A Randomized, Double-blind, Placebo-controlled, Multicenter Phase III Clinical Trial to Evaluate the Efficacy and Safety of TTYP01 Tablets in the Treatment of Acute Ischemic Stroke
Phase: PHASE3
Conditions: Acute Ischemic Stroke
Sponsor: Shanghai Auzone Biological Technology Co., Ltd.

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
Registration classification: Class 2.2 chemical drug
A randomized, double-blind, placebo-controlled, multicenter phase III clinical trial to
evaluate the efficacy and safety of TTYP01 tablets in the treatment of acute ischemic stroke
Protocol No.: TTYP01-III-AIS
Version:
V2.0
Version Date: June 30, 2023
Sponsor:
Suzhou Auzone Biotechnology Co., Ltd.
Leading Site of Clinical Study:
Army Medical Center of PLA
Principal Investigator:
Prof. Yanjiang Wang
Data Management and Statistical Analysis
Unit:
Beijing SSYP Data Technology Development
Co., Ltd.
Contract Research Organization:
Guoxin Medical Technology (Beijing) Co., Ltd.
Confidentiality Statement
All information contained in this protocol is proprietary to Suzhou Auzone Biological Technology Co., Ltd., and
therefore will only be provided to relevant medical institutions including investigators, co-investigators, ethics
committees and regulatory authorities for review. Without the written approval of Suzhou Auzone Biotechnology
Co., Ltd., no copies, circulation or other dissemination may be made except for necessary explanation when
signing the informed consent form with the subject who may participate in this study.

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
1
Statement and Signature Page of Sponsor
I have read and approved this protocol, Protocol No.: TTYP01-III-AIS, Version No.: V1.0 (dated
28 Oct 2022). I agree to the contents of this protocol and will conduct the study in strict accordance
with this protocol. I will also strictly fulfill my obligations to the sponsor and other relevant
requirement as required by the laws of China, Declaration of Helsinki, Good Clinical Practice (GCP)
and this study protocol. I agree to comply with all SOPs of the hospital and Suzhou Auzone
Biological Technology Co., Ltd. related to the conduct of this trial.
I will be responsible for initiating, applying for, organizing, funding, and monitoring this clinical
trial in compliance with GCP regulations. I will establish a quality control and quality assurance
system for the clinical trials and may conduct audits to ensure the quality of the study. I will cover
the costs of treatment and provide appropriate economic compensation for subjects who experience
trial-related injuries or death during the clinical trial. Additionally, I will offer legal and financial
guarantees for the investigators involved.
At the same time, I will appoint a qualified CRO to manage and monitor the project, ensuring that
the entire trial process is accurate, complete, and standardized.
Sponsor: Suzhou Auzone Biological Technology Co., Ltd.
Responsible Person: Xiaolong Hou
Signature: ____________
__DD__MM__YYYY

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
2
Statement and Signature Page of Principal Investigator
I have read and approved this protocol, Protocol No.: TTYP01-III-AIS, Version No.: V1.0 (dated
28 Oct 2022). I agree to perform my duties in strict accordance with the laws of China, the
Declaration of Helsinki, GCP, and this study protocol. I will provide copies of this protocol to all
study teams involved in this trial and will discuss the protocol and related materials with them to
ensure that they fully understand the study drug and how to conduct the trial prior to its initiation.
I will submit a CV to the Ethics Committee and, if necessary, to the Drug Administration before the
start of the study. The study will only commence after receiving approval from the Ethics
Committee. During the study, I will conduct the research in strict accordance with the requirements
outlined in this protocol. Any modifications to the protocol will be implemented only after notifying
the sponsor to obtain consent and securing re-approval or filing from the Ethics Committee, unless
immediate measures are necessary to protect the safety, rights, and interests of the subjects.
My study team will make medical decisions related to the clinical trial to ensure that subjects
receive timely treatment in the event of adverse events during the trial. I will ensure that all
personnel are aware of the requirements for proper reporting of serious adverse events (SAEs) and
will record and report these events as required.
I guarantee that the data will be accurately, completely, timely and legally recorded in the source
documents and clinical observation record forms. I will accept monitoring or audits conducted by
the monitor or auditor appointed by the sponsor, as well as audits and inspections by the drug
regulatory authority, to ensure the quality of the clinical trial.
I agree that the research results may be used for drug registration and publicly published.
At the same time, I will keep this protocol and related content confidential.
Clinical Research Unit: Army Medical Center of PLA
Principal Investigator: Yanjiang Wang
Signature: ____________
__DD__MM__YYYY

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
3
Statement and Signature Page of Subcenter Investigator
I have read and approved this protocol, Protocol No.: TTYP01-III-AIS, Version No.: V1.0 (dated
28 Oct 2022). I agree to perform my duties in strict accordance with the laws of China, the
Declaration of Helsinki, GCP, and this study protocol. I will provide copies of this protocol to all
study teams involved in this trial and will discuss the protocol and related materials with them to
ensure that they fully understand the study drug and how to conduct the trial prior to its initiation.
I will submit a CV to the Ethics Committee and, if necessary, to the Drug Administration before the
start of the study. The study will only commence after receiving approval from the Ethics
Committee. During the study, I will conduct the research in strict accordance with the requirements
outlined in this protocol. Any modifications to the protocol will be implemented only after notifying
the sponsor to obtain consent and securing re-approval or filing from the Ethics Committee, unless
immediate measures are necessary to protect the safety, rights, and interests of the subjects.
My study team will make medical decisions related to the clinical trial to ensure that subjects
receive timely treatment in the event of adverse events during the trial. I will ensure that all
personnel are aware of the requirements for proper reporting of serious adverse events (SAEs) and
will record and report these events as required.
I guarantee that the data will be accurately, completely, timely and legally recorded in the source
documents and clinical observation record forms. I will accept monitoring or audits conducted by
the monitor or auditor appointed by the sponsor, as well as audits and inspections by the drug
regulatory authority, to ensure the quality of the clinical trial.
I agree that the research results may be used for drug registration and publicly published.
At the same time, I will keep this protocol and related content confidential.
Clinical Research Unit:
Principal Investigator:
Signature: ____________
__DD__MM__YYYY

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
4
Statement and Signature Page of Contract Research Organization
I have read and approved this protocol, Protocol No.: TTYP01-III-AIS, Version No.: V1.0 (dated
28 Oct 2022). I agree to this study protocol and perform my duties in strict accordance with the
laws of China, the Declaration of Helsinki, GCP, and this study protocol. I will ensure that all
personnel involved in this trial receive a copy of the study protocol. I will discuss the protocol and
relevant materials with them to ensure that they fully understand the study drug and the procedures
for conducting the trial prior to its initiation.
I will be responsible for medical and safety affairs, project management, clinical monitoring, and
related tasks in accordance with GCP regulations and the requirements of the contract with the
sponsor. I will establish a quality control and quality assurance system for the clinical trial and
appoint qualified personnel to monitor and audit the entire process in line with the company's
quality system, thereby ensuring that the trial process is accurate, complete, and standardized.
Contract Research Organization: Guoxin Medical Technology (Beijing) Co., Ltd.
Project Leader:
Signature: ____________
__DD__MM__YYYY

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
5
Statement and Signature Page of Data Management and Statistical Analysis Unit
I have read and approved this protocol, Protocol No.: TTYP01-III-AIS, Version No.: V1.0 (dated
28 Oct 2022). I agree to this study protocol and perform my duties in strict accordance with the
laws of China, the Declaration of Helsinki, GCP, and this study protocol. I will provide copies of
this protocol to all relevant personnel involved in data management and statistical analysis of this
trial within our company. I will discuss the protocol and relevant data with them to ensure that they
fully understand the protocol and how to effectively perform data management and statistical
analysis.
Data Management and Statistical Analysis Unit: Beijing SSYP Data Technology Development Co.,
Ltd.
Responsible Person: Jianmin Zhao
Signature: ____________
__DD__MM__YYYY

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
6
Table of Contents
Statement and Signature Page of Sponsor........................................................................................... 1
Statement and Signature Page of Principal Investigator......................................................................2
Statement and Signature Page of Subcenter Investigator.................................................................... 3
Statement and Signature Page of Contract Research Organization..................................................... 4
Statement and Signature Page of Data Management and Statistical Analysis Unit............................ 5
Table of Contents.................................................................................................................................6
Abbreviations.....................................................................................................................................10
Protocol Synopsis...............................................................................................................................12
Schedule of Study Activities..............................................................................................................21
1. Background Information................................................................................................................23
1.1 Rationale for this trial.......................................................................................................... 23
1.2 Study Product Description................................................................................................... 24
1.2.1 Basic Information......................................................................................................24
1.2.2 Mechanism of Action................................................................................................25
1.3 Nonclinical Studies.............................................................................................................. 25
1.3.1 Pharmacology Studies...............................................................................................25
1.3.2 Toxicology Studies................................................................................................... 25
1.3.3 Non-clinical pharmacokinetics study........................................................................29
1.4 Clinical Studies.................................................................................................................... 31
1.4.1 Clinical Pharmacokinetics.........................................................................................32
1.4.2 Clinical Safety...........................................................................................................34
1.4.3 Clinical Efficacy....................................................................................................... 34
1.5 Risk/Benefit Assessment......................................................................................................36
1.5.1 Known Potential Risk............................................................................................... 36
1.5.2 Known Potential Benefits......................................................................................... 37
1.5.3 Evaluation of Potential Risks and Benefits...............................................................37
2. STUDY OBJECTIVES..................................................................................................................37
3. STUDY DESIGN...........................................................................................................................37
3.1 Overall Design..................................................................................................................... 37
3.2 Design Rationale..................................................................................................................38
3.3 Number of Subjects..............................................................................................................39
3.5 Definition of End-of-Study.................................................................................................. 40
3.6 Randomization Method........................................................................................................40

Phase III Clinical Trial Protocol of TTYP01 Tablets
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3.7 Blinding................................................................................................................................41
4. STUDY POPULATION................................................................................................................ 41
4.1 Inclusion Criteria..................................................................................................................41
4.2 Exclusion Criteria................................................................................................................ 42
4.3 Withdrawal Criteria..............................................................................................................43
4.3.1 Withdrawal/withdrawal as determined by the investigator.......................................43
4.4 Trial Suspension Criteria..................................................................................................... 45
5. STUDY INTERVENTION............................................................................................................45
5.1 Study Drug Information.......................................................................................................45
5.2 Study Drug Dosing Regimen...............................................................................................46
5.3 Packaging and Labeling of Investigational Drugs............................................................... 46
5.4 Management of Investigational drugs..................................................................................47
5.5 Concomitant Medication......................................................................................................48
5.5.1 Permitted Concomitant Drugs During the Trial........................................................48
5.5.2 Prohibited Drugs During the Trial............................................................................ 48
5.5.3 Study Treatment Compliance....................................................................................49
6. Study Procedure.............................................................................................................................49
6.1 Treatment Period (D1 to D28; V1 to V3)............................................................................ 49
6.2 Follow-up Period (D29–D90; V4–V5)................................................................................ 51
7. Study Evaluation............................................................................................................................52
7.1 Efficacy Evaluation..............................................................................................................52
7.1.1 Primary Outcome Measure....................................................................................... 52
7.1.2 Secondary Outcome Measure................................................................................... 52
8. Adverse Event................................................................................................................................53
8.1 Definition............................................................................................................................. 53
8.1.1 Adverse event............................................................................................................53
8.1.2 Serious adverse event................................................................................................54
8.1.3 Suspected unexpected serious adverse reaction........................................................55
8.2 Risk of drug use................................................................................................................... 55
8.2.1 Acute renal failure (unspecified degree)...................................................................55
8.2.2 Abnormal hepatic function, jaundice (all unspecified degree)................................. 55
8.2.3 Thrombocytopenia (unspecified degree).................................................................. 56
8.2.4 Disseminated intravascular coagulation (DIC) (unspecified degree)....................... 56
8.3 Observation and recording of adverse events...................................................................... 56

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Protocol No.: TTYP01-III-AIS
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8.4 Adverse event assessment....................................................................................................57
8.4.1 Judgment for the severity of adverse events............................................................. 58
8.4.2 Determination of the causal relationship of adverse events to the investigational
drug.................................................................................................................................... 58
8.5 Subject risk control measures.............................................................................................. 59
8.6 Reporting procedure.............................................................................................................59
8.6.1 Reporting procedures of serious adverse events.......................................................59
8.6.2 Reporting procedure for SUSARs.............................................................................60
8.6.3 Reporting procedures for development safety update reports (DSURs)...................61
8.6.4 Reporting of pregnancy.............................................................................................61
8.6.5 About lack of efficacy...............................................................................................62
8.6.6 Independent Data Monitoring Committee................................................................ 62
8.7 Risk control measures for protocol deviations.....................................................................62
9. Data Management and Statistical Analyses...................................................................................62
9.1 Data management.................................................................................................................63
9.1.1 Data management of EDC........................................................................................ 63
9.1.2 External data transfer................................................................................................ 63
9.1.3 Medical coding..........................................................................................................63
9.2 Statistical analyses............................................................................................................... 64
9.2.1 Statistical hypotheses................................................................................................64
9.2.2 Sample size determination........................................................................................ 64
9.2.5 Subject disposition....................................................................................................65
9.2.6 Demographic and baseline characteristics................................................................ 65
9.2.7 Extent of exposure and treatment compliance.......................................................... 65
9.2.8 Efficacy analyses.......................................................................................................65
9.2.9 Safety analyses..........................................................................................................66
9.2.10 Interim analysis.......................................................................................................66
10. Quality control and quality assurance..........................................................................................66
10.1 Clinical monitoring............................................................................................................ 66
10.2 Audit...................................................................................................................................67
10.3 Quality assurance of the clinical trial process....................................................................67
10.4 Recording and retention of study data............................................................................... 68
10.5 Storage, management and archiving of test data................................................................68
11. Ethical and Regulatory Requirements..........................................................................................69

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
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11.1 GCP and ethical requirements............................................................................................69
11.2 Informed consent procedure...............................................................................................69
11.3 Protocol deviation.............................................................................................................. 69
11.4 Suspension or termination of study/ closure of site........................................................... 69
11.5 Confidentiality and privacy................................................................................................70
11.6 Revision of study protocol and informed consent form.....................................................71
12. Right to Publish Privacy.............................................................................................................. 71
13. References....................................................................................................................................72
14. Appendix......................................................................................................................................73
14.1 Appendix 1. Modified Rankin Scale (mRS)...................................................................... 73
14.2Appendix 2. National Institutes of Health Stroke Scale (NIHSS)...................................... 75
14.3 Appendix 3. Barthel Index (BI) of Activities of Daily Living...........................................79
14.4 Appendix 4. Montreal Cognitive Assessment Scale (MoCA) (Beijing version)...............80
14.5 Appendix 5. Hamilton Depression Rating Scale (HDRS)................................................. 86
14.6 Appendix 7. Protocol Version Development and Amendment Schedule..........................88

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
10
Abbreviations
Abbreviation
Definition
ADR
Adverse drug reaction
AE
Adverse event
AIS
Acute ischemic stroke
ALB
Albumin
A/G
Serum albumin to globulin ratio
ALT
Alanine aminotransferase
ALP
Alkaline phosphatase
ALS
Amyotrophic lateral sclerosis
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC0-24h
Area under the drug concentration-time curve from time 0 to 24 hours
AUC0-last
Area under the concentration-time curve from 0 to the last measurable
concentration
BASO
Basophils
BI
Barthel Index
BID
Twice daily
BUN
Blood urea nitrogen
CDE
Center for Drug Evaluation, NMPA
CFDA
China Food and Drug Administration
CI
Confidence interval
CK
Creatine kinase
CL
Clearance
Cmax
Maximal concentration
Cr
Serum creatinine
CRE
Creatinine
CRO
Contract research organization
CT
Computed tomography
CTCAE
Common terminology criteria for adverse events
DIC
Disseminated intravascular coagulation
DMP
Data management plan
DSUR
Development safety update report
DVP
Data verification plan
eCRF
Electronic case report form
EDC
Electronic data capture
EOS
Eosinophils
FAS
Full Analysis Set
FDA
Food and Drug Administration
FIB
Fibrinogen
GCP
Good Clinical Practice
GLU
Blood glucose
HCT
Haematocrit
HDRS
Hamilton Depression Scale-21
HGB
Hemoglobin
IC50
Half maximal inhibitory concentration
ICF
Informed consent form
IDMC
Independent Data Monitoring Committee
INR
International normalized ratio
IWRS
Interactive Web Response System
LDH
Lactate dehydrogenase
LY
Lymphocytes
MCI
Mild cognitive impairment
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MONO
Monocyte

