant illness is defined as those conditions started prior to and ended on or after 
the date of the first administration of study drug. If end date of one condition could not show earlier 
than date of the first administration of study drug then it will be classified into concomitant illness.  
13.5 
TREATMENT OF ATOPIC DERMATITIS  
Treatment of atopic dermatitis includes atopic dermatitis medication treatment and non-drug 
treatment. The number of patients treated, and types of treatment will be summarized by treatment 
group. Prior and concomitant medication treatment/non-drug treatment will be summarized 
separately. Prior medication treatment is defined as medication treatment ended prior to the date of 
initial dose of IMP. Concomitant medication treatment is defined as medication treatment 
administered at least one time after date of initial dose of IMP. In the case where it is not possible 
to define a medication as prior, concomitant, this medication will be classified as concomitant. 
Medications stopped on the same day as the first study treatment will be considered as prior 
medication only. Medications started prior and ended on date of initial dose of IMP will be 
classified into both prior and concomitant medication. Prior and concomitant non-drug treatment 
are defined in same manner with medication treatment. 
13.6 
PRIOR AND CONCOMITANT MEDICATIONS/NON-DRUG TREATMENTS  
Prior and concomitant medication and non-drug treatment data are captured in the CRF. Prior and 
concomitant medications will be coded by WHODD and summarized by anatomical therapeutic 
chemical (ATC) classification system and preferred name (PN). Prior and concomitant non-drug 
treatment will be coded by MedDRA and summarized by system organ class (SOC) and preferred 
term (PT) respectively. 
The definition of prior and concomitant medications/non-drug treatments are the same as prior and 
concomitant medications/non-drug treatments for atopic dermatitis.  


 
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 EFFICACY ANALYSIS  
14.1 
OVERVIEW OF EFFICACY ANALYSES  
The following hypotheses will be tested based on the primary endpoint and objective:  
• 
H01: Percentage of subjects achieving an IGA response in the SHR0302 8 mg QD dose group 
at Week 12 - Percentage of subjects achieving an IGA response in the placebo group at Week12 
= 0;  
• 
H11: Percentage of subjects achieving an IGA response at Week 12 in the SHR0302 8 mg QD 
dose group - Percentage of subjects achieving an IGA response at Week 12 in the placebo 
group ≠ 0.  
• 
H02: Percentage of subjects achieving an IGA response in the SHR0302 4 mg QD dose group 
at Week 12 - Percentage of subjects achieving an IGA response in the placebo group at Week12 
= 0;  
• 
H12: Percentage of subjects achieving an IGA response at Week 12 in the SHR0302 4 mg QD 
dose group - Percentage of subjects achieving an IGA response at Week 12 in the placebo 
group ≠ 0.  
By using the Hochberg1 incremental procedure, the type I error for the primary endpoint will be 
controlled at the level of 0.1 bilaterally. Two p-values will be gained and sorted (p(2)≥p(1)). Then 
start with the least significant comparison (p(2)) and continue as long as the test is not significant 
until the first time when a significant comparison occurs, and all remaining hypotheses will be 
rejected. The decision rules are provided in below figure 2. 
 
Figure 2 The decision rules of hypothesis 
NOTE: H(01) is the corresponding null hypothesis of the smallest p value p(1)  
Analyses of secondary efficacy and other analyses will be provided for comparison 4 mg QD and 
8 mg QD versus placebo, respectively.  
14.2 
PRIMARY EFFICACY ANALYSIS  
Analysis of the primary efficacy endpoint will be based on FAS.  
The primary efficacy endpoint for this study is the percentage of subjects achieving IGA response 
at Week 12. IGA is the investigator's global assessment of the subject's general condition and 
consists of a 6-point severity scale from clear to very severe disease ("complete clearance", "almost 