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
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Abbreviation
Definition
MRI
Magnetic resonance imaging
mg
Milligram
ml
Milliliter
mRS
Modified Rankin Scale
MoCA
Montreal Cognitive Assessment
MTD
Maximum tolerated dose
NEUT
Neutrophils
NIHSS
National Institutes of Health Stroke Scale
NMPA
National Medical Products Administration
NOAEL
No-observed-adverse-effect level
PMDA
Pharmaceuticals and Medical Devices Agency
PLT
Platelets
PPS
Per-Protocol Analysis Set
PT
Prothrombin time
PT
Preferred term
QD
Quaque die
RBC
Red blood cell
RDW
Red blood cell distribution width
RET
Reticulocyte
SAE
Serious adverse event
SDV
Source data verification
SOC
System organ class
SS
Safety Set
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Elimination half-life
TBIL
Total bilirubin
TC
Total cholesterol
TEAE
Treatment emergent adverse event
TG
Triglycerides
Tmax
Time to maximum
TP
Total protein
TT
Thrombin time
UA
Uric acid
UNL
Upper limit of normal
Urea
Urea
WBC
White blood cells
WHO
World Health Organization
γ-GTP
Gamma-glutamyltranspeptidase

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
12
Protocol Synopsis
Study Title
A randomized, double-blind, placebo-controlled, multi-center, phase III clinical trial to
evaluate the efficacy and safety of TTYP01 tablets in the treatment of acute ischemic
stroke
Registration
Category
Class 2.2 chemical drug
Investigational
Drug Name
TTYP01 tablets
Study Phase
III
Sponsor
Suzhou Auzone Biological Technology Co., Ltd.
Indication
Acute ischemic stroke
Study Objective
To evaluate the efficacy and safety of TTYP01 tablets in the treatment of acute
ischemic stroke
Sample Size
The trial is expected to enroll 618 subjects, and all subjects are randomized (1:1) to the
investigational drug group (TTYP01 group) and placebo control group (control group),
with 309 subjects in each group.
Study Design
The study is designed as a multi-center, randomized, double-blind, parallel, placebo-
controlled trial to evaluate the efficacy and safety of TTYP01 tablets in the treatment
of AIS.
Study groups:
309 subjects in the TTYP01 group and 309 subjects in the control group are
randomly enrolled in parallel:
• TTYP01 group: 2 tablets (edaravone, 60 mg) of TTYP01, twice daily,
administered 30–60 minutes before breakfast or dinner;
• Control group: 2 tablets (edaravone, 0 mg) of placebo, twice daily, administered
30–60 minutes before breakfast or dinner.
Course of treatment:
Subjects in the TTYP01 group or control group are orally administrated with two
TTYP-01 tablets (edaravone 30 mg per tablet) or two placebo tablets (edaravone 0 mg
per tablet) twice daily for consecutive 28 days (56 times in total), respectively. The
first dose should be given within 1 hour after randomization and remaining doses
should be administrated within 30–60 minutes before breakfast or dinner. In case of
postprandial randomization, the second dose should not be earlier than 6 hours after
the first dose.
Study periods:
Normally, the duration of the study is approximately 90 days. There are two periods
in the study, with five visits in total: the Treatment period: Day 1–Day 28, with a
minimum of 7 days of the inpatient treatment, including 3 visits (V1–V3); and the
Follow-up period: Day 29–Day 90, including 2 visits (V4: Day 60 ± 5, telephone visit;
V5: Day 90 ± 5, returning to hospital for the End-of-Study visit).
Eligible subjects will be screened based on inclusion and exclusion criteria, treated
with either the investigational drug or placebo, and evaluated for the efficacy and
safety of the investigational drug.
Neurological and clinical symptom assessments:
- modified Rankin Scale (mRS)
- National Institutes of Health Stroke Scale (NIHSS)
- Barthel Index (BI)
- Montreal Cognitive Assessment Scale (MoCA)
- 21-item Hamilton Depression Rating Scale (HDRS)

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
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Investigational
drug
Item
Investigational drug
Control drug
Name
TTYP01 tablets
Placebo
(Simulant TTYP01 Tablets)
Dosage
formulation
Oral tablet
Oral tablet
Strength
30 mg
0 mg
Ingredients
Edaravone, polyvinyl
caprolactam-polyvinyl
acetate-polyethylene glycol
graft copolymer (Soluplus),
sodium
bisulfite,microcrystalline
cellulose, polycrystalline
Microcrystalline
cellulose,magnesium stearate
Storage conditions
Store at room temperature
Store at room temperature
Shelf life
18 months tentatively
18 months tentatively
Manufacturer
STA Pharmaceutical Co. Ltd.
STA Pharmaceutical Co. Ltd.
Supplier
Suzhou Auzone Biological
Technology Co., Ltd.
Suzhou Auzone Biological
Technology Co., Ltd.
Dosing Regimen
Treatment group (TTYP01 tablets):
Subjects in the TTYP01 group are orally administrated with two TTYP01 tablets
(edaravone 30 mg per tablet) twice daily for consecutive 28 days (56 times in total).
The first dose should be given within 1 hour after randomization and remaining doses
should be administrated within 30–60 minutes before breakfast or dinner. In case of
postprandial randomization, the second dose should not be earlier than 6 hours after
the first dose.
Control group (placebo tablets, simulant TTYP01 tablets):
Subjects in the control group are orally administrated with two placebo tablets
(edaravone 0 mg per tablet) twice daily for consecutive 28 days (56 times in total). The
first dose should be given within 1 hour after randomization and remaining doses
should be administrated within 30–60 minutes before breakfast or dinner. In case of
postprandial randomization, the second dose should not be earlier than 6 hours after
the first dose.
Inclusion Criteria
Subjects eligible for enrollment in this trial must meet all of the following inclusion
criteria:
1. Patient whose age is ≥18 and ≤80 years;
2. Patients diagnosed with AIS according to the Guidelines for the Early Management
of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the
Early Management of Acute Ischemic Stroke: A Guideline for Healthcare
Professionals From the American Heart Association/American Stroke Association;
3. Patients who refuse thrombolysis or thrombectomy, or do not meet the indications
for thrombolysis or thrombectomy;
4. Patients who are within ≤24 hours after the symptom onset. For patients with
uncertain onset time due to wake-up stroke, aphasia, consciousness disorders, etc.,
the last known asymptomatic time is considered as the onset time;
5. Patients with a first stroke, or a recurrent stroke who recovered well from a previous
stroke (mRS score ≤1);
6. Patients whose NIHSS score is ≥6 and ≤20, and the sum of upper limb and lower
limb scores in item 5 and 6 is ≥2 at the initial diagnosis;
7. Patients or their legal guardians are informed of and voluntarily participate in this
study, and have signed a written informed consent form.

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
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Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study:
1. Patients with any contraindications for CT or MRI examination such as metal
implants, pacemakers, claustrophobia, etc.;
2. Patients with intracranial hemorrhage confirmed by CT or MRI including but not
limited to cerebral hemorrhage, epidural hematoma, subdural hematoma,
intracranial hematoma, ventricular hemorrhage, subarachnoid hemorrhage,
traumatic cerebral hemorrhage, hemorrhagic transformation in this stroke, etc.;
3. Patients with massive cerebral infarction (i.e., the infarcted area > 1/3 of the cerebral
hemisphere as indicated by CT or MRI);
4. Patients with consciousness disorders (Ia > 1 in NIHSS), posterior circulation
infarction, or transient ischemic attack (TIA);
5. Patients who are unable or unwilling to cooperate with the study due to comorbidity
such as severe mental disorders, depression, Alzheimer's disease, Parkinson's
dementia, and Louis body dementia;
6. Patients who are scheduled for or have already received intravenous thrombolysis
after the onset of this stroke, or those who plan to receive endovascular therapy
urgently or within following 90 days;
7. Patients with a history of malignant tumors or parasitic diseases in the brain;
8. Patients with a history of severe traumatic brain injury or intracranial infection and
with a mRS score > 1 before this stroke onset;
9. Patients with severe hypertension (systolic blood pressure ≥220 mmHg or diastolic
blood pressure ≥120 mmHg) before the first administration, which cannot be
controlled by treatment;
10. Patients with blood glucose < 2.7 mmol/L and being untreated, or blood glucose >
22.2 mmol/L at initial diagnosis;
11. Patients with dysphagia;
12. Patients with a history of rheumatic heart disease or atrial fibrillation, or with heart
rate < 40 or > 120 beats/min, or with second- or third-degree atrioventricular block
and being untreated, or with other kinds of malignant arrhythmia, or with acute
myocardial infarction or heart failure (grade III–IV according to the New York
Heart Association [NYHA]) or cardiac intervention within the past 6 months;
13. Patients with other serious systemic or organ diseases which, in the opinion of the
investigator, may hinder the evaluation of efficacy or make it unlikely for the
patient to complete the expected course of treatment and follow-up (e.g.,
malignancy with the life expectancy < 90 days);
14. Patients with severe liver or kidney diseases, or significant abnormalities in renal
or hepatic function tests such as alanine aminotransferase [ALT] or aspartate
aminotransferase [AST] ≥3.0 × upper limit of normal [ULN], or serum creatinine
[Cr] > 2.0 × ULN;
15. Patients with bleeding tendencies (e.g., the platelet count [PLT] < 75.0×109/L), or
severe bleeding within 90 days before this stroke onset;
16. Patients with contraindications for antiplatelet or statin therapy;
17. Patients who are allergic to edaravone or excipients;
18. Patients with a suspected or proven history of alcohol or drug abuse;
19. Female patients who are pregnant, lactating, having a recent pregnancy plan, or
unwilling to use contraception;
20. Patients who have participated in other clinical trials within 90 days before this
stroke onset or are participating in other clinical trials;
21. Patients who, in the opinion of the investigator, are not suitable to participate in the
clinical trial.
Withdrawal
Criteria
Withdrawal as determined by the investigator
1. Subjects who experience other comorbidities, complications, or special
physiological changes during the study, such as recurrent stroke or symptomatic
intracranial hemorrhage (sICH), classified as PH I or II according to ECASS
criteria;

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
15
2. Subjects with poor compliance, such as failure to take investigational drugs after
enrollment, lack of records for follow-up visits, unauthorized self-dressing changes,
or the use of prohibited drugs specified in the protocol, which may adversely affect
the assessment of the efficacy and safety;
3. Subjects who are taking other concurrent treatments that compromised the
evaluation in this trial;
4. Serious adverse events (SAEs) or significant adverse events (AEs) may occur,
making it inappropriate to continue the trial;
5. The occurrence of intolerable toxicity related to the drug may include any of the
following criteria: (1) serum ALT or AST levels > 8× ULN; (2) ALT or AST
levels > 5 × ULN for two consecutive weeks; (3) ALT or AST levels > 3 × ULN
with total bilirubin (TBIL) > 2 × ULN; (4) ALT or AST levels > 3 × ULN
accompanied by progressively worsening fatigue and gastrointestinal symptoms,
and/or eosinophilia (> 5%); (5) serum creatinine (Cr) levels reaching three times the
baseline value or higher;
6. Subjects who do not meet the inclusion criteria or who meet any of the exclusion
criteria are mistakenly included in this trial;
7. Subjects who participate in another intervention study during this trial;
8. Because of changes in the subject's medical condition unrelated to the
investigational drug that occurred during treatment period, such as severe
nosocomial infections, heart failure (graded III–IV according to NYHA), and
epilepsy that was difficult to control with medication, the investigator determines
that it is not in the subject's best interest to continue participation in this trial;
9. Other conditions that, in the opinion of the investigator, necessitate withdrawal from
this trial.
Subjects’ voluntary withdrawal from the trial
1. Subjects who are unwilling or unlikely to continue in this trial may request
withdrawal to the investigator;
2. Subjects may withdraw spontaneously for various reasons, including perceived poor
efficacy, intolerance to certain adverse reactions, economic factors, or other
unexplained reasons. The reason for withdrawal should be recognized as far as
possible and documented;
3. Subjects who, although not explicitly withdrawing from the trial, no longer undergo
visits and are lost to follow-up.
Study Procedure
This trial is divided into two periods, with a total of five visits. The treatment
period: Day 1–Day 28 (the minimum length of in-hospital treatment is not less than 7
days), which includes 3 visits (V1 to V3); The follow-up period: Day 29–Day 90,
including 2 visits (V4: Day 60 ± 5 for telephone visit; V5: Day 90 ± 5, returning to
hospital for End-of-Study visit).
Treatment period (D1–D28; V1–V3)
V1 (D1):
• Signing the informed consent form;
• Assessment based on inclusion and exclusion criteria;
• Demographic data collection, including initials, sex, date of birth, ethnicity,
height, weight, education level, etc.;
• Recording of the relevant medical history, including history of present illness,
past
history
(including
dementia/cognitive
dysfunction,
depression,
etc.),
medication
history,
allergy
history,
smoking
history,
history
of
alcohol
consumption, etc.;
• Vital signs, including body temperature, blood pressure, pulse, and respiratory
rate;
• Physical examination, including general condition, head, face, skin, lymph nodes,
eyes, ears, nose, throat, mouth, respiratory system, cardiovascular system,
abdomen, muscles, bones, and nervous system;

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
16
• 12-lead electrocardiogram (ECG);
• Laboratory tests: Blood routine, blood biochemistry, coagulation function, urine
routine, etc.;
• Head CT or MRI scanning (T1, T2, FLAIR, and DWI + ADC);
• Blood or urine pregnancy test (for pre-menopausal women only);
• Randomization;
• Hospitalization;
• Distribution of investigational drugs: Distribution of investigational drugs of day
1 to day 7;
• mRS score;
• NIHSS score;
• BI score;
• Recording concomitant therapies and drugs;
• Collection and evaluation of adverse events.
V2 (D7):
• Vital sign examination;
• Physical examination;
• 12-lead ECG;
• Laboratory tests: Blood routine, blood biochemistry, coagulation function, urine
routine, etc.;
• Distribution of investigational drugs: Distribution of investigational drug for the
period until the next visit;
• Distribution of subject diary cards: Distribution of subject diary cards required at
the next visit;
• mRS score;
• NIHSS score;
• BI score;
• MoCA score: Completing baseline assessment within 7 days (including day 7)
after enrollment;
• HDRS score: Completing baseline assessment within 7 days (including day 7)
after enrollment;
• Record concomitant therapies and concomitant drugs;
• Collection and evaluation of adverse events.
V3 (D28 + 3):
• Vital sign examination;
• Physical examination;
• 12-lead ECG;
• Laboratory tests: Blood routine, blood biochemistry, coagulation function, urine
routine, etc.;
• Head MRI scanning: Selecting some eligible sites to perform post-stroke head
MRI scanning (T1, T2, and FLAIR);
• Return of investigational drugs: Subjects returning unused drugs and/or empty
packages to investigators;
• Collection and assessment of subject diary cards: Subjects submitting completed
diary cards to investigators for assessment;
• Distribution of subject diary cards: Distribution of the subject diary cards
required for the next return visit;
• mRS score;
• NIHSS score;
• BI score;
• MoCA score;
• HDRS score;
• Recording concomitant therapies and drugs;
• Collection and evaluation of adverse events.
Note:

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Protocol No.: TTYP01-III-AIS
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17
1. V1 should be conducted during this episode prior to the first administration of the
treatment.
2. If the subject has completed some protocol-required examinations (e.g., physical
examination, 12-lead ECG, laboratory tests, and blood or urine pregnancy tests)
at the site within 24 hours of admission, and the investigator deems these
examinations sufficient to support the screening of the subject, they may not be
repeated. This consideration is based on the potential health risks associated with
conducting these examinations in a short time, which could also significantly
impact the subject's treatment schedule.
3. Selected sites with specific medical conditions will conduct head MRI scans on
Day 2 and Day 5 (including T1, T2, FLAIR, and DWI + ADC) and on Day 28 +
3 (T1, T2, and FLAIR). It is expected to collect MRI data from approximately
75% of all subjects and perform centralized reading to compare changes in MRI
variables (infarct volume and area). If a participant undergoes an MRI scan on
Day 1, the MRI scan on Day 2 can be skipped and only the remaining MRI tests
are required.
4. Dosing regimen during the treatment period: Subjects in the TTYP01 group or
control group are orally administrated with two TTYP01 tablets (edaravone 30
mg per tablet) or two placebo tablets (edaravone 0 mg per tablet) twice daily for
consecutive 28 days (56 times in total), respectively. The first dose should be
given within 1 hour after randomization and remaining doses should be
administrated within 30–60 minutes before breakfast or dinner. In case of
postprandial randomization, the second dose should not be earlier than 6 hours
after the first dose.
Follow-up period (D29–D90; V4–V5)
V4 (D60 ± 5, telephone visit):
• mRS score;
• Recording concomitant therapies and concomitant drugs;
• Collection and evaluation of adverse events.
Note:
The investigator will record the telephone visiting for the subject or his/her guardian
on Day 60 ± 5.
V5 (D90 ± 5, returning to hospital for End-of-Study visit):
• Vital sign examination;
• Physical examination;
• 12-lead ECG;
• Laboratory tests: Blood routine, blood biochemistry, coagulation function, urine
routine, etc.;
• Blood or urine pregnancy tests (pre-menopausal women only);
• mRS score;
• NIHSS score;
• BI score;
• MoCA score;
• HDRS score;
• Collection and assessment of subject diary cards: Subjects submitting completed
diary cards to the investigator for the assessment;
• Recording concomitant therapies and concomitant drugs;
• Collection and evaluation of adverse events.
Note:
Efficacy and safety data for early withdrawal subjects are collected as much as
possible by performing the same processes and examination items as V5.
Concomitant
medications
Permitted Concomitant Drugs During the Trial
Basic medication
Basic drugs are administered according to the Guideline for the Prevention and