 
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complete clearance", "mild", "moderate", "severe", and "very severe"). IGA response is defined as 
IGA score of 0/1 (complete or almost complete clearance of skin lesions) with an improvement in 
IGA score by ≥ 2 from baseline.  
Subjects who early withdraw from the study for any reason will be considered as non-responders 
at each post-withdrawal assessment time point. Descriptive summaries of the primary efficacy 
endpoint will be based on non-missing data only.  
Due to the impact of the COVID-2019 pandemic, subjects may have their primary efficacy 
endpoint assessed outside the scheduled time window of visit 6. If the primary efficacy endpoint is 
missing within the planned time window (between study days 82 and 88), it will be considered to 
impute with results of assessment within 89 to 102 study day (ie, extended visit).  
The method of normal approximation to binomial will be used to test whether each active drug 
group is superior to the placebo group. Estimation of the difference and its 90% confidence interval 
between each drug group and the placebo group, as well as the corresponding p value for test will 
be provided. 
Referenced SAS code:  
PROC FREQ DATA = adam.adeff;  
TABLE treat*aval/CHISQ RISKDIFF (CL = WALD) ALPHA = 0.1;  
RUN;  
In the above codes, variables are defined as follows:  
Aval = IGA response at Week12  
Treat = treatment group  
In addition, IGA response and its 90% confidence interval at Week 12 will also be provided for 
each treatment group.  
14.3 
SECONDARY EFFICACY ANALYSES  
The secondary efficacy endpoints in this study are defined in section 3.2.2.  
Unless otherwise specified, analyses of secondary efficacy endpoints are based on the FAS.  
For dichotomous secondary efficacy endpoints, subjects who early withdraw from the study for 
any reason will be considered as non-responders at each post-withdrawal assessment time point. 
Descriptive summaries of secondary efficacy endpoints will be based on non-missing data only.  
For continuous secondary efficacy endpoints, missing values will not be imputed.  
For comparison of dichotomous endpoints, if both the expected number of subjects achieving 
response and the expected number of subjects not achieving response are ≥ 5 in each treatment 
group, the normal approximation method will be used for analysis; otherwise, Fisher's exact method 
described in Section 14.4.1 will be used instead.  


 
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14.3.1 Percentage of subjects achieving IGA response at Week 1, Week 4, Week 8  
Rates of IGA response at other specified efficacy assessment point (Week 1, Week 4, and Week 8) 
will analyzed using the method of normal approximation to binomial or Fisher's exact test.  
14.3.2 Percentage of EASI change from baseline at Weeks 1, 4, 8, and 12  
The EASI score is the sum of the skin lesion severity scores and the integral and coefficient product 
of the area affected by the skin lesions in the four parts of the body: head and neck, trunk, upper 
limbs, and lower limbs. The EASI score ranges from 0.0 to 72.0 and can be varied in increments 
of 0.1, Higher scores indicate greater severity.  
A mixed-effects repeated measures model (MMRM) will be used to analysis percentage of EASI 
change from baseline including treatment group, baseline value, visit, and treatment-by-visit 
interaction as fixed effect and visit as repeated variable. An unstructured covariance matrix will be 
used to model the within-subject variance-covariance errors. If model fails to converge , the 
following options will be considered in order until convergence achieved : TOEPH (Heterogeneous 
Toeplitz) 、AR(1)(Heterogeneous autoregressive) 、TOEP(Toeplitz) and CS (Compound 
symmetry). The Kenward-Roger approximation will be used to estimate the degrees of freedom. 
The comparisons of interest will be the contrasts between each active dose and placebo at every 
time point. For the treatment difference of each active dose versus placebo at each visit, the model 
estimated least square means, standard error, p-value, and two-sided 90% confidence interval will 
be reported. 
Referenced MMRM SAS code:  
PROC MIXED DATA=adam.adeff METHOD=REML; 
 CLASS treat visit subj; 
 MODEL chgEASI= treat visit treat*visit basval /SOLUTION DDFM=KR; 
 REPEATED visit/SUBJECT=subj TYPE=UN; 
 LSMEANS treat*visit/DIFF PDIFF CL; 
RUN; 
In the above code, variables are defined as follows:  
ChgEASI = change from baseline in EASI for each visit  
Treat = treatment group  
Visit = visit  
Subj = subject 
Basval = baseline EASI score  
Least square means of change from baseline in EASI score at each assessment visit will be 
graphically displayed for each treatment using a line plot.  