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
18
Treatment of Stroke in China (Version 2021), including general treatment, antiplatelet
therapy, etc. Drugs prohibited in this trial, such as neuroprotective agents, should be
excluded.
Other permitted drugs during the trial
In case of adverse reactions, the investigator should decide whether the symptomatic
treatment is needed, and should record the drug name, administration route, dosage,
and starting and ending time of administration in the source records and electronic case
report form (eCRF).
All other treatments administered for the subject between the enrollment and the
End-of-Study are considered concomitant therapies, and the drugs are recorded in the
eCRF in the generic name. Concomitant drugs during the trial must be essential for the
subject, and the investigator should ensure concomitant drugs do not interfere with the
trial drug. The dose should be kept at the minimum level.
Non-pharmacological treatment
It’s necessary to accurately and thoroughly document any permitted non-
pharmacological treatments during the trial, such as rehabilitation therapy.
Prohibited drugs during the trial
The combination use of neuroprotective agents listed in the Chinese Guideline for
Diagnosis of Acute Ischemic Stroke 2018, the Guideline for the Prevention and
Treatment of Stroke in China (Version 2021), or the Chinese Guideline for the
Secondary Prevention of Ischemic Stroke and Transient Ischemic Attack (Version
2010) is prohibited in this trial, such as commercial available edaravone, edaravone
dexborneol,
nimodipine,
gangliosides,
phosphatidylcholine,
piracetam,
olactam,
butylphthalide,
urinary
kallindinogenase,
cinepazide,
nerve
growth
factor,
cerebrolysin, brain protein hydrolysate, deproteinised calf serum injection, and
deproteinisd calf blood extract injection, as well as herbs with neuroprotective effects
stated in instructions, etc. Other drugs in trial or unmarketed are also prohibited in this
trial.
Efficacy
Evaluation
Measures
Primary outcome measure:
Proportion of subjects with mRS score ≤1 on Day 90 after stroke onset.
Secondary outcome measure:
1. mRS score on day 90 after stroke onset;
2. Proportion of patients with a mRS score ≤2 on Day 90 after stroke onset;
3. Changes from baseline in mRS score on Day 7, 28, 60, and 90 after stroke onset;
4. Proportion of patients with an improvement of ≥4 in NIHSS score on Day 7, 28,
and 90 after stroke onset;
5. Proportion of patients with a NIHSS score of 0–1 on Day 7, 28, and 90 after
stroke onset;
6. Changes from baseline in NIHSS score on Day 7, 28, and 90 after stroke onset;
7. Proportion of patients with Barthel Index (BI) score ≥95 on Day 7, 28, and 90
after stroke onset;
8. Changes from baseline in BI score on Day 7, 28, and 90 after stroke onset;
9. MoCA score on Day 7, 28, and 90 after stroke onset ;
10. HDRS score on Day 7, 28, and 90 after stroke onset;
11. Changes from baseline in brain MRI variables (e.g., infarct volume and area) on
Day 5 and 28 after stroke onset.
Safety Evaluation
Measures
Safety endpoints include the occurrence of adverse events (AEs) from the start of
study to the end of follow-up period, including treatment-emergent adverse events
(TEAEs), adverse drug reactions (ADRs), serious adverse events (SAEs), and TEAEs
leading to subject termination from the trial.
1. Proportion of all-cause deaths within 90 days after stroke onset;
2. Proportion of symptomatic intracranial hemorrhages within 90 days after stroke

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
19
onset;
3. Proportion of recurrent ischemic strokes within 90 days after stroke onset;
4. Proportion of AEs within 90 days after stroke onset;
5. Proportion of SAEs within 90 days after stroke onset;
6. Discontinuation due to any AE within 90 days after stroke onset;
7. Discontinuation due to any other non-AE within 90 days after stroke onset.
Statistical
Analyses
Sample Size Determination:
A sample size of 274 subjects per each treatment group (total of 548 subjects) will
provide at least 90% power to detect a difference of 15% (60% in the TTYP01 group
versus 45% in the placebo group) for the primary endpoint the proportion of subjects
who achieved mRS ≤1 on Day 90 with a one-sided α value of 0.025. Assuming drop-
out rate of ~20%, 618 subjects (309 in each group) will be planned to be enrolled for
the trial.
Analysis Sets:
1. Full analysis set (FAS): FAS will included all the randomized subjects who
receive at least one dose of investigational drug and who have at least one post-
dose primary efficacy assessment (i.e., mRS).
2. Per-protocol set (PPS): As the subset of FAS, PPS will include all the subjects
who have the primary efficacy endpoint available on D90, with treatment
compliance of 80% to 120% and who have no major protocol deviations affecting
the primary efficacy assessment (e.g. not meeting important inclusion criteria,
use of prohibited medications impacting the primary efficacy outcomes during
the trial).
3. Safety set (SS): SS will include all the subjects who receive at least one dose of
investigational drug.
General Consideration:
All statistical analyses will be performed using SAS version 9.4 or above. Detailed
statistical methods will be described in the SAP and finalized prior to database lock.
In general, all study data will be pooled and summarized/analyzed by treatment group:
descriptive statistics (n, mean, median, first quartile (Q1), third quartile (Q3), standard
deviation, minimum and maximum values) will be used for continuous variables;
categorical variables will be described using frequency tables (frequencies and
percentages).
All statistical hypothesis tests will use a 2-sided test at α = 0.05 and two-sided 95%
confidence intervals (CIs) will be calculated, unless otherwise specified.
Demographics and Baseline Characteristics
Demographic data (Age and Age Group (<65, ≥65), Race, Gender, Height, Weight,
Body Mass Index (BMI)) will be analyzed with descriptive statistics as appropriate,
respectively. In addition, baseline disease characteristics including AIS history, time
from onset of AIS to treatment, baseline NIHSS, concomitant illness with AIS
(hypertension, diabetes, hyperlipidemia and cardiac disease), alcohol history, smoking
history and etc. will be also summarized.
Efficacy Analyses:
The number and percentage of subjects achieving mRS≤1 on Day 90 and the
corresponding 95% CI will be summarized (Clopper-Pearson interval) by treatment
group. The treatment group difference between TTYP01 and placebo group will be
tested using Chi-square test, and the 95% CI of the difference will be estimated. In
addition, odds ratio (OR) with the 95% CI as well as p-value will be also reported
using logistic regression. Multiple imputation will be used to account for missing
mRS; Death will be scored as 6 in mRS and thus there will be no missing mRS values
due to death. If the data are applicable, supplementary or sensitivity analyses will be
performed to assess the robustness of the primary analysis results. Further more,
subgroup analyses will be conducted based on the demographic and baseline
characteristics of subjects as applicable.

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
20
The shift in Day 90 mRS as a 6-category ordinal scale will be analysed using ordinal
logistic regression, common OR, the associated 95% CI as well as the p-value will be
reported. Similar statistical methods as the primary endpoint will be applied for binary
secondary endpoints including mRS ≤2 on Day 90, NIHSS improvement ≥4 or NIHSS
≤1 on Day 7, 28 and 90 and etc. For the continuous secondary outcomes such as
change in NIHSS from baseline, the least-square mean differences with 95% CI
between treatment groups will be estimated by analysis of covariance (ANCOVA) or
analysis of variance (ANOVA) as appropriate.
Safety Analyses:
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA). AE
analysis will be based on TEAE. Based on SS, the number and percentage of subjects
in each treatment group with overall and various types of TEAEs including all TEAEs,
all ADRs, CTCAE grade ≥3 TEAEs/ADRs, SAEs, serious ADRs, TEAEs/ADRs that
leading to treatment discontinuation will be counted and also summarized by System
Organ Class (SOC) and Preferred Term (PT), respectively.
The proportions of all AEs, symptomatic intracranial hemorrhage, recurrent
symptomatic stroke (cerebral infarction), all-cause mortality, serious adverse events,
discontinuation due to any adverse event and etc. and the corresponding 95% CI will
be summarized by treatment group. The relative risk of the treatment group compared
to the control group and the associated 95% CI will be also reported.
Cross-tabulation tables before and after treatment will be provided to analyze the post-
treatment changes in the laboratory tests, 12-lead ECG, and other applicable safety
parameters. Vital signs and the changes from baseline will be analyzed using
descriptive statistics by treatment group.
Interim Analysis:
An interim analysis will be planned at the timing of 50% subjects complete D90 or
early terminate, whichever occurs first, for the assurance of patient safety and trial
integrity and monitoring the effectiveness data. To maintain an overall one-sided α of
0.025, the α-spending function to approximate O'Brien-Fleming will be implemented.
The interim analysis will be monitored by Independent Data Monitoring Committee
(IDMC). The purpose of IDMC, IDMC members and their responsibilities, meeting
frequency and etc. will be described in the IDMC Charter.

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
21
Schedule of Study Activities
Trial Phase
Treatment Period
Follow-up Period
Test Days
D1
D7
D28 + 3
D60±5
D90±5
Visit Number
V1a
V2
V3
V4
Telephone visitb
V5/Early
withdrawalc
Signing the informed consent form
X
Assessment based on inclusion and
exclusion criteria
X
Collection of demographic data
X
Recording relevant medical history
(present, past, etc.)
X
Vital signs examination1
X
X
X
X
Physical examination2
X
X
X
X
12-lead ECG examination
X
X
X
X
Randomization
X
Hospitalization3
----------------------
-
Distribution of investigational drugs4
X
X
Administration of investigational
drugs
------------------------------------
Distribution of the subject diary card5
X
X
Return of investigational drugs6
X
Collection and Assessment of the
subject diary card7
X
X
Blood routine test8
X
X
X
X
Urine routine test9
X
X
X
X
Blood biochemistry10
X
X
X
X
Coagulation function11
X
X
X
X
Blood or urine pregnancy test12
X
X
Head computed tomography (CT) or
magnetic resonance imaging (MRI)13
X
X
Modified Rankin Scale (mRS)
Score14
X
X
X
X
X
National Institutes of Health Stroke
Scale (NIHSS) score15
X
X
X
X
Barthel Index (BI) score16
X
X
X
X
Montreal Cognitive Assessment
(MoCA) score17
X
X
X
Hamilton Depression Scale (HDRS)
score18
X
X
X
Collection and evaluation of adverse
events (AEs)
X
Concomitant Drugs
X
Concomitant Therapies
X
Note:
If the subject has completed all protocol-required examinations (e.g., physical examination, 12-lead ECG,
laboratory tests, imaging tests) at the participating site within 24 hours of admission for this episode, and the
investigator deems these examinations sufficient to support the diagnosis of the subject's condition, they may not
be repeated. This consideration is based on the potential health risks associated with conducting these
examinations in a short time frame, which could also significantly impact the subject's treatment schedule.
a. V1: V1 should be conducted during this episode prior to the first administration of the treatment.
b. V4 Telephone visit: The investigator shall conduct a telephone visit with the subject or their guardian on Day
60 ± 5, and document the conversation. At this visit, the investigator will complete the modified Rankin Scale
(mRS) score assessment, record basic treatments, record any concomitant treatments and drug combinations,

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
22
and collect and evaluate any adverse events.
c. Early withdrawal: Efficacy and safety data should be collected from participants who withdraw early, following
the same procedures and tests as those conducted at the V5 whenever possible.
1. Vital signs: Including body temperature, blood pressure, pulse, and respiratory rate.
2. Physical examination: Including general condition, head, face, skin, lymph nodes, eyes, ears, nose, throat,
mouth, respiratory system, cardiovascular system, abdomen, muscles, bones, and nervous system.
3. Hospitalization: The length of hospitalization in this trail will be determined by the actual condition of the
patients; however, the minimum duration will be set at no less than 7 days. This corresponds to the treatment
period from Day 1 to Day 28, during which a minimum of 7 days of hospitalization is required.
4. Distributing investigational drugs: Investigational drugs from Day 1 to Day 7 will be distributed on Day 1, and
investigational drugs required for the next visit will be distributed on Day 7.
5. Distribution of the subject diary card: Subject diary cards for the next return visit will be distributed at V2 and
V3.
6. Return of investigational drugs: Subjects return unused drugs and/or empty packaging to investigators at V3.
7. Collection and assessment of subject diary cards: Subjects submit completed diary cards to investigators for
assessment at V3 and V5.
8. Blood routine test: White blood cell (WBC), neutrophil (NEUT), eosinophil (EOS), basophil (BASO),
lymphocyte (LY), monocyte (MONO), red blood cell (RBC), hemoglobin (HGB), platelet (PLT), and
hematocrit (HCT). Assessments were performed on Day 1, Day 7, Day 28 + 3, Day 90 ± 5, or early withdrawal.
9. Urine routine test: Including pH value, urine specific gravity, urine protein (albumin), glucose, ketone body,
red blood cells, white blood cells, and urine occult blood. Assessments were performed on Day 1, Day 7, Day
28 + 3, Day 90 ± 5, or early withdrawal. If results of the urine routine test are not available due to emergency,
investigational drugs can be administered first. If the subject has no urine temporarily, the test results of first
urine sample collected upon admission will serve as baseline data.
10. Blood biochemistry: Total bilirubin (TBIL), total protein (TP), albumin (ALB), serum albumin-to-globulin
ratio (A/G), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CRE), total
cholesterol (TC), triglyceride (TG), urea (Urea), uric acid (UA), alkaline phosphatase (ALP), creatine kinase
(CK), blood glucose (GLU), sodium, potassium, calcium, chloride and phosphorus or blood urea nitrogen
(BUN). Assessments of high-density lipoprotein (HDL), low-density lipoprotein (LDL), and D-dimer will be
performed on Day 1, Day 7, Day 28 + 3, Day 90 ± 5 or upon early withdrawal.
11. Coagulation function: Including international normalized ratio (INR), activated partial thromboplastin time
(APTT), prothrombin time (PT), and fibrinogen (FIB). Assessments performed on D1, D7, D28+ 3, D90±5.
12. Blood or urine pregnancy test: For premenopausal women only. Conduct tests on Day 1 and Day 90 (± 5 days)
during the follow-up period.
13. Head computed tomography (CT) or magnetic resonance imaging (MRI): Head CT or MRI will be performed
on Day 1 (including T1, T2, FLAIR, and DWI + ADC). Selected sites with specific conditions will conduct
head MRI scans on post-stroke Day 2 and Day 5 (including T1, T2, FLAIR, and DWI + ADC) and on Day 28 +
3 (including T1, T2, and FLAIR). The plan is to collect MRI data from approximately 75% of the subjects and
perform centralized reading to compare changes in MRI findings (infarct volume and area). If a participant
undergoes an MRI scan on Day 1, the MRI scan on Day 2 may be skipped, and only subsequent MRI scans are
required.
14. Modified Rankin Scale (mRS) scores will be assessed on Day 1, Day 7, Day 28 + 3, Day 60 ± 5 by telephone
visit, and Day 90 ± 5.
15. National Institutes of Health Stroke Scale (NIHSS) scores will be assessed on Day 1, Day 7, Day 28 + 3, and
Day 90 ± 5.
16. Barthel Index (BI) scores will be assessed on Day 1, Day 7, Day 28 + 3, and Day 90 ± 5.
17. Montreal Cognitive Assessment (MoCA) scores will be assessed at baseline within 7 days (including Day 7)
after enrollment, as well as on Day 28 + 3 and Day 90 ± 5.
18. Hamilton Depression Rating Scale (HDRS) scores will be assessed at baseline within 7 days (including Day 7)
after enrollment, as well as on Day 28 + 3 and Day 90 ± 5.