 
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EASI score and change from baseline will be summarized by treatment at each efficacy assessment 
visit, and statistics including mean, standard deviation, and 90% confidence interval will be 
provided. Same statistics will also be provided for each site score as well as for the four symptoms.  
14.3.3 Percentage of subjects with ≥ 50%, 75%, and 90% EASI improvement from baseline 
(EASI50, EASI75, EASI90) at Weeks 1, 4, 8, and 12  
Percentage of EASI change from baseline will also be derived as a dichotomous result according 
to the following three criteria: ≥ 50% (EASI50), ≥ 75% (EASI75), and ≥ 90% (EASI90). For each 
derived dichotomous EASI result, the comparison between 4 mg QD and 8 mg QD versus placebo 
will be performed by method of normal approximation to binomial or Fisher's exact test, 
respectively, according to actual data distribution.  
The number and percentage of subjects achieving EAS50, EAS75, and EAS90 will also be 
summarized for each treatment group at each efficacy assessment visit.  
14.3.4 Change from baseline in SCORAD at Week 1, Week 4, Week 8, and Week 12  
The SCORAD score integrates the observational assessment of physicians and patients. The 
scoring scale consists of three major sections: the objective signs section includes lesion area and 
lesion severity, and the subjective symptoms include the degree of itching and sleep effects. 
SCORAD scores range from 0 to 103.  
SCORAD quantitative results will be analyzed using the same MMRM method as EASI.  
The SCORAD scores and change from baseline at each assessment visit will be summarized, and 
the scores of each objective sign sections (lesion area, lesion severity) and the subjective symptom 
(pruritus, impact on sleep) will be summarized using statistics including mean, standard deviation 
and 90% confidence interval. A line graph will be used to graphically display the least squares 
mean of change from baseline in SCORAD score for each treatment assessment visit (including 
five scales: Total Score, A Lesion Area, B Lesion Severity, C Pruritus and sleeplessness).  
14.3.5 Percentage of subjects With ≥ 50%, 75%, and 90% SCORAD improvement from 
baseline (SCORAD50,SCORAD75, SCORAD90) at Weeks 1, 4, 8, and 12  
Percentage of SCORAD change from baseline will also be derived as a dichotomous result based 
on the following three criteria: ≥ 50% (SCORAD50), ≥ 75% (SCORAD75), and ≥ 90% 
(SCORAD90). For each derived dichotomous SCORAD result, the comparison between 4 mg QD 
and 8 mg QD versus placebo will be performed using method of normal approximation to binomial 
or Fisher's exact test, respectively, according to actual data distribution.  
The number and percentage of subjects achieving SCORAD50, SCORAD75 and SCORAD90 will 
also be reported.  
14.3.6 Percent of pruritus numerical Rating scale (NRS) change from baseline at Weeks 1, 4, 
8, and 12  
At each visit, the degree of pruritus/scratching is assessed by the subject on an 11-grade rating scale 
from 0 (no pruritus/scratching) - 10 (severe pruritus/scratching) for the first 24 hour of the visit.  
The NRS quantitative results will be analyzed using the same MMRM method as for EASI.  


 
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The NRS score and change from baseline at each efficacy assessment visit will be summarized by 
treatment and mean, standard deviation and 90% confidence interval will be provided.  
14.3.7 Percentage of subjects achieving pruritus NRS improvement ≥3 from baseline in at 
Weeks 1, 4, 8, and 12  
Percentage of NRS change from baseline will also be derived into two categories: ≥ 3 points and < 
3 points. Dichotomized NRS results will be compared between 4 mg QD and 8 mg QD versus 
placebo groups using method of normal approximation to binomial or Fisher's exact test, 
respectively, according to actual data distribution, noting that the comparison of NRS differences 
will only be performed in the population with baseline NRS score ≥ 3.  
The number and percentage of NRS will also be reported as follows: 0, 1-3, 4-6, 7-9 and 10 points 
for 5 grades.  
14.3.8 Change from baseline in dermatology life quality index (DLQI) at Weeks 1, 4, 8, and 
12  
The DLQI is a dermatology-related questionnaire that allows subjects to assess the impact of skin 
disease on quality of life through 10 questions with total score ranging from 0 to 30.  
The rules for scoring the 10 questions are as follows:  
• 
Not at all: 0 points (Item 7 Question: No (Not at all), 0 points);  
• 
A little: 1 point (question 7: no (a little), 1 point);  
• 
Many: 2 points (question 7: No (many), 2 points);  
• 
Very much: 3 points (question 7: Yes, 3 points).  
Change from baseline in DLQI will be analyzed using the same MMRM model as the EASI.  
The DLQI score and change from baseline at each treatment visit will be summarized using 
statistics including mean, standard deviation, and 90% confidence interval.  
14.3.9 Change from baseline in biomarker IgE at Weeks 1, 4, 8 and 12  
Atopic dermatitis is divided into endogenous and exogenous types. Patients with exogenous AD 
usually present with elevated serum total IgE.  
Change from baseline in IgE will be analyzed using the same MMRM model as the EASI.  
IgE and change from baseline will be summarized by treatment group at each efficacy assessment 
visit using statistics including mean, standard deviation and 90% confidence interval.  
14.3.10Change in absolute eosinophil count from baseline at Weeks 1, 4, 8, and 12  
The change from baseline in absolute eosinophil count will be analyzed using the same MMRM 
model as described for the EASI.  
Absolute eosinophil counts and changes from baseline will be summarized by treatment group at 
each efficacy assessment visit using statistics including mean, standard deviation, and 90% 
confidence intervals.  


 
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14.4 
SENSITIVITY ANALYSES  
14.4.1 Statistical analysis methods  
The primary efficacy endpoint of IGA response at Week 12 specified in Section 14.2 will be tested 
based on the full analysis set (FAS) using Fisher's exact test together with Exact Unconditional 90% 
confidence interval of difference between active groups versus placebo group. The 90% confidence 
interval of IGA response rate at Week 12 based on Clopper-Pearson method will also be reported 
for each treatment group.  
Referenced SAS code:  
PROC FREQ DATA = adam.adeff;  
TABLE treat*aval/CHISQ RISKDIFF ALPHA = 0.1;  
EXACT RISKDIFF (METHOD = SCORE);  
RUN;  
14.4.2 Analysis set  
Sensitivity analyses of the primary efficacy endpoint (IGA response at Week 12), EASI50, EASI75, 
EASI90, and EASI quantitative results at Week 12 will be performed based on the per protocol set 
(PPS) and the efficacy sensitivity analysis set (ESS) using the same analysis methods described in 
Section 14.2, Section 14.3.3, and Section 14.3.2, respectively.  
14.4.3 Remote assessment  
Considering the influence of assessment on efficacy evaluation by remote visits (i.e., efficacy 
endpoints are assessed at non study sites), the analyses of the primary efficacy endpoint IGA 
response at Week 12, and the secondary endpoints of EASI50, EASI75, and EASI90 at Week 12 
will also be evaluated based on the full analysis set (FAS) using the same analysis methods as 
described in section 14.2, section 14.3 according to different strategies handling remote visit such 
as treated as missing or imputed (see section 14.4).  
14.4.4 Handling of missing data  
Missing data will be considered as non-response as described in Section 14.2, Section 14.3, for 
dichotomous efficacy endpoints. The impact of different imputation methods dealing with missing 
data such as last observation carried forward (LOCF) will also be further explored based on the full 
analysis set (FAS) to verify robustness of conclusion.  
Last observation carried forward (LOCF): If a patient has no observation at a post-baseline visit 
(missing), then it will be filled in by last valid observation. Note that only scheduled efficacy 
assessment results are included in LOCF imputation.  
Analysis data sets chosen, rules of handling remote visit assessment and missing data for primary 
and sensitivity analyses of dichotomous efficacy endpoints are specified in table 8.  
 
 


 
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Table 8 Summary of analysis for dichotomous efficacy endpoints  
 
Remote evaluation 
Missing data 
Prolonged 
visit 
Evaluation 
endpoint 
  
Used 
Non-
response 
Deleted 
Non-
response 
LOCF Deleted 
Used 
Primary 
analysis 
(FAS) 
Y 
 
 
Y 
 
 
Y 
IGA at week 
12, 
(Method of 
normal 
approximation 
to binomial) 
Secondary 
analysis 
(FAS) 
Y 
 
 
Y 
 
 
Y 
All 
dichotomous 
efficacy 
endpoints 
Sensitivity 
analysis 1 
(PPS) 
 
 
Y 
 
 
Y 
Y 
IGA at week 
12, 
EASI50/75/90 
at week 12 
Sensitivity 
analysis 2 
(FAS) 
Y 
 
 
Y 
 
 
Y 
IGA at week 
12 (exact test) 
Sensitivity 
analysis 3 
(FAS) 
 
Y 
 
Y 
 
 
Y 
IGA at week 
12, 
EASI50/75/90 
at week 12 
Sensitivity 
analysis 4 
(FAS) 
Y 
 
 
 
Y 
 
Y 
IGA at week 
12, 
EASI50/75/90 
at week 12 
Sensitivity 
analysis 5 
(ESS) 
 