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
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23
1. Background Information
1.1 Rationale for this trial
Acute ischemic stroke (AIS) is the most common type of stroke, with localized softening or
necrosis of brain tissue caused by cerebral blood supply disorder and hypoxia-ischemia. Stroke is
the third leading cause of death worldwide, causing 5.7 million deaths annually and is one of the
most common causes of death, long-term disability and hospitalization [1]. AIS is the most common
type of stroke, accounting for 69.6% to 70.8% of stroke in China. The time division of acute phase
is not uniform, which generally refers to within 2 weeks after onset, within 1 week for mild cases
and within 1 month for severe cases. The mortality of inpatients with AIS in China is 2.3% to 3.2%
within 1 month, 9% to 9.6% at 3 months, with a death/disability rate of 34.5% to 37.1%. The one-
year mortality is 14.4% to 15.4% and the death/disability rate is 33.4% to 33.8%. Management of
AIS includes early diagnosis and treatment, early prevention of recurrence (secondary prevention)
and early rehabilitation [2]. The rising incidence of AIS has placed a great burden on China's health
care system. AIS has high recurrence rate, complication rate, disability rate and case fatality rate,
bringing great pain and economic burden to patients and families [3].
The acute phase of ischemic stroke is often accompanied by complications, including cerebral
edema and intracranial hypertension, hemorrhagic transformation, epilepsy, dysphagia, pneumonia,
dysuria and urinary tract infection, deep vein thrombosis, etc. Among them, cerebral edema and
intracranial hypertension, hemorrhagic transformation and pneumonia are the main causes of death
of stroke patients. Stroke in China has become a serious medical and public health problem. Its high
morbidity, high disability rate, high mortality, high recurrence rate and high economic burden bring
heavy burden to society and family. It is urgent to develop effective prevention and treatment
strategies and drugs with clinical value to improve the current situation.
Currently, basic therapy with specific medication is still the major treatment of AIS. Commonly
used drugs mainly include those to improve cerebral blood circulation (intravenous thrombolysis,
antiplatelet therapy, anticoagulation, fibrin reduction, volume expansion, vasodilatation, etc.),
statins, neuroprotective agents (calcium antagonists, free radical scavengers, cell membrane
stabilizers, etc.) and traditional Chinese medicine preparations for activating blood circulation and
dredging collaterals. Thrombolysis treatment in the ultra-early stage yields the best efficacy. But it
has multiple limitations and is accompanied by the risk of bleeding transformation; Anti-platelet
agents and cerebral protective agents are the most popular treatment for stroke, where
neuroprotective agents have not yet demonstrated satisfactory clinical efficacy, and anti-platelet
therapy may also result in reperfusion injury. Therefore, there is still large unmet clinical request in
the treatment of ischemic stroke, where it is urgent to find new drugs with wide effect, multiple

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
24
mechanisms, which can really reduce the mortality, improve the neurological deficit, reduce the
complications and sequelae, and with higher safety [2].
Edaravone is a novel radical scavenger that has been shown to inhibit lipid peroxidation and
vascular endothelial cell injury and improve brain edema, tissue damage, and delayed neuronal
death [4]. Currently, edaravone injection has been approved for the treatment of AIS in China and
Japan, and for the treatment of amyotrophic lateral sclerosis (ALS) in Japan, South Korea, the
United States, Canada, Switzerland, and China. However, for either AIS or ALS, the first course of
treatment requires consecutive administration for 14 days, which is extremely inconvenient for
clinical use and has poor patient compliance.
The TTYP01 tablet is an edaravone oral tablet independently developed by Suzhou Auzone
Biological Technology Co., Ltd., which is derived from the modified form of edaravone injection.
The non-clinical study results show that TTYP01 tablet has good safety and tolerability. Phase I
clinical trials in Australia and China have demonstrated good safety and tolerability of TTYP01
tablets. Compared with edaravone injection, TTYP01 tablets can be administered by patients
themselves without relying on professional medical personnel, which improves compliance, reduces
medical costs, leading to significant clinical development potential. In this clinical trial, the efficacy
and safety of TTYP01 tablets in the treatment of AIS will be studied to provide a more scientific
and reasonable basis for the use of TTYP01 tablets in patients with AIS and to maximize the
benefits to them.
1.2 Study Product Description
1.2.1 Basic Information
Generic name: Edaravone Tablets
R&D code: TTYP01
Main ingredient: Edaravone
Chinese chemical name: 3-甲基-1-苯基-5吡唑啉酮
English chemical name: 3-Methyl-1-phenyl-5-pyrrazolone
Structure formula:
Molecular formula: C10H10N2O
Molecular weight: 174.20

Phase III Clinical Trial Protocol of TTYP01 Tablets
Protocol No.: TTYP01-III-AIS
Version No./Version Date: V2.0/June 30, 2023
25
Strength: 30 mg
Excipients:
Polyvinyl
caprolactam-polyvinyl
acetate-polyethylene
glycol
graft
copolymer
(Soluplus), sodium bisulfite, microcrystalline cellulose, polyvinylpyrrolidone, magnesium stearate
Storage condition: Store at room temperature
Validity period: 18 months tentatively
1.2.2 Mechanism of Action
Edaravone inhibits membrane lipid peroxidation chain reaction by providing electrons to oxygen
free radicals, thereby attenuating cytotoxicity caused by oxygen free radicals and inhibiting
irreversible destruction of protein and nucleic acid mediated by oxygen free radicals [5].
1.3 Nonclinical Studies
1.3.1 Pharmacology Studies
According to the pharmacological review of FDA [6] and the review report of PMDA [7], edaravone,
as a free radical scavenger, will be converted in tissues to 2-oxo-3-(phenylhydrazino)-butyric acid,
which is its free radical reaction product, indicating its interaction with free radicals (IC50=6.7 μM).
In in vitro studies, edaravone has been demonstrated to reduce lipid peroxidation in rat brain
homogenate (IC50=15.3 μM) by preventing linoleic acid oxidation via hydrogen peroxide (IC25 =
33.8 μM), and to reduced oxidative damage to cultured endothelial cells and neuronal apoptosis [7,8].
The safety pharmacology of edaravone includes assessment of respiratory function, central nervous
system and cardiovascular system. In vitro test results showed that edaravone does not inhibit the
hERG channel. For the central nervous system, the associated symptoms include mainly increased
lacrimation and ptosis and decreased spontaneous movement in male mice and rats following a
single intravenous injection of 30 or 100 mg/kg of edaravone. A decrease in body temperature was
observed in male mice following a single intravenous injection of 100 mg/kg edaravone. In beagle
dogs, a single intravenous injection of 30 or 100 mg/kg edaravone caused a temporary decrease in
blood pressure and an increase in carotid blood flow and heart rate. A single intravenous injection
of edaravone up to 100 mg/kg in beagle dogs did not affect respiratory rate [6].
1.3.2 Toxicology Studies
As is demonstrated in the literature of the marketed edaravone injection Radicava®, the no observed
adverse effect level (NOAEL) in rats is the lowest in toxicity studies, where rats are believed to be
the most sensitive species, and are therefore selected for general toxicity studies of TTY01-ASD
oral formulation, including single-dose and repeat-dose toxicity studies.
1.3.2.1 Single-dose toxicity
Under good laboratory practice of drug (GLP) conditions, TTY01-ASD was administered to
Sprague dawley (SD) rats at a single dose of 0, 50, 250, or 500 mg/kg/day by oral gavage twice

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daily at 8-hour intervals (administration doses of 0, 100, 500, and 1000 mg/kg/day) for 14 days,
where the maximum tolerated dose (MTD) of the study product, the reversibility, persistence, or
delayed effects of toxic effects were observed and assessed. No unscheduled deaths or test product-
related changes in body weight, food consumption, hemagglutination, serum chemistry, urinalysis
parameters, and macroscopic necropsy were reported during the study. Slight test product-related
salivation was observed in both males and females in the ≥500 mg/kg/day dose groups, and
episodic abnormal respiratory sounds and/or decreased activity was observed in both males and
females in the 1000 mg/kg/day dose group. Clinical signs related to drug administration were only
seen on the day of administration and were no longer evident 24 hours after administration. A slight
decrease in the neutrophil count was observed in animals in the administration groups (-30.06% in
males and -25.79% in females). Since this change is small and reversible, it is not considered a
harmful change. The MTD is 1000 mg/kg (500 mg/kg, twice daily).
In addition, single-dose intravenous toxicity studies of edaravone have been conducted in mice,
rats, and beagle dogs. The MTD of edaravone administered by intravenous bolus injection was less
than 478 mg/kg in mice, 580 mg/kg in rats, and 600 mg/kg in beagle dogs. Edaravone was
administered by intravenous drip over 4 hours and the MTD in beagle dogs was 500 mg/kg.
Specific study results can be found in the pharmacologic review of Edaravone Radicava® published
by the Food and Drug Administration (FDA) [6].
1.3.2.2 Repeat-dose toxicity
1.3.2.2.1 Relevant tests of TTY01-ASD
Under non-GLP conditions, TTY01-ASD was administered by oral gavage to SD rats twice daily
for 14 consecutive days at doses of 40, 150, or 400 mg/kg/dose, and no animals were found to be
moribund or dead during the test. Test product-related clinical signs included salivation (slight to
moderate) in both sexes at 400 mg/kg/day and transient fecal abnormalities (red/brown) in females.
No relevant histopathological changes were noted. Therefore, this change is considered harmless.
At the end of the dosing period, a slight and dose-dependent decrease in body weight was observed
in females in the low, medium and high treatment groups, compared to the control group (-3.27%, -
3.45% and -6.76% respectively). These changes were due to decreased body weight gain and
abnormal feces. Consistent with the observed decrease in body weight gain, decreased food
consumption was observed in females in all test product-treated groups. These changes were
considered test product-related but not harmful due to their small magnitude. Test product-related
hematology changes were limited to an increase in monocytes in males of each treatment group
(49.30%, 52.11%, and 73.24% in the low, mid, and high dose groups, respectively). Since no
relevant histopathological changes were found, the changes were considered non-hazardous. There

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were no test product-related changes in hemagglutination, serum chemistry, urine, organ weights,
macroscopic and histopathological changes.
Therefore, oral gavage administration of TTY01-ASD to SD rats for 14 consecutive days at doses
of 40, 150, or 400 mg/kg/day was tolerated, and clinical signs in both sexes at 400 mg/kg/day,
decreases in body weight and food consumption in females in each treatment group, and
hematological changes in males were considered harmless. The NOAEL was 400 mg/kg/day. At
this dose, AUC0-24h and Cmax were 96000 h*ng/mL and 96800 ng/mL in males and 110000h*ng/mL
and 77000 ng/mL in females after the last dose.
Administration of TTY01-ASD at doses of 0, 20, 75, or 200 mg/kg/dose (0, 40, 150, or 400
mg/kg/day) by oral gavage to rats for 28 consecutive days under GLP conditions followed by a 28-
day recovery period was well tolerated.
All animals survived to the scheduled dissection day. Test product-related clinical signs included
salivation (slight to moderate) in both sexes in the medium and high dose groups, occasional fecal
abnormalities in females and abnormal respiratory sounds in both sexes in the 400 mg/kg/day dose
group. All of the above symptoms recovered during the recovery period and were considered
harmless due to the mild severity of the symptoms. Test product-related changes in body weight and
food consumption were also observed in animals in the medium and high dose groups. At the end of
the dosing period, compared with the control group, a slight decrease in body weight was observed
in both sexes of animals in the medium and high dose groups (Males: -2.23% and -10.23%; Females:
-4.42% and -8.38%). These changes were dose-related. Decreased body weight was associated to
declined food consumption (males: -2.6% and -10.0%; Females: -5.2% and -10.4%). These changes
were considered harmless due to their small magnitude.
Test product-related clinical pathology changes were limited to changes in hematology
parameters in females of each treatment group. At the end of the dosing period, dose-related
decreases in RBC, HGB, and HCT, accompanied by increases in RET and RDW were observed in
females in each treatment group. These changes were within historical reference values and
associated histopathological changes were not available, they were considered test product-related
but non-adverse. These changes were partially recovered at the end of the recovery period. No test
product-related changes were observed in ophthalmology, hemagglutination, blood chemistry,
urinalysis, macroscopic observations, organ weights, and histopathological examinations in any
dose group.
For toxicokinetics, the time to maximum concentration in each dose group was observed at 0.1
hours after the first or second dose and 0.2 hours after the first dose. There were no apparent gender
differences in any of the dose groups except for the 40 and 150 mg/kg/day dose groups, where

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females had higher systemic exposure than males on day 1. Systemic exposure increased dose-
proportionally on day 1 and day 28 in female rats as dose increased from 40 to 400 mg/kg/day, but
increased more than dose-related proportion in male rats. No significant drug accumulation was
observed in any of the dose groups except for the increase in systemic exposure in males in the 400
mg/kg/day dose group.
In conclusion, administration of TTY01-ASD to rats at doses of 0, 20, 75, or 200 mg/kg (0, 40,
150, 400 mg/kg/day) by oral gavage twice daily for 28 consecutive days followed by a 28-day
recovery period was well tolerated. Oral administration of the test product did not cause death of the
animals or result in any adverse change in associated clinical signs, body weight, food consumption,
ophthalmological examination, clinical examination, or histopathology. NOAEL for this test was
determined to be 400 mg/kg/day. At this dose, the AUC0-24h and Cmax of edaravone were 72100
h*ng/mL and 32100 ng/mL in males and 99000h*ng/mL and 45100 ng/mL in females, respectively.
1.3.2.2.2 Studies on Edaravone Radicava®
Repeat-dose toxicity of edaravone was evaluated in rats, beagle dogs, and cynomolgus monkeys by
intravenous bolus and 24-hour intravenous infusion. Results of the study are presented in the FDA
published pharmacology review of Edaravone Radicava® [6]. A summary of the results are as
follows:
1.3.2.2.2.1 Repeat-dose toxicity study in rats
Under GLP conditions, Radicava® was given to Wistar rats through intravenous bolus
administration at 10, 30, 100, and 300 mg/kg/day for 28 consecutive days. The NOAEL for this
study was 10 mg/kg/day. Major findings included incomplete lid closure and lacrimation at doses
greater than 30 mg/kg in the intravenous bolus experiment. At 300 mg/kg, a decrease in righting
reflex was observed immediately after injection, with a transition to unsteady gait after 5 minutes.
All clinical symptoms disappeared within 24 hours. Decreased RBC, HCT and HGB, and elevated
RET and MCV were observed in the high dose (300 mg/kg/day) group, which were associated with
increases in bone marrow erythroid cells in the high dose group. All these changes were reversible
during the recovery period. The NOAEL for this experiment was finally determined to be 10
mg/kg/day.
1.3.2.2.2.2 Repeat-dose toxicity study in Beagle dogs
A 28-day repeat-dose toxicity study of Edaravone (Radicava®) was conducted in Beagle dogs under
GLP conditions by daily intravenous bolus injection (10, 30, 100, and 300 mg/kg/day). The
NOAEL was 30 mg/kg/day.
In the daily intravenous bolus study, clinical signs observed at doses greater than 30 mg/kg/day
included decreased activity, hindlimb weakness, convulsions, sneezing, and salivation. Examination

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of the sample revealed signs of anemia at 300 mg/kg/day. Bone marrow smear results showed an
approximately 50% decrease in the granulocyte/red blood cell ratio at this dose relative to the
baseline value. Enlarged and dark spleen was observed at 100 and 300 mg/kg/day. The mean
absolute liver and spleen weights were increased at 300 mg/kg/day. These findings were associated
with increased congestion and hemosiderin deposition in the spleen, as well as the increase of
hematopoietic cells and hemosiderin deposition in hepatic Kupffer cells.
1.3.2.3 Genotoxicity
Genotoxicity of edaravone has been fully assessed by the Ames test, the in vitro chromosome
aberration test, and the in vivo micronucleus test in mice, all of which showed negative results. The
results of the study can be found in the FDA published pharmacology review of Edaravone
Radicava® [6].
Three impurities in TTY01-ASD tablets were genotoxic predicted by Leadscope software. The
results indicated low genotoxic risk.
1.3.3 Non-clinical pharmacokinetics study
Pharmacokinetic studies evaluated the absorption of TTY01-ASD in SD rats and Beagle dogs
following single or multiple oral administration. The metabolism of edaravone in rats and Beagle
dogs was compared between intravenous injection and single oral administration, and the excretion
of edaravone in rats after a single oral dose of TTY01-ASD was investigated. The results of tissue
distribution and drug-drug interactions are primarily referenced from FDA data on marketed
injections.
1.3.3.1 Absorption
The in vivo pharmacokinetics of edaravone and its preparation TTY01-ASD were studied in SD rats
and Beagle dogs, including: (1) A study of single intravenous administration of edaravone; (2) Dose
escalation study of intragastric administration of TTY01-ASD; and (3) A study of TTY01-ASD
following the administration of once a day for 7 consecutive doses by gavage.
The test results of Caco-2 were referenced to the information of the marketed injections, where
edaravone has good permeability at a concentration of 100 μM (32.0×10-6 cm/sec) [8].
After single gavage administration of TTY01-ASD at 20, 60, and 180 mg/kg to male and female
SD rats, the mean bioavailability was 40.7%, 44.1%, and 58.8%, respectively, and the systemic
exposure (AUC0-last and Cmax) increased generally in proportion to the dose. There was a marked
difference in AUC0-last of edaravone in male and female SD rats at 60 and 180 mg/kg by gavage.
The corresponding Cmax ratios (female/male) were 1.63, 1.75, and 1.36 and the AUC0-last ratios
(female/male) were 1.86, 2.05, and 2.06 at doses of 20, 60, and 180 mg/kg, respectively. After
administration of 60 mg/kg of TTY01-ASD by gavage once daily for 7 consecutive days, systemic

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exposure to the drug was essentially unchanged with no apparent accumulation.
The bioavailability of TTY01-ASD was 29.3%, 58.2%, and 93.7% in male and female Beagle
dogs after single gavage administration of 5, 15, and 50 mg/kg TTY01-ASD, respectively. As the
gavage dose increased from 5 to 15 mg/kg, the systemic exposure to edaravone (AUC0-last and Cmax)
increased more than dose proportionally in male Beagle dogs, while Cmax increased more than dose
proportionally in female Beagle dogs, but AUC0-last increased generally in proportion to the dose.
Systemic exposure (AUC0-last and Cmax) to the drug in male and female Beagle dogs increased
generally dose-proportionally as the gavage dose increased from 15 mg/kg to 50 mg/kg. There were
no significant gender differences in the systemic exposure (AUC0-last and Cmax) of edaravone in male
and female Beagle dogs at each gavage dose. When TTY01-ASD was administered by gavage at 15
mg/kg once daily for 7 consecutive days, systemic exposure to the drug was essentially unchanged
with no apparent accumulation in male and female Beagle dogs.
1.3.3.2 Distribution
Data on marketed injections [6,8] show that the protein binding of edaravone injection in human
serum is between 91 and 92%, and the amount of edaravone in the brain is about 5% of the plasma
content at 5 minutes of administration. 14C-edaravone labeled experiments showed that tissues with
radioactivity levels above plasma levels were the aorta and kidney.
1.3.3.3 Metabolism
The main metabolic pathway of edaravone is glucuronide conjugation, where multiple uridine
diphosphate glucuronosyltransferases
(UGT1A6,
UGT1A9,
UGT2B7,
and
UGT2B17) and
sulfotransferase are involved. Edaravone is mainly metabolized to sulfate conjugates and
glucuronide conjugates in human plasma [6].
Comparison of the metabolism of edaravone in rats and Beagle dogs by injection and oral
administration showed that the major metabolic pathways of edaravone in rats and Beagle dogs
plasma were sulfate binding and glucuronide binding, and the secondary metabolic pathway was
oxidation. Compared with intravenous administration, no new metabolites were produced after oral
administration of TTY01-ASD.
1.3.3.4 Excretion
Edaravone is excreted mainly in the urine as a sulfate conjugate and a glucuronide conjugate [6]. The
ratio of the parent drug and its metabolites excreted in the urine after 24 h of intravenous
administration is shown in Table 1 Proportions of parent drug and its metabolites excreted in the
urine 24 h after intravenous administration:
Table 1 Proportions of parent drug and its metabolites excreted in the urine 24 h after intravenous

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administration
Species
%Excretion in Urine
Parent drug
Sulfuric acid conjugate
Glucuronide Conjugate
Total Quantity
Rats
1.59
51.19
8.25
61.04
Beagle dogs
2.82
64.47
9.15
76.44
Cynomolgus
monkeys
7.4
52.3
40.4
83
Human
0.68
6.58
83.17
90.43
After oral administration of TTY01-ASD to rats for 72 h, the recoveries were 57.0 ± 6.35% and
62.7 ± 8.50% in urine, 0.594 ± 0.361% and 0.280 ± 0.0826% in feces and 29.5 ± 10.9% and 22.4 ±
19.1% in bile in male and female rats, respectively. The total recovery from feces, urine and bile
accounted for 87.0 ± 13.2% and 85.4 ± 11.6% of the administered dose in male and female SD rats,
respectively, with urine being the major route of excretion.
Edaravone and 15 metabolites were detected in the urine of both male and female rats. Gluconate
conjugate and sulfate conjugate were the two most abundant metabolites in both male and female
rats. The relative abundance of the two substances was 18.42% and 68.91% for males and 36.79%
and 51.46% for females, respectively. The relative abundance of other metabolites was less than
5%-6%. The relative abundance of edaravone in urine of male and female rats was 5.99% and
5.88%, respectively.
Edaravone and 11 metabolites were detected in the bile of both male and female rats. Gluconate
conjugate and sulfate conjugate remained the two most abundant metabolites. The relative
abundance of both substances was 82.16% and 12.10% for males and 84.34% and 11.06% for
females, respectively, and the relative abundance of the other metabolites was less than 4%. The
relative abundance of edaravone in bile of both male and female rats was ≤0.09%.
1.3.3.5 Drug-Drug Interactions
The effect of edaravone as an inhibitor or inducer on cytochrome enzymes P450 has been reported
in the marketed injection dossier [8]. Edaravone and its sulfate conjugates did not inhibit CYP1A2,
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1 and UGT2B7 (IC50 > 50
μM). Edaravone and its sulfate conjugates induced CYP1A2, CYP3A4 and CYP2B6, where the
induction effect on CYP1A2 > CYP3A4 > CYP2B6, but not at therapeutic dose.
1.4 Clinical Studies
A Phase I clinical study of TTYP01 Tablets has been completed in healthy subjects in Australia,
including a single dose ascending study (60 mg, 120 mg, 180 mg, and 240 mg, Part A), a
comparative study of bioavailability between TTYP01 Tablets and edaravone Injection (30 mg
intravenous infusion within 30 minutes and 60 mg intravenous infusion within 60 minutes) (Part B),
and a food impact study (Part C).
The Phase I clinical study of TTYP01 Tablets has been completed in Chinese healthy subjects,

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including the bioavailability study of TTYP01 Tablets (60 mg), edaravone injection (30 mg) and
TTYP01-I Tablets (original process, 60 mg) (Part I), study on safety, tolerability and
pharmacokinetic characteristics (Part II, two dose groups of 60 mg BID and 120 mg QD), and food
impact study (Part III: 120 mg).
1.4.1 Clinical Pharmacokinetics
1.4.1.1 TTYP01
1.4.1.1.1 Phase I clinical trial in Australia
The pharmacokinetic results of the single dose ascending study (60 mg, 120 mg, 180 mg, 240 mg,
Part A) showed [6]: After a single oral dose of TTYP01, the median Tmax of edaravone in the 60 mg-
240 mg dose groups was 0.5-1.0 h, and the mean elimination half-life t1/2 was 3.09-4.06 h. The
mean Cmax of edaravone in the 60 mg-240 mg dose groups was 712 to 3114 ng/mL, the mean AUC0-
last was approximately 634 to 5496 ng*h/mL, and the mean AUC0-inf was approximately 645 to 5534
ng*h/mL. PK exposure (AUC and Cmax) after single oral administration of TTYP01 from 60 mg to
240 mg increased with the increasing dose. After single oral administration of TTYP01, the mean
CL/F and Vd/F of edaravone in the 60 mg to 240 mg dose groups were about 53 to 110 L/h and 273
to 480 L, respectively, which tended to decrease with increasing dose. The mean MRT was about
1.73 to 2.42 h. The increase in Cmax of edaravone over the dose range of 60 mg to 240 mg was
similar to that of the dose, and the increase in AUC was slightly more than dose proportion [6].
Results of the comparative bioavailability study (Part B) showed: Compared with intravenous
infusion of 30 mg Radicut ®, the time to maximum concentration of edaravone was consistent after
a single oral dose of 60 mg TTYP01, with slightly lower Cmax and slightly higher AUC with a mean
Fabs value of 59.84% after oral administration. Compared with intravenous infusion of 60 mg
Radicut ®, after a single oral dose of 120 mg TTYP01, the time to peak was slightly earlier and the
PK exposure levels (AUC and Cmax) were higher for edaravone compared to that in the intravenous
group, with a mean Fabs of 71.37%.
Results of the food impact study (Part C) in the Phase I clinical trial in Australian healthy
population showed that the mean Cmax was 1323.2793 ng/mL, the mean AUC0-t was 1428.2053
h*ng/mL, the mean AUC0-inf was 1449.5175 h*ng/mL, and the median Tmax was 0.5 mg/mL
following the oral administration of TTYP01 tablets in the fasting state; Oral administration of 120
mg of TTYP01 tablets after a high-fat meal resulted in a mean Cmax of 282.1838 ng/mL, a mean
AUC0-t of 693.7419 h*ng/mL, a mean AUC0-inf of 717.7111 h*ng/mL, and a median Tmax of 1.5 h.
The results showed that food significantly reduced the exposure level of TTYP01 (AUC and Cmax)
and delayed the time to maximum concentration Tmax. Conclusion: There were statistically
significant differences in AUC, Cmax, and Tmax under different fed conditions. The PK exposure

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(AUC and Cmax) of edaravone was significantly lower in the postprandial group compared to that in
the fasting group, while Tmax was slightly prolonged.
1.4.1.1.2 Phase I clinical trial in Chinese healthy population
The Phase I clinical study of TTYP01 Tablets has been completed in Chinese healthy subjects,
including the bioavailability study of TTYP01 Tablets (60 mg), edaravone injection (30 mg) and
TTYP01-I Tablets (original process, 60 mg) (Part I), study on safety, tolerability and
pharmacokinetic characteristics (Part II, two dose groups of 60 mg BID and 120 mg QD), and food
impact study (Part III: 120 mg). The test results are as follows:
Part I: Compared with intravenous infusion of edaravone injection at 30 mg, the mean Fabs of
edaravone was 59.38% after a single oral dose of 60 mg TTYP01 Tablets; After a single oral
administration of TTYP01-I Tablets at 60 mg, the mean Fabs for edaravone was 52.59%. The mean
Frel for edaravone was 116.91% after a single oral dose of 60 mg TTYP01 Tablets compared to a
single oral dose of 60 mg TTYP01-I Tablets.
Part II: Following multiple oral administration of TTYP01 tablets at 60 mg BID (N=9) and 120
mg QD (N=9) to healthy subjects, the mean (±SD) Ra (AUC) of edaravone was 1.00±0.00,
1.03±0.16 and the mean (±SD) Ra (Cmax) was 1.20±0.42 and 1.06±0.49, respectively. The results
showed no significant accumulation of edaravone following multiple consecutive oral doses of
TTYP01 tablets at 60 mg BID or 120 mg QD.
Part III: Food significantly reduced edaravone exposure (Cmax and AUC) and prolonged time to
maximum concentration (Tmax) following oral administration of 120 mg TTYP01 tablets under
fasting or postprandial conditions.
1.4.1.2 Edaravone Injection
Healthy adult male subjects and healthy elderly subjects were given 0.5 mg/kg of edaravone
injection, twice a day by intravenous drip over 30 minutes for 2 consecutive days. From the start of
administration to 12 hours after administration, 0.7 to 0.9% of the parent drug and 71.0 to 79.9% of
the metabolites were excreted in urine [9].
In a multi-center, double-blind, placebo-controlled clinical trial where European AIS patients
aged 40-80 years with a National Institute of Health Stroke Scale (NIHSS) score of 3-15 and onset
within 24 h were enrolled, subjects were divided into 2 groups: Group 1 received a loading dose of
0.08 mg/kg of edaravone injection followed by a continuous intravenous infusion of 0.2 mg/kg/h for
72 h, and Group 2 received a loading dose of 0.16 mg/kg followed by a continuous intravenous
infusion of 0.4 mg/kg/h for 72 h. The geometric mean of plasma edaravone concentrations at the
end of intravenous infusion was 391 ng/mL for patients in Group 1 and 1595 ng/mL for patients in
Group 2 [10]. Edaravone does not accumulate in the body [9], and age, gender and race have no

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influence on the pharmacokinetics of edaravone in vivo [11].
The human serum protein binding of edaravone is 92%, predominantly to albumin [11]. The
metabolites of edaravone in both plasma and urine are predominantly sulfuric acid conjugates [9]
The mean terminal elimination half-life of edaravone ranges from 4.5 to 6 hours and the half-life of
the metabolites ranges from 2 to 2.8 hours [11].
1.4.2 Clinical Safety
1.4.2.1 TTYP01
1.4.2.1.1 Phase I clinical trial in Australia [12]
In the completed Phase 1 clinical study in healthy Australian subjects, safety results showed that
single oral doses of TTYP01 tablets (60 mg, 120 mg, 180 mg, and 240 mg, Part A) were safe and
well tolerated in healthy Australian subjects; During the comparative bioavailability study (Part B),
oral administration of TTYP01 at 60 mg was comparable to the administration of edaravone
injection at 30 mg in terms of safety and tolerability; Oral administration of TTYP01 tablets under
both fasting and postprandial conditions was safe and well tolerated (Part C).
1.4.2.1.2 Phase I clinical trial in Chinese healthy population
The Phase I clinical study of TTYP01 tablets has been completed in Chinese healthy subjects. The
safety results showed that a single oral dose of TTYP01 tablets at 60 mg was safe and well tolerated
by Chinese healthy subjects, and was comparable to that of edaravone injection at 30 mg. Multiple
oral doses of TTYP01 tablets at 60 mg BID or 120 mg QD were safe and well tolerated; Oral
administration of TTYP01 tablets under both fasting and postprandial conditions was safe and well
tolerated.
1.4.2.2 Edaravone Injection
In a Phase III clinical trial in Japanese patients with AIS, 252 subjects were enrolled and the results
showed no significant difference in the frequency of adverse reactions in the edaravone group
compared to that in the placebo group [13]. The clinical observation of more than 500,000 AIS
patients in the four years after the approval of edaravone injection in Japan showed that the
proportion of patients with adverse reactions was very low, and treatment of AIS using edaravone
injection is safe.
1.4.3 Clinical Efficacy
1.4.3.1 TTYP01 Tablets
Currently, no clinical trial has been conducted for TTYP01 tablets in AIS patients, and no clinical
efficacy information is available.
1.4.3.2 Edaravone Injection
In a multicenter, randomized, placebo-controlled, double-blind Phase III clinical trial, 252 patients

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with AIS in Japan were enrolled where 125 were randomized to edaravone group and 127 were
randomized to the placebo-control group. Patients within 72 hours of onset were treated with 30 mg
twice daily for 14 consecutive days. Efficacy was assessed using the mRS scale in patients who
were discharged within 3 months or in patients with 3 months of onset. A total of 250 patients
(edaravone: control = 1:1) were included in the efficacy analysis set, and 2 patients in the placebo-
control group were excluded due to subarachnoid hemorrhage and disseminated intravascular
coagulation (DIC). The results showed significant efficacy in the edaravone group compared with
that in the placebo-control group (p = 0.0382), as is shown in Table 2. The efficacy assessment was
extended to 3, 6, and 12 months after onset, and the edaravone group still exhibited better efficacy,
as is shown in Table3. In addition, the edaravone group had significant efficacy (p = 0.0001) when
evaluated at 24 hours after treatment [13].
It has reported a real-world clinical study in Japan where 61048 AIS patients aged 18 years or
older, with ≤14 days of hospitalization after onset were enrolled. In this study, patients were
stratified according to ischemic stroke subtype, including large artery atherosclerosis, cardiogenic
embolism, small vessel occlusion, and cryptogenic/undetermined. Stroke severity was assessed by
the NIHSS score. The results showed an increase in ΔNIHSS (Discharge NIHSS-Admission NIHSS)
scores in patients treated with edaravone compared to those with no use in all ischemic stroke
subtypes. The mean ΔNIHSS was -0.46 with 95% confidence interval (CI) of -0.75 to -0.16 in the
large artery atherosclerosis group, -0.64 with 95% CI of -1.09 to -0.2 in the cardiac embolization
group, and -0.25 with 95% CI of -0.4 to -0.09 in the small vessel occlusion group. Edaravone
improves the neurological symptoms [15].
Table 2 Assessment of patients discharged within 3 months or patients with 3 months of onset
using the mRS score
Grading
0
1
2
3
4
5
Death
Statistics
Edaravone
(n=125)
27
36
29
12
10
7
4
p=0.0382*
Placebo
(n=125)
12
35
40
12
15
6
5
Grade 0: No symptoms; Grade 1: No obvious symptoms of disability; Grade 2: Slight disability; Grade 3:
Moderate disability; Grade 4: Serious disability; Grade 5: Severe disability.
Table3 Assessment of patients with 3, 6, and 12 months of onset using the mRS score
0
1
2
3
4
5
Death
Statistics
3
months
Edaravone
(n=115)
26
34
24
10
9
7
5
p=0.0481*
Placebo
(n=113)
10
39
26
11
14
7
6
6
months
Edaravone
(n=105)
27
35
15
11
3
8
6
p=0.0112*
Placebo
(n=103)
9
37
23
10
9
7
8
12
Edaravone
27
31
14
8
4
6
10
p=0.0248*