 
Y 
Y 
 
 
Y 
IGA at week 
12, 
EASI50/75/90 
at week 12 
 
 SAFETY ANALYSIS  
Safety evaluation will be performed based on SS. Safety evaluation endpoints includes AEs, SAEs, 
laboratory test results (hematology, blood biochemistry, urinalysis, lipid test, and TSH), vital signs 
(including blood pressure, pulse, body temperature, and respiratory rate), electrocardiograms, and 
physical examinations. The duration of medication, total drug exposure information and medication 
compliance will be summarized. 
All safety data will be summarized by treatment group and total.  
15.1 
STUDY DRUG EXPOSURE AND TREATMENT COMPLIANCE  
The total days of actual dosing, total amount of actual dosing and total amount of planned dosing 
for study drug will be summarized by treatment group using statistics including means, standard 


 
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deviation and so on. Proportion of subjects with overdose and omission/interruption will also be 
provided. Treatment compliance will be calculated based on the administration plan and actual total 
amount and summarized using statistics including means, standard deviation and so on. The 
proportion of subjects with treatment compliance < 80%, 80% -120%, and > 120% will be reported, 
respectively.  
The number and percentage of overdoses (i.e., actual daily dose greater than planned), overdoses 
leading to adverse events (i.e., actual daily dose greater than planned and resulting in clinical signs 
and symptoms) will also be summarized separately.  
The total days of actual dosing, total amount of actual dosing, average amount of actual dosing for 
study drug and treatment compliance will be derived as follows:  
• 
The total days of actual dosing (days) = (end date 1 - start date 1 + 1) + (end date 2 - start date 
2 + 1) +... + (end date of n- start date n + 1), note that only records with actual daily tablets > 
0 will be summarized;  
• 
The total amount of actual dosing (tablets) = (end date 1 - start date 1 + 1) * actual daily tablets 
1 + (end date 2 - start date 2 + 1) * actual daily tablets 2 +... + (end date n- start date n + 1) * 
actual daily tablets n;  
• 
The total amount of planned dosing (tablets):  
o 
If early withdrawal occurs before the end date of the treatment period (i.e., withdrawal 
before Week 12), The total amount of planned dosing (tablets) = (date of early withdrawal 
- date of first dose + 1) *2;  
o 
If not withdrawn or withdrawn after the end date of the treatment period, The total amount 
of planned dosing (tablets) = min {max (date of last dose - date of first dose + 1, 82), 88} 
2;  
• 
Treatment compliance (%) = The total amount of actual dosing (tablets)/ The total amount of 
planned dosing (tablets).  
15.2 
ADVERSE EVENTS  
According to the Medical Dictionary for Regulatory Activities (MedDRA) (Version 21.0 or later), 
AEs will be coded using the system organ class (SOC) and preferred terms (PT). Drug related AEs 
includes "definitely related", "probably related", and "possibly related" AEs. Missing relationship 
to study drug will be classified as drug-related AEs. The investigator will grade the severity of each 
adverse event as mild, moderate, and severe. Missing severity will be treated as moderate.  
AE will be summarized by SOC and PT. The incidence rate of AE in summary table will be sorted 
by descending order among SOCs and within a SOC. And the incidence rate is based on the number 
of subjects with AE(s), not the number of events. If a subject happened more than one same AEs, 
in the SOC or PT of this AE, only count once for this subject. 
AEs during screening phase are defined as any AEs with before the time of start of investigational 
product administration. Treatment-emergent adverse events (TEAEs) are defined as AEs which 
commence on or after the time of start of investigational product administration. In the cases where 
date of AEs is missing or incomplete and it is not possible to define an AE as treatment emergent 


 
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or not, the AEs will be classified TEAEs. Serious infections are defined as any infection (viral, 
bacterial, and fungal) requiring hospitalization or parenteral antimicrobials. 
15.2.1 All adverse events  
The following summaries will be provided for all adverse events (AEs):  
• 
Summary of all AEs, screening AEs, TEAEs, including incidence and number of events;  
• 
Summary of all TEAEs by Maximum severity; 
• 
Summary of all study drug related TEAEs;  
• 
Summary of all study drug related TEAEs by maximum severity.  
15.2.2 Serious adverse event  
The following summaries will be provided for all serious adverse events (SAEs):  
• 
Summary of all treatment emergent SAEs;  
• 
Summary of all study drug related treatment emergent SAEs.  
15.2.3 Death  
The following summaries will be provided for all deaths:  
• 
Summary of TEAEs with an outcome of death.  
15.2.4 Adverse events affecting administration of study drug or leading to study withdrawal  
The following summaries will be provided:  
• 
Summary of all TEAEs affecting administration of study drug (including dose increased, dose 
reduced, drug interrupted, and drug withdrawn); 
• 
Summary of all TEAEs leading to withdrawal from study. 
15.2.5 Adverse events of special interest  
The following summaries will be provided for treatment-emergent adverse events of special interest:  
• 
Serious infection  
o 
Summary of all treatment-emergent serious infections  
o 
Summary of all drug-related treatment-emergent serious infections  
• 
Thyroid disorders (hypothyroidism, hyperthyroidism)  
• 
Hepatic injury  
15.3 
CLINICAL LABORATORY EVALUATIONS  
Laboratory tests include hematology, biochemistry, urinalysis, lipid profile test and thyroid 
function test.  