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months
(n=100)
Placebo
(n=94)
8
35
19
7
11
5
9
1.5 Risk/Benefit Assessment
1.5.1 Known Potential Risk
TTYP01 is an oral tablet with edaravone as the active pharmaceutical ingredient. TTYP01 is a Class
2 innovative chemical drug independently developed by Suzhou Auzone Biological Technology Co.,
Ltd. where the formulation of edaravone injection is modified.
The Phase I clinical study of TTYP01 tablets has been completed in Chinese healthy subjects.
The safety results show that the main adverse reactions were neutropenia, elevated triglyceride,
urinary occult blood, headache, elevated uric acid, premature beats, elevated total bilirubin, elevated
direct bilirubin, and elevated indirect bilirubin.
The currently known risks for edaravone injection are the following: According to 569 clinical
cases in Japan, 26 cases (4.57%) developed adverse reactions. The main manifestations were
abnormal liver function in 16 cases (2.81%) and rash in 4 cases (0.70%). Of the 569 cases, 122
cases (21.4%) had abnormal changes in clinical test values, mainly abnormal liver function test
values such as AST increased by 7.71% (43/558), ALT increased by 8.23% (46/559) and so on.
Serious adverse reactions include:
1. Acute renal failure (unspecified degree): During the course of medication, multiple renal
function examination and close observation are required. In case of symptoms such as low renal
function or oliguria, the invesigational drugs should be suspended and proper treatment should be
provided.
2. Abnormal liver function and jaundice (unspecified degree): Accompanied by elevation of AST,
ALT, ALP, γ-GTP, LDH and other abnormal liver function and jaundice. The liver function should
be tested and closely observed during the course of medication. In case of any abnormality, the
invesigational drugs should be suspended and proper treatment should be provided.
3. Thrombocytopenia (unspecified degree): manifestation of thrombocytopenia. During the
course of medication, close observation is required. In case of any abnormality, the invesigational
drugs should be suspended and proper treatment should be provided.
4. DIC (unspecified degree): DIC may appear, where regular examination is required during the
course of administration. In case of laboratory manifestations and clinical symptoms suspected of
DIC, the invesigational drugs should be suspended and proper treatment should be provided.
Other adverse reactions (incidence) and main manifestations include:
1. Anaphylaxis (0.1%–5%): Mainly manifested as rash, flushing, swelling, herpes, and itching;
2. Blood cell system (0.1%–5%): Mainly manifested as decreased red blood cell and increased

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white blood cells, increased white blood cells, decreased white blood cells, decreased hematocrit
value, decreased hemoglobin, increased platelets, and decreased platelets;
3. Injection site (0.1%–5%): Mainly manifested as rash, redness, and swelling at the injection site;
4. Liver (incidence > 5%): Mainly manifested as AST elevation, ALT elevation, LDH elevation,
ALP elevation, and γ-GTP elevation; Liver (0.1%–5%): elevated total bilirubin, positive
urobilinogen and bilirubinuria;
5. Kidney (0.1%–5%): Mainly manifested as elevated BUN, elevated serum uric acid, decreased
serum uric acid, elevated proteinuria, hematuria, and creatinine (unspecified degree);
6. Digestive system (0.1%–5%): belching;
7. Others (0.1%–5%): fever, heat sensation, elevated blood pressure, elevated serum cholesterol,
serum cholesterol decreased, elevated triglyceride, serum total protein decreased, elevated CK
(CPK), CK (CPK) decreased, serum potassium decreased, and serum calcium decreased.
1.5.2 Known Potential Benefits
Direct potential benefit: All subjects enrolled in this trial can receive standard diagnosis and
treatment and systematic examination of the disease by clinical experts, which will benefit the
subsequent treatment of the disease. Subjects in the treatment group may experience improved
conditions.
Long-term potential benefit: All subjects enrolled in this trial can receive standard diagnosis and
treatment and systematic examination of the disease by clinical experts, which will benefit the
subsequent treatment of the disease. On the success of this trial, more patients will be able to take
the drug and obtain the corresponding treatment and benefits.
1.5.3 Evaluation of Potential Risks and Benefits
The study product is a modified new drug that has not been marketed either at home or abroad.
According to Section 1.4 Clinical Studies, the efficacy of similar products was better than that of
the placebo, with good safety and tolerability, and the quality of life was improved after long-term
use. Compared with edaravone injection, TTYP01 tablets can be administered by patients
themselves without relying on professional medical personnel, which improves compliance, reduces
medical costs, and has significant clinical development potential. Therefore, the overall benefit to
the patient is believed to outweigh the possible risks.
2. STUDY OBJECTIVES
To evaluate the efficacy and safety of TTYP01 tablets in the treatment of AIS through a multicenter,
randomized, double-blind, parallel placebo-controlled design clinical trial.
3. STUDY DESIGN
3.1 Overall Design

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A multicenter, randomized, double-blind, parallel, placebo-controlled trial design is used to
evaluate the efficacy and safety of TTYP01 tablets in the treatment of patients with AIS.
It is estimated that 618 patients will be enrolled and randomly assigned to the treatment group
and the placebo control group in a 1:1 ratio, with 309 patients in each group. Normally, the duration
of this study is approximately 90 days. This trial will be divided into two periods, with a total of
five visits: Treatment period: Day 1–Day 28 (the minimum length of in-hospital observation will be
not less than 7 days), including three visits (V1–V3); Follow-up period: Day 29–Day 90, including
two visits (V4: Day 60 ± 5 for telephone visit; V5: Day 90 ± 5, returning to hospital for End-of-
Study visit).
3.2 Design Rationale
The rationale is as follows:
(1) Technical Guidelines for Clinical Trials of Drugs for Acute Ischemic Stroke, CFDA, February
09, 2018;
(2) Points to Consider on Clinical Investigation of Medicinal Products for the Treatment of Acute
Stroke, EMEA, January 2001;
(3) Guidelines for General Considerations in Clinical Trials of Drugs, CFDA, January 18, 2017;
(4) Standards and Procedures for Expedited Reporting of Safety Data during Drug Clinical
Trials, CFDA, April 27, 2018;
(5) Guidelines for Prevention and Treatment of Stroke in China (2021);
(6) The Fourth National Academic Conference on Cerebrovascular Diseases of the Chinese
Medical Association · Diagnostic Points of Various Cerebrovascular Diseases (2021);
(7) Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke in China (2018);
(8) 2019 AHA/ASA Guidelines for Ischemic Stroke.
According to the Technical Guidelines for Clinical Trials of Drugs for the Treatment of Acute
Ischemic Stroke issued by the National Medical Products Administration (NMPA, formerly China
Food and Drug Administration) in 2018, "At present, there is no sufficient clinical evidence to
prove the efficacy of other drugs including neuroprotective agents, and placebo is recommended for
clinical trials." "However, for other types of drugs such as neuroprotection, a superiority trial design
(e.g., placebo-controlled) is recommended." Therefore, a superiority design is adopted for this trial
with placebo as control.
In terms of subject selection, in accordance with China's Good Clinical Practice and Ethical
Review Methods for Biomedical Research Involving Human, it is required that “for subjects with
incapacity or limited capacity, project investigators shall obtain written informed consent from their
guardian or legal acceptable representative”, and “children, pregnant women, mentally retarded

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persons, mental patients, prisoners and other vulnerable groups shall be specially protected”. The
inclusion/exclusion criteria for this trial comply with regulations protecting vulnerable populations
and the informed consent of the guardian will be obtained for patients who are unable to consent
during the informed consent process.
3.3 Number of Subjects
A total of 618 subjects (309 in each treatment group) will be planned to be enrolled for the trial to
ensure at least 274 subjects per each group (total of 548 subjects) complete the trial, assuming drop-
out rate of ~20%.
3.4 Justification for Dose Selection
The dose selection for the Phase III clinical trial of TTYP01 tablets is primarily based on the results
of both overseas and domestic Phase I clinical studies.
3.4.1 Phase I Clinical Trial in Australia
A phase I clinical study of TTYP01 tablets have been completed in healthy subjects in Australia,
including a single-dose escalation study (60 mg, 120 mg, 180 mg, and 240 mg, Part A), a
comparative bioavailability study of TTYP01 and edaravone injection (Part B), and a food effect
study (120 mg, Part C). The safety results demonstrated that TTYP01 tablets exhibited good safety
and tolerability.
3.4.2 Phase I Clinical Trial in China
A Phase I clinical study of TTYP01 tablets has been completed in healthy Chinese subjects. This
study included a bioavailability assessment of TTYP01 tablets (60 mg), edaravone injection (30
mg), and TTYP01-I tablets (original process, 60 mg) in Part 1; a safety, tolerability, and
pharmacokinetic profile study in Part 2 (which included two dose groups: 60 mg BID and 120 mg
QD); and a food effect study in Part 3 (administering a dose of 120 mg). The test results are as
follows:
3.4.2.1 Safety Results
A single oral dose of TTYP01 tablets (60 mg) was found to be safe and well tolerated in healthy
Chinese subjects, comparable to edaravone injection (30 mg). Additionally, multiple oral doses of
TTYP01 tablets administered at either 60 mg BID or 120 mg QD dosing regimens were also safe
and well tolerated. Furthermore, the oral administration of TTYP01 tablets in both fasted and fed
states demonstrated similar safety and tolerability.
3.4.2.2 Pharmacokinetic Results
Part I: Compared with intravenous infusion of edaravone injection at 30 mg, the mean Fabs of
edaravone was 59.38% after a single oral dose of 60 mg TTYP01 tablets; After a single oral
administration of TTYP01-I tablets at 60 mg, the mean Fabs for edaravone was 52.59%. Compared

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to a single oral dose of 60 mg TTYP01-I tablets, the mean relative bioavailability (Frel) of
edaravone was 116.91% after a single oral dose of 60 mg TTYP01 tablets.
Part II: After multiple consecutive oral doses of TTYP01 tablets at 60 mg BID (n = 9) and 120 mg
QD (n = 9) in healthy subjects, the mean (± SD) edaravone area under the curve (AUC) was 1.00 ±
0.00 and 1.03 ± 0.16, respectively. The mean (± SD) values for the Ra(Cmax) were 1.20 ± 0.42 and
1.06 ± 0.49, respectively. The results showed no significant accumulation of edaravone following
multiple consecutive oral doses of TTYP01 tablets at 60 mg BID or 120 mg QD.
Part III: Food significantly reduced edaravone exposure (Cmax and AUC) and prolonged time to
maximum concentration (Tmax) following oral administration of 120 mg TTYP01 tablets under
fasting or postprandial conditions.
In summary, the recommended Phase III dosage of TTYP01 tablets is set at 60 mg BID, which
corresponds to two TTYP01 tablets (60 mg) taken twice daily, administered 30–60 minutes before
breakfast and dinner.
3.5 Definition of End-of-Study
A subject is considered to have completed the study if they have finished all phases, including the
last visit or final study procedure as outlined in the Schedule of Study Activities. The end of the
clinical trial is defined as the last visit of the last subject.
3.6 Randomization Method
This trial employed a block randomization method stratified by NIHSS score. SAS software
(version 9.4 or above) will be utilized to generate the randomization numbers and assign the
corresponding treatment groups. The randomization numbers will be then assigned through the
central randomization system (IWRS) for clinical trials. The randomization list (blinded) will be
sent to the project statistician by the randomization construction personnel (exported from the
randomization system) at the end of the study and after database lock with the approval of the
sponsor.
At screening, each subject will be assigned a screening number, formatted as S followed by five
Arabic numerals (e.g., S01001, S02001). In this format, '01' in S01001 indicates the first site, while
'001' denotes the first subject. Thus, S01001 refers to the first screened subject at site number 01,
and so on. Randomization will occur on Day 1 of the trial, with subjects who pass the screening
receiving randomization numbers in the order of their eligibility. The randomization number for the
trial will be formatted as R followed by three Arabic numerals (e.g., R001).
Randomized subjects who withdraw or are withdrawn from the trial for any reason, whether or
not they are taking study medication, will retain their randomization number and will not be
allowed to re-enter the trial.

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3.7 Blinding
This trial adopts a double-blind design. Investigational drugs will be manufactured, packaged, and
supplied by the sponsor in accordance with the double-blind principle.
(1) Blinding: The on-site blinding of the drug will be conducted by personnel from the statistical
unit and the sponsor, who are not involved in this trial. The drug packaging numbers and
corresponding treatment group will be generated using SAS software (version 9.4 or above). The
drug package number for the investigational drug or the control drug will be affixed to the label.
Investigational drugs will be packaged as per subject, with a single package for each subject.
(2) Blinding record: The on-site drug blinding process will be documented in a blinding record,
which is stored as part of the clinical trial documentation.
(3) Emergency letter: In this trial, electronic emergency letters will be used, with each random
number corresponding to an electronic emergency letter that records the treatment group. The
emergency letter is used for emergency unblinding and authorization to the investigator. The IWRS
will maintain the protocol for emergency unblinding operations.
(4) Emergency unblinding: In case of emergency, if the investigator determines that knowing the
drug used by the subject will be beneficial for treating an adverse event, emergency unblinding can
be conducted through the IWRS.
(5) Unblinding: The trial unblinding will be conducted after the finalization of the statistical
analysis plan and data review report, and database locked. The project statistician will request the
unblinding, and upon approval by the sponsor, the treatment groups corresponding to the random
numbers will be revealed for grouped statistical analysis of all data.
4. STUDY POPULATION
4.1 Inclusion Criteria
Subjects eligible for enrollment in this trial must meet all of the following inclusion criteria:
1. Patient whose age is ≥18 and ≤80 years;
2. Patients diagnosed with AIS according to the Guidelines for the Early Management of Patients
With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management
of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart
Association/American Stroke Association;
3. Patients who refuse thrombolysis or thrombectomy, or do not meet the indications for
thrombolysis or thrombectomy;
4. Patients who are within ≤24 hours after the symptom onset. For patients with uncertain onset
time due to wake-up stroke, aphasia, consciousness disorders, etc., the last known
asymptomatic time is considered as the onset time;

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5. Patients with a first stroke, or a recurrent stroke who recovered well from a previous stroke
(mRS score ≤1);
6. Patients whose NIHSS score is ≥6 and ≤20, and the sum of upper limb and lower limb scores
in item 5 and 6 is ≥2 at the initial diagnosis;
7. Patients or their legal guardians are informed of and voluntarily participate in this study, and
have signed a written informed consent form.
4.2 Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study:
1. Patients with any contraindications for CT or MRI examination such as metal implants,
pacemakers, claustrophobia, etc.;
2. Patients with intracranial hemorrhage confirmed by CT or MRI including but not limited to
cerebral hemorrhage, epidural hematoma, subdural hematoma, intracranial hematoma,
ventricular hemorrhage, subarachnoid hemorrhage, traumatic cerebral hemorrhage,
hemorrhagic transformation in this stroke, etc.;
3. Patients with massive cerebral infarction (i.e., the infarcted area > 1/3 of the cerebral
hemisphere as indicated by CT or MRI);
4. Patients with consciousness disorders (Ia > 1 in NIHSS), posterior circulation infarction, or
transient ischemic attack (TIA);
5. Patients who are unable or unwilling to cooperate with the study due to comorbidity such as
severe mental disorders, depression, Alzheimer's disease, Parkinson's dementia, and Louis
body dementia;
6. Patients who are scheduled for or have already received intravenous thrombolysis after the
onset of this stroke, or those who plan to receive endovascular therapy urgently or within
following 90 days;
7. Patients with a history of malignant tumors or parasitic diseases in the brain;
8. Patients with a history of severe traumatic brain injury or intracranial infection and with a mRS
score > 1 before this stroke onset;
9. Patients with severe hypertension (systolic blood pressure ≥220 mmHg or diastolic blood
pressure ≥120 mmHg) before the first administration, which cannot be controlled by treatment;
10. Patients with blood glucose < 2.7 mmol/L and being untreated, or blood glucose > 22.2
mmol/L at initial diagnosis;
11. Patients with dysphagia;
12. Patients with a history of rheumatic heart disease or atrial fibrillation, or with heart rate < 40
or > 120 beats/min, or with second- or third-degree atrioventricular block and being untreated,

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or with other kinds of malignant arrhythmia, or with acute myocardial infarction or heart
failure (grade III–IV according to the New York Heart Association [NYHA]) or cardiac
intervention within the past 6 months;
13. Patients with other serious systemic or organ diseases which, in the opinion of the
investigator, may hinder the evaluation of efficacy or make it unlikely for the patient to
complete the expected course of treatment and follow-up (e.g., malignancy with the life
expectancy < 90 days);
14. Patients with severe liver or kidney diseases, or significant abnormalities in renal or hepatic
function tests such as alanine aminotransferase [ALT] or aspartate aminotransferase [AST] ≥
3.0 × upper limit of normal [ULN], or serum creatinine [Cr] > 2.0 × ULN;
15. Patients with bleeding tendencies (e.g., the platelet count [PLT] < 75.0×109/L), or severe
bleeding within 90 days before this stroke onset;
16. Patients with contraindications for antiplatelet or statin therapy;
17. Patients who are allergic to edaravone or excipients;
18. Patients with a suspected or proven history of alcohol or drug abuse;
19. Female patients who are pregnant, lactating, having a recent pregnancy plan, or unwilling to
use contraception;
20. Patients who have participated in other clinical trials within 90 days before this stroke onset
or are participating in other clinical trials;
21. Patients who, in the opinion of the investigator, are not suitable to participate in the clinical
trial.
4.3 Withdrawal Criteria
4.3.1 Withdrawal/withdrawal as determined by the investigator
Investigator-initiated withdrawal refers to the fact that the investigator decides to withdraw the
enrolled subject from the trial when the conditions that make the further study unsuitable occur in
the subject during the study process.
1. Subjects who experience other comorbidities, complications, or special physiological changes
during the study, such as recurrent stroke or symptomatic intracranial hemorrhage (sICH),
classified as PH I or II according to ECASS criteria;
2. Subjects with poor compliance, such as failure to take investigational drugs after enrollment, lack
of records for follow-up visits, unauthorized self-dressing changes, or the use of prohibited drugs
specified in the protocol, which may adversely affect the assessment of the efficacy and safety;
3. Subjects who are taking other concurrent treatments that compromised the evaluation in this trial;
4. Serious adverse events (SAEs) or significant adverse events (AEs) may occur, making it

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inappropriate to continue the trial;
5. The occurrence of intolerable toxicity related to the drug may include any of the following
criteria: (1) serum ALT or AST levels > 8× ULN; (2) ALT or AST levels > 5 × ULN for two
consecutive weeks; (3) ALT or AST levels > 3 × ULN with total bilirubin (TBIL) > 2 × ULN; (4)
ALT or AST levels > 3 × ULN accompanied by progressively worsening fatigue and
gastrointestinal symptoms, and/or eosinophilia (> 5%); (5) serum creatinine (Cr) levels reaching
three times the baseline value or higher;
6. Subjects who do not meet the inclusion criteria or who meet any of the exclusion criteria are
mistakenly included in this trial;
7. Subjects who participate in another intervention study during this trial;
8. Because of changes in the subject's medical condition unrelated to the investigational drug that
occurred during treatment period, such as severe nosocomial infections, heart failure (graded III–
IV according to NYHA), and epilepsy that was difficult to control with medication, the
investigator determines that it is not in the subject's best interest to continue participation in this
trial;
9. Other conditions that, in the opinion of the investigator, necessitate withdrawal from this trial.
4.3.2 Subjects’ voluntary withdrawal from the trial
According to the informed consent form, the subject or his/her guardian has the right to withdraw
from the trial during any phase, or the subject/guardian may be considered to have withdrawn if the
subject no longer accepts investigational drugs or examinations and is lost to follow-up without
revoking the consent (also referred to as withdrawal, or dropout).
1. Subjects who are unwilling or unlikely to continue in this trial may request withdrawal to the
investigator;
2. Subjects may withdraw spontaneously for various reasons, including perceived poor efficacy,
intolerance to certain adverse reactions, economic factors, or other unexplained reasons. The
reason for withdrawal should be recognized as far as possible and documented;
3. Subjects who, although not explicitly withdrawing from the trial, no longer undergo visits and are
lost to follow-up.
If a subject is unable to determine whether they should withdraw from the trial, the legal guardian
has the obligation to make the decision. For subjects who withdraw from the trial for any reason,
the investigator should record the reason for their withdrawal as much as possible, and complete
and report all observation results in detail.
If a subject withdraws from the trial due to an adverse event (AE) or an abnormal laboratory test
result, this important special event and test result should be recorded in the Case Report Form

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(eCRF).
Except for cases where the subject withdraws consent or is lost to follow-up, attempts should be
made to collect post-termination visit data up to the end of the study as specified in the protocol.
For subjects who drop out or are lost to follow-up, the investigator should take active measures to
complete the last visit, ensuring their efficacy and safety data can be analyzed. The reasons for
dropout should be recorded in detail, and efforts should be made to obtain safety and efficacy data
of the subject. All data should be preserved complete and available for review.
Subjects who sign the informed consent form and have been randomized cannot be replaced.
All subjects who withdraw (drop out) from the trial are expected to complete the corresponding
observations specified in the protocol. The reason for termination should be noted in the source
document. If a subject withdraws due to an adverse event, the final examination and follow-up
specified in the protocol should be conducted. Additionally, appropriate treatment should be
provided, and the adverse event should be recorded.
4.4 Trial Suspension Criteria
Trial suspension refers to the termination of the study process before the end of the last visit as per
the protocol. The main purpose of trial suspension is to protect the rights and interests of subjects,
ensure the quality of the trial, and avoid unnecessary economic losses. All parties to the study
should be notified of the suspension in time. Conditions under which a clinical trial may be
suspended include, but are not limited to:
(1) When serious safety issues are identified during the study process, and the investigator
considers that the safety of subjects may be compromised;
(2) If the investigational drug is determined to have no clinical value during the study process;
(3) If a major error is identified in the design of the trial protocol, making it difficult to evaluate
the drug, or if there is a significant deviation in the implementation of the protocol that affects
the final evaluation of the drug;
(4) If the sponsor requires the trial to be halted for reasons such as funding constraints or
administrative issues;
(5) If drug regulatory authorities order the trial to be stopped for any reason;
(6) If other factors prevent the continuation of the trial.
Once the trial is suspended, the investigator should immediately inform subjects or the guardians,
report to the Ethics Committee (EC) and the clinical trial office, explain the reason for the
suspension of the trial, and inform the subjects in writing of any potential risks to their health.
5. STUDY INTERVENTION
5.1 Study Drug Information

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Table 4 Study Drug Information Form
Item
Investigational drug
Control drug
Name
TTYP01 tablets
Placebo
(Simulant TTYP01 Tablets)
Dosage form
Tablet
Tablet
Strength
30 mg
0 mg
Ingredients
Edaravone, polyvinyl caprolactam-
polyvinyl acetate-polyethylene glycol
graft copolymer (Soluplus), sodium
bisulfite, microcrystalline cellulose,
polyvinylpyrrolidone, magnesium
stearate
Microcrystalline cellulose, magnesium stearate
Storage
conditions
Store at room temperature
Store at room temperature
Shelf life
18 months tentatively
18 months tentatively
Manufacturer
STA Pharmaceutical Co. Ltd.
STA Pharmaceutical Co. Ltd.
Supplier
Suzhou Auzone Biological Technology
Co., Ltd.
Suzhou Auzone Biological Technology Co.,
Ltd.
5.2 Study Drug Dosing Regimen
Treatment group (TTYP01 tablets):
Subjects in the TTYP01 group are orally administrated with two TTYP-01 tablets (edaravone 30 mg
per tablet) twice daily for consecutive 28 days (56 times in total). The first dose should be given
within 1 hour after randomization and remaining doses should be administrated within 30–60
minutes before breakfast or dinner. In case of postprandial randomization, the second dose should
not be earlier than 6 hours after the first dose.
Control group (placebo, simulant TTYP01 Tablets):
Subjects in the control group are orally administrated with two placebo tablets (edaravone 0 mg per
tablet) twice daily for consecutive 28 days (56 times in total). The first dose should be given within
1 hour after randomization and remaining doses should be administrated within 30–60 minutes
before breakfast or dinner. In case of postprandial randomization, the second dose should not be
earlier than 6 hours after the first dose.
5.3 Packaging and Labeling of Investigational Drugs
The investigational drug should be provided by the sponsor with appropriate labeling and packaging.
The sponsor shall label all investigational drugs in accordance with GCP requirements. The label
shall be reviewed and approved according to the sponsor’s review and approval process, and the
research organization may keep copies of the labels. Complete records of all investigational drugs
including lot numbers and shelf life, as well as drug labels, will be maintained in the sponsor file.
5.3.1 Drug packaging
According to the protocol-specified dosage, the sponsor should provide sufficient investigational
drugs.

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5.3.2 Drug labeling
Each box of drugs is labeled on the outer package and includes drug name, protocol number,
strength, drug packaging number, packaging specification, storage conditions, shelf life, batch
number, dosage and administration, sponsor information, and other relevant information. The label
also prominently displays the phrase 'For Clinical Trial Only' along with any necessary precautions.
The size of the bag label is smaller, with content only showing key information such as the name, s
protocol number, strength, drug packaging number, storage conditions, dosage and administration
and sponsor of the investigational product.

Sample of the outer packaging label
TTYP01 Tablets for Clinical Study
(For clinical trials only)
Drug name: TTYP01 Tablet/Placebo
Protocol No.: TTYP01-Ⅲ-AIS
Drug package number: [here to apply label]
Strength: 30 mg /tablet
Packaging specification: 10 tablets per bag, 3 or 9 bags in total.
Dosage and administration: Administered 30-60 minutes before breakfast and dinner, bid, 2 tablets each time
Batch No.: Omitted, subject to actual situation
Expiry date: Omitted, subject to the actual situation
Storage conditions: Store at room temperature.
Sponsor: Suzhou Auzone Biological Technology Co., Ltd.
Note: To avoid accidental administration, leftover drugs and empty packages need to be collected.

Sample of the inner packaging label
TTYP01 Tablets for Clinical Study
(For clinical trials only)
Drug name: TTYP01 Tablet/Placebo
Protocol No.: TTYP01-Ⅲ-AIS
Drug package number: [here to apply label]
Strength: 30 mg /tablet
Dosage and administration: Administered 30-60 minutes before breakfast and dinner, bid, 2 tablets each time
Storage conditions: Store at room temperature.
Sponsor: Suzhou Auzone Biological Technology Co., Ltd.
Note: To avoid accidental administration, leftover drugs and empty packages need to be collected.
5.4 Management of Investigational drugs
The shipment of investigational drugs is the responsibility of the sponsor, who will ship the
qualified investigational drugs to each site via the cold chain of medical devices. The drug
administrator designated by the clinical trial institutions and participating departments of each site
shall receive and count the drugs and relevant documents, and make relevant records. In case of
damage, loss, and other abnormalities, it should be recorded exactly and reported to the sponsor and
monitor in time. At the same time, the site keeps the drug handover form and/or waybill as well as
the temperature records of the whole process.
The investigational drug can only be used in this trial and can only be administered by a
designated person authorized by the investigator. The investigator/pharmacist in charge of drug
management dispenses and retrieves the investigational drug and keep accurate record according to
the study procedures. Records of investigational drug management should include date, quantity,

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batch/serial numbers, shelf life, and allocation codes, signatures, etc. The investigator should keep
records of the amount and dose of investigational drugs used in each subject. The amount of the
used and the remaining investigational drug should match the amount provided by the sponsor.
After the end of the trial, the drug administrator is responsible for the recovery and accountability
of the remaing unused drugs or the expired drug, which are returned to the sponsor, and destroyed
by the sponsor in a concentrated way.
In order to strictly manage and use the investigational drug, each participating hospital should
establish a strict management system, specifically a system for managing and dispensing
investigational drugs by specific personnel in drug storage facility and trial department of the
clinical trial institution. The investigational drug should be stored at room temperature.
5.5 Concomitant Medication
5.5.1 Permitted Concomitant Drugs During the Trial
5.5.1.1 Basic medication
Basic drugs are administered according to the Guideline for the Prevention and Treatment of Stroke
in China (Version 2021), including general treatment, antiplatelet therapy, etc. However, drugs
prohibited in this trial, such as neuroprotective agents, should be excluded.
5.5.1.2 Other permitted drugs during the trial
In case of adverse reactions, the investigator should decide whether symptomatic treatment is
needed, and should record the drug name, administration route, dosage, and starting and ending
time of administration in the original records and eCRF.
All other treatments between the enrollment and the End-of-Study are considered concomitant
therapies, and the drugs are recorded in the eCRF in the generic name. Concomitant drugs during
the trial must be essential for the subject, and the investigator should ensure concomitant drugs do
not interfere with the investigational drug. The dose should be kept at the minimum level.
5.5.1.3 Non-pharmacological treatment
It’s necessary to accurately and thoroughly document any permitted non-pharmacological
treatments during the trial, such as rehabilitation therapy.
5.5.2 Prohibited Drugs During the Trial
The combination use of neuroprotective agents listed in the Chinese Guideline for Diagnosis of
Acute Ischemic Stroke 2018, the Guideline for the Prevention and Treatment of Stroke in China
(Version 2021), or the Chinese Guideline for the Secondary Prevention of Ischemic Stroke and
Transient Ischemic Attack (Version 2010) is prohibited during the study, such as commercial
available
edaravone,
edaravone
dexborneol,
nimodipine,
gangliosides,
phosphatidylcholine,
piracetam, olactam, butylphthalide, urinary kallindinogenase, cinepazide, nerve growth factor,

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cerebrolysin, brain protein hydrolysate, deproteinised calf serum injection, and deproteinisd calf
blood extract injection, as well as herbs with neuroprotective effects stated in instructions, etc.
Other drugs in trial or unmarketed are also prohibited in this study.
5.5.3 Study Treatment Compliance
During the trial, investigational drugs should be administered according to the administration
method specified in the protocol. If deviations from the administration method occur (such as
deviations in administration time or dosage from the protocol), it is necessary for the investigator to
record them in the source documents and eCRF. These deviations should serve as the basis for
assessing the medication compliance. Before locking the database for statistical analysis, the
principal investigator and statistical experts should decide on a case-by-case basis whether to
include the data in the data analysis and to which data set they belong.
6. Study Procedure
6.1 Treatment Period (D1 to D28; V1 to V3)
V1 (D1):
• Signing the informed consent form;
• Assessment based on inclusion and exclusion criteria;
• Demographic data collection, including initials, sex, date of birth, ethnicity, height, weight,
education level, etc.;
• Recording of the relevant medical history, including history of present illness, past history
(including dementia/cognitive dysfunction, depression, etc.), medication history, allergy
history, smoking history, history of alcohol consumption, etc.;
• Vital signs, including body temperature, blood pressure, pulse, and respiratory rate;
• Physical examination, including general condition, head, face, skin, lymph nodes, eyes, ears,
nose, throat, mouth, respiratory system, cardiovascular system, abdomen, muscles, bones, and
nervous system;
• 12-lead electrocardiogram (ECG);
• Laboratory tests: Blood routine, blood biochemistry, coagulation function, urine routine, etc.;
• Head CT or MRI scanning (T1, T2, FLAIR, and DWI + ADC);
• Blood or urine pregnancy test (for pre-menopausal women only);
• Randomization;
• Hospitalization;
• Distribution of investigational drugs: Distribution of investigational drugs of day 1 to day 7;
• mRS score;
• NIHSS score;

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• BI score;
• Recording concomitant therapies and drugs;
• Collection and evaluation of adverse events.
V2 (D7):
• Vital sign examination;
• Physical examination;
• 12-lead ECG;
• Laboratory tests: Blood routine, blood biochemistry, coagulation function, urine routine, etc.;
• Distribution of investigational drugs: Distribution of investigational drug for the period until
the next visit;
• Distribution of subject diary cards: Distribution of subject diary cards required at the next visit;
• mRS score;
• NIHSS score;
• BI score;
• MoCA score: Completing baseline assessment within 7 days (including day 7) after enrollment;
• HDRS score: Completing baseline assessment within 7 days (including day 7) after enrollment;
• Record concomitant therapies and concomitant drugs;
• Collection and evaluation of adverse events.
V3 (D28 + 3):
• Vital sign examination;
• Physical examination;
• 12-lead ECG;
• Laboratory tests: blood routine, blood biochemistry, coagulation function, urine routine, etc.;
• Head MRI scanning: selecting some eligible sites to perform post-stroke head MRI scanning
(T1, T2, and FLAIR);
• Return of investigational drugs: subjects returning unused drugs and/or empty packages to
investigators;
• Collection and assessment of subject diary cards: subjects submitting completed diary cards to
investigators for assessment;
• Distribution of subject diary cards: Distribution of subject diary cards required for the next
return visit;
• mRS score;
• NIHSS score;
• BI score;