 
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The quantitative results and change from baseline will be summarized for each laboratory item at 
each evaluation time point. For categorical data, the number and percentage of subjects in each 
category will be provided.  
Shift table from baseline according to normal range criteria will summarize categorical results of 
by visit.  
Shift tables representing categorical change of laboratory results (normal and abnormal, according 
to normal range criteria) from baseline to each post will be provided. Shift table will also summarize 
categories of clinical significance from baseline to worst post-baseline value (abnormal with 
clinically significant > abnormal without clinically significant >normal>missing), and unscheduled 
visit will be included.  
Line plot of the following laboratory tests over time will be provided together with its mean and 
90% confidence interval by treatment group. 
o 
Hematology: hemoglobin, absolute lymphocyte count, absolute neutrophil count, and 
platelet count;  
o 
Lipid profile tests: total cholesterol, low density lipoprotein, high density lipoprotein, and 
triglycerides;  
o 
Thyroid function tests: thyroid stimulating hormone (TSH), free T3 (fT3) and free T4 
(fT4).  
The following hepatic events will also be summarized by visit for liver chemistry:  
o 
ALT or AST > 8 × ULN, or  
o 
ALT or AST > 5 × ULN, or  
o 
ALT or AST > 3 × ULN with elevated total bilirubin > 2 × ULN.  
Listings of laboratory parameters will display observed values and change from baseline, if 
applicable, with the flag for values, which are outside of normal range. And the listings of abnormal 
values will be provided with flag for clinically significant abnormalities. listings containing only 
clinically significant laboratory values will also be provided. If there are no clinical significance 
evaluations, listings of abnormal values will be provided instead. 
15.4 
VITAL SIGNS  
Vital signs to be summarized include blood pressure, heart rate, body temperature, and respiratory 
rate. Observed values and change from baseline will be summarized using descriptive statistics. A 
subject listing of all vital signs will also be presented. 
15.5 
ELECTROCARDIOGRAM (ECG)  
ECG parameters to be analyzed include heart rate (HR), PR interval, QRS tachycardia, QT interval, 
and corrected QT interval (QTcF).  
Triplicate ECG measurements are collected at each visit. The averaged value of quantitative 3 ECG 
results and worst clinical assessment (abnormal clinically significant > abnormal not clinically 
significant > normal > unable to assess > missing) will be summarized for each visit, with the.  


 
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Descriptive summaries of observed value and change from baseline will be presented for ECG 
measurements. The number and percentage of patients with QTcB/QTcF>500ms and QTc changes 
from baseline > 60ms will also be provided. Shift table will summarize change of ECG results from 
baseline to worst post-baseline value (abnormal with clinically significant > abnormal without 
clinically significant >normal>missing), and unscheduled visit will be included. 
The ECG listing will display observed values and change from baseline. And listings of abnormal 
results with clinically significant and prolonged QTcF will be provided. 
15.6 
PHYSICAL EXAMINATION  
Physical examination data will be listed. One more listing will be provided including patients with 
abnormal values only. 


 
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 REFERENCES  
1. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika 1988; 75:800-2  
2. Guideline on Biostatistics in Drug Clinical Trials (2016 CFDA)   
3. Guideline for the Planning and Reporting of Data Management and Statistical Analysis 
of Drug Clinical Trials (2016 CFDA)  
4. ICH E9: Statistical Principles for Clinical Trials 1998  


机密 
统计分析计划                                  
瑞石生物医药有限公司 
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 APPENDICES  
17.1 
TIME AND EVENT TABLE  
 


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统计分析计划                                  
瑞石生物医药有限公司 
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17.2 
STATISTICAL TABLES, FIGURES AND LISTINGS  
The shells for the tables, figures and listings will be provided in a separate document.