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• MoCA score;
• HDRS score;
• Recording concomitant therapies and drugs;
• Collection and evaluation of adverse events.
Note:
1. V1 should be conducted during this episode prior to the first administration of the treatment.
2. If the subject has completed some protocol-required examinations (e.g., physical examination,
12-lead ECG, laboratory tests, and blood or urine pregnancy tests) at the site within 24 hours
of admission, and the investigator deems these examinations sufficient to support the screening
of the subject, they may not be repeated. This consideration is based on the potential health
risks associated with conducting these examinations in a short time, which could also
significantly impact the subject's treatment schedule.
3. Selected sites with specific medical conditions will conduct head MRI scans on Day 2 and Day
5 (including T1, T2, FLAIR, and DWI + ADC) and on Day 28 + 3 (T1, T2, and FLAIR). It is
expected to collect MRI data from approximately 75% of all subjects and perform centralized
reading to compare changes in MRI variables (infarct volume and area). If a participant
undergoes an MRI scan on Day 1, the MRI scan on Day 2 can be skipped and only the
remaining MRI tests are required.
4. Dosing regimen during the treatment period: Subjects in the TTYP01 group or control group
are orally administrated with two TTYP01 tablets (edaravone 30 mg per tablet) or two placebo
tablets (edaravone 0 mg per tablet) twice daily for consecutive 28 days (56 times in total),
respectively. The first dose should be given within 1 hour after randomization and remaining
doses should be administrated within 30–60 minutes before breakfast or dinner. In case of
postprandial randomization, the second dose should not be earlier than 6 hours after the first
dose.
6.2 Follow-up Period (D29–D90; V4–V5)
V4 (D60 ± 5, telephone visit):
• mRS score;
• Recording concomitant therapies and concomitant drugs;
• Collection and evaluation of adverse events.
Note:
The investigator will record the telephone visiting for the subject or his/her guardian on Day 60 ±
5.
V5 (D90 ± 5, returning to hospital for End-of-Study visit):

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• Vital sign examination;
• Physical examination;
• 12-lead ECG;
• Laboratory tests: Blood routine, blood biochemistry, coagulation function, urine routine, etc.;
• Blood or urine pregnancy tests (pre-menopausal women only);
• mRS score;
• NIHSS score;
• BI score;
• MoCA score;
• HDRS score;
• Collection and assessment of subject diary cards: Subjects submitting completed diary cards to
the investigator for the assessment;
• Recording concomitant therapies and concomitant drugs;
• Collection and evaluation of adverse events.
Note:
Efficacy and safety data for early withdrawal subjects are collected as much as possible by
performing the same processes and examination items as V5.
7. Study Evaluation
7.1 Efficacy Evaluation
7.1.1 Primary Outcome Measure
Proportion of subjects with mRS score ≤1 on Day 90 after stroke onset.
7.1.2 Secondary Outcome Measure
(1) mRS score on day 90 after stroke onset;
(2) Proportion of patients with a mRS score ≤2 on Day 90 after stroke onset;
(3) Changes from baseline in mRS score on Day 7, 28, 60, and 90 after stroke onset;
(4) Proportion of patients with an improvement of ≥4 in NIHSS score on Day 7, 28, and 90 after
stroke onset;
(5) Proportion of patients with a NIHSS score of 0–1 on Day 7, 28, and 90 after stroke onset;
(6) Changes from baseline in NIHSS score on Day 7, 28, and 90 after stroke onset;
(7) Proportion of patients with Barthel Index (BI) score ≥95 on Day 7, 28, and 90 after stroke
onset;
(8) Changes from baseline in BI score on Day 7, 28, and 90 after stroke onset;

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(9) MoCA score on Day 7, 28, and 90 after stroke onset;
(10) HDRS score on Day 7, 28, and 90 after stroke onset;
(11) Changes from baseline in brain MRI variables (e.g., infarct volume and area) on Day 5 and
28 after stroke onset.
7.2 Safety Evaluation
Safety endpoints include the occurrence of adverse events (AEs) from the start of study to the end
of follow-up period, including treatment-emergent adverse events (TEAEs), adverse drug reactions
(ADRs), serious adverse events (SAEs), and TEAEs leading to subject termination from the trial.
(1) Proportion of all-cause deaths within 90 days after stroke onset;
(2) Proportion of symptomatic intracranial hemorrhages within 90 days after stroke onset;
(3) Proportion of recurrent ischemic strokes within 90 days after stroke onset;
(4) Proportion of AEs within 90 days after stroke onset;
(5) Proportion of SAEs within 90 days after stroke onset;
(6) Discontinuation due to any AE within 90 days after stroke onset;
(7) Discontinuation due to any other non-AE within 90 days after stroke onset.
8. Adverse Event
8.1 Definition
8.1.1 Adverse event
An AE refers to any adverse medical event that occurs after the subject in the trial receives the
investigational drug. An AE does not necessarily have a causal relationship with the treatment. AEs
include adverse, abnormal signs (including abnormal tests, examination findings), symptoms or
illnesses that are temporally related to the use of the (experimental) medication, whether or not they
are related to the (experimental) medication. An AE can therefore be a new occurrence, an
exacerbation or an increase in frequency of the underlying diseases, or the exacerbation of an
abnormal diagnostic test result including an abnormal laboratory value, etc.
Medical events that occur after signing informed consent should be collected and recorded.
Medical events that occur after signing the informed consent form and before the first dose of
investigational drugs are recorded in the eCRF as medical history/concomitant illnesses and are not
recorded as AEs, unless they are relevant to the screening process.
For abnormal test results, the following criteria should be used to determine whether an abnormal
laboratory test result should be reported as an AE:
(1) Symptoms accompanied with the test result, and/or;
(2) Test results requires further diagnostic testing or medical/surgical intervention, and/or;

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(3) Test results lead to the dosage modification of the investigational drug (beyond the protocol-
specified dosage) or;
(4) In the opinion of the investigator or sponsor, the test results constitute an AE.
The repetition of abnormal tests alone does not constitute an AE if it does not meet any of the
above criteria. Test results reported in error do not need to be reported as AEs.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be
reported as AEs. However, the disease for which the procedure be performed meets the definition of
an AE, it should be reported as an AE. For example, acute appendicitis that occurs during the AE
reporting period should be reported as an AE, and appendectomy performed to treat the condition
should be recorded as the treatment for the AE.
8.1.2 Serious adverse event
Serious adverse event (SAE) refers to adverse medical events such as death, life-threatening (refer
to those in which the subject is at immediate risk of death at the time of the event, rather than
indicating a potential risk of death in more severe situations), permanent or severe disability or loss
of function, the condition that causes the subject to be hospitalized or to prolong the hospitalization,
and congenital abnormalities or birth defects after the subject receives the investigational drug.
Significant Adverse Event: Significant haematological and other laboratory abnormalities (except
for SAE) and any event leading to the intervention, including cessation of trial/investigational
product treatment, dose reduction, or important other concomitant treatment, except those reported
as SAE.
Other important medical events: Medical and scientific judgment must be exercised in deciding
whether expedited reporting in other situations, such as important medical events may not be
immediately life-threatening, death, or hospitalization but may also be considered serious if medical
treatments is needed to prevent one of the situations listed above. Examples include the intensive
treatment in an emergency room, allergic bronchospasm or convulsions occurring at home, a
development of drug dependency or addiction, etc.
(1) Unlisted (unexpected) adverse event/reference safety information
For investigational drugs, the expectation of an AE will be judged based on whether or not it is
listed in the Investigator’s Brochure.
The following conditions are not considered hospitalizations or SAEs: Hospital observation for
less than 24 hours; hospitalization for routine examinations (hospitalization for less than 24 hours);
hospitalization due to social reasons (such as lack of caregiver support); hospitalization for
scheduled surgery agreed upon prior to the study; hospitalization for a pre-existing condition that is
not associated with a new AE or exacerbation of a pre-existing adverse condition (e.g., examination

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of persistent pre-treatment laboratory abnormalities); pre-planned treatment or surgery for the entire
study protocol and/or for an individual subject should be recorded in the baseline documentation;
hospitalization or prolongation of hospitalization as required by the protocol, such as hospitalization
for dosing or completion of protocol-required examinations does not qualify as an AE.
(2) Serious adverse event start time
The onset date of the AE upgraded to SAE is taken as the start time of the SAE.
(3) Serious adverse event end time
The end time of the AE is considered to be that the AE is resolved, stabilized, and reasonably
explained. The time shall be as exact as date, month and year, or as month and year if the
information is not collected completely. If the AE is judged to have caused “death” directly or as
the primary cause, the end time is the time of the subject’s death.
8.1.3 Suspected unexpected serious adverse reaction
The suspected unexpected serious adverse reaction (SUSAR) refer to suspected and unexpected
serious adverse reactions whose clinical manifestations in terms of nature and severity exceed the
existing information such as the Investigator’s Brochure of the investigational drug, the instructions
of the marketed drug, or the summary of product characteristics.
8.2 Risk of drug use
According to the Investigator’s Brochure and previous reports on edaravone injection, the following
AEs are classified as identified or potential risks during the trial.
It mainly includes acute renal failure (unspecified degree), abnormal hepatic function, jaundice
(unspecified
degree),
thrombocytopaenia
(unspecified
degree),
disseminated
intravascular
coagulation (DIC) (unspecified degree).
8.2.1 Acute renal failure (unspecified degree)
During the study, if a subject’s serum Cr, eGFR and other renal indicators increase to different
degrees in a short period (refer to RIFLE or AKIN criteria), acute kidney injury or renal failure is
very likely to occur, and the drug should be stopped immediately. According to the severity, the
investigator should promptly give targeted standard medical treatment and symptomatic treatment
as per the operation process of the hospital, and closely monitor the renal function and its outcome
through serum creatinine and urine output.
8.2.2 Abnormal hepatic function, jaundice (all unspecified degree)
Drug induced liver injury (DILI) refers to the direct or indirect liver damage to different degrees
caused by the drug itself or its metabolites during the use of drugs within the range of doses in
normal therapy or clinical trials.
During the trial, if a subject is accompanied by abnormal liver function such as increase of AST,

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ALT, ALP, γ-GTP and/or LDH, and jaundice, or even gastrointestinal symptoms such as asthenia,
decreased appetite, oil anorexia, distending pain in the liver area and epigastric discomfort, it is very
likely that acute liver injury occurs, and the investigational drug dose should be immediately
stopped or reduced. The investigator should promptly give targeted standard medical treatment and
symptomatic treatment according to the severity of liver injury as per the operation process of the
hospital, and closely monitor the outcome of the liver injury.
8.2.3 Thrombocytopenia (unspecified degree)
Thrombocytopenia (unspecified degree) is associated with a decreased platelet count. Close
observation should be made during the administration course of the investigational drug. It should
to stop the adiministration of the investigational drug and treat it properly in case of abnormal
conditions.
8.2.4 Disseminated intravascular coagulation (DIC) (unspecified degree)
There may be manifestations of disseminated intravascular coagulation. It should be detected
regularly during the administration course of the investigational drug. If laboratory tests and clinical
symptoms suspected of disseminated intravascular coagulation occur, the investigational drug
should be stopped and proper treatment should be given.
8.3 Observation and recording of adverse events
All adverse events spontaneously reported by subjects or elicited in response to open-ended
questions by the investigator,"Since your last visit/or since last question, have you experienced any
health problems?", should be collected and recorded in the eCRF, as well as adverse events
identified through observation. The details of the adverse events should be specifically documented,
including the starting time , severity, ending time, intervention, and outcome.
When collecting adverse event data, it is preferable to record the diagnosis (if possible) rather
than the series of signs and symptoms, i.e., the name of the adverse event should be the medical
terminology and the medical diagnosis should be used in preference. However, if a diagnosis is
known but the patient still has other signs or symptoms that do not match the diagnosis, each sign or
symptom should be recorded respectively. If the laboratory test abnormality is part of the syndrome,
the syndrome or medical diagnosis should be recorded (e.g., anemia with decreased hemoglobin
should be recorded as “anemia” rather than “hemoglobin decreased” alone).
8.3.1 Follow-up of adverse events
When an AE occurs to a subject during the trial, the clinician shall take necessary treatment
measures according to the specific situation, and notify the sponsor if necessary. The investigator
will follow the AEs that have occurred, and follow up the AEs that have not resolved after the end
of the trial until the event has resolved, stabilized, or until there is a reasonable explanation, or until

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no further follow-up is required as judged by the investigator, or the subject is lost to follow-up, or
the subject withdraws from the trial early. The treatment process, follow-up data, and outcome
(including recovery, improvement, persistence, aggravation, and death) should be fully recorded in
the study medical record and eCRF, and the relevant examination report should be attached.
The sponsor reserves the right to request further information, if necessary, from any subject
regarding an ongoing AE/SAE after the end of the trial.
(1) Follow-up endpoints
A subject treated with investigational drug will need to be followed if:
(1) The subject has been followed up as per protocol until day 90 ± 5 after stroke onset;
(2) The subject is dead during the follow-up;
(3) Serious deviations of the inclusion/exclusion criteria are found after enrollment, and follow-
up termination is deemed necessary by both the investigator and sponsor;
(4) The subject withdraws from the trial due to various reasons, and the follow-up endpoint is the
last visit time;
(5) The subject needs to be withdrawn from the clinical trial at the discretion of the investigator,
and the follow-up endpoint is the last visit time.
(2) Post-trial events
After the subject’s final visit or the permanent discontinuation from the trial, the investigator is no
longer obligated to actively inform the subject of any new AEs or SAEs that occur after the safety
follow-up. However, if the investigator learns of any SAE (including death) in a subject after the
subject has been permanently discontinued from the study, and there is a reasonable possibility that
the event is related to the investigational drug, the investigator should notify the sponsor’s
pharmacovigilance team or representative.
(3) Variables
The following variables will be collected for each AE:
(1) AE term (verbatim);
(2) Starting and ending dates;
(3) Common terminology criteria for adverse events (CTCAE) classification;
(4) Whether it constitutes a SAE;
(5) Investigator’s assessment of causal relationship between the AE and investigational drug;
(6) Action taken to the investigational drug;
(7) Treatment of the AE;
(8) Outcomes.
8.4 Adverse event assessment

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8.4.1 Judgment for the severity of adverse events
Attention should be paid to distinguishing between SAE and the severity of AE. According to the
definition of SAE, AEs that are severe in severity do not necessarily have to be SAEs. For example,
vomiting lasting several hours may be considered severe vomiting but not a SAE. A stroke that
results in only minor functional impairment may be considered a mild stroke but is a SAE.
The investigator should assess the severity of each AE and SAE reported during the trial. AEs
and SAEs should be assessed and graded according to NCI-CTCAE v5.0.
For adverse events not included in the criteria, refer to the following criteria:
Grade
Expression
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not
indicated;
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting ageappropriate instrumental
activities of daily living (ADL) (refer to preparing meals,shopping for groceries or clothes, using
thetelephone, managing money, etc.).
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of
hospitalization indicated; disabling; limiting self care ADL (refer to bathing, dressing andundressing,
feeding self, using the toilet, taking medications, and not bedridden).
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE.
Note: The semicolon (;) used in the description of the grade refers to “or”.
8.4.2 Determination of the causal relationship of adverse events to the investigational drug
8.4.2.1 Judgment basis of adverse event causality:
(1) Whether there is a reasonable temporal relationship between the initiation of the drug and the
occurrence of the suspected AEs;
(2) Whether the suspected adverse event is consistent with the type of known AEs of the
investigational drug;
(3) Whether the suspected AEs can be explained by the effects of concomitant medication, the
clinical condition of the patient or the influence of other therapies;
(4) Whether the suspected AE disappeared or abated after discontinuation or dose reduction;
(5) Whether the same reaction occurs again after exposure to suspected drugs.
8.4.2.2 Criteria for causality determination:
Make judgment according to the above 5 judgment indexes.
Judgment result
Judgment index
1
2
3
4
5
Definitely related
+
+
–
+
+
Probably related
+
+
–
+
？
Possibly related
+
+
±
±
？
Possibly unrelated
+
–
±
±
？
Not related
+
–
+
–
–
Description: + positive, – negative, ± hard to confirm positive or negative, and ? unknown situation.
According to the above table, the relationship of the following Grade 5 adverse events to the drug is judged:
Where “definitely related”, “probably related” and “possibly related” are summed as the numerator for

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adverse reaction incidence calculation, and the denominator is the total number of subjects used for safety
evaluation.
Note: The judgment of the relationship between adverse events and drug is the result of individual judgment
of the investigator. When summarizing safety data in the clinical trial, the principal investigator should also
make a general judgment according to the composition of the formulation, the results of non-clinical safety
studies, the frequency, severity, trend of adverse events, and the occurrence of adverse events in the control
group.
8.5 Subject risk control measures
Strengthen the informed consent, fully inform the subjects of the possible risks of using the drug,
especially the SAEs that may exist when using the drug at a high dose, and ensure that the subject is
informed fully and voluntarily signs the informed consent form.
For the important risk events of possible adverse reactions, the medical personnel shall be trained
according to the corresponding treatment methods specified by the clinical study unit, and the
facilities and equipment, including medical personnel and drugs required for emergency treatment
of the above-mentioned serious adverse events are available in the hospital. The first-aid treatment
and medical care conditions of the hospital should be evaluated typically in the selection of the
research unit. In case of serious adverse events, the principal investigator should participate in the
treatment and make medical treatment decisions, and contact experts in other medical departments
for consultation and treatment if necessary.
Investigators shall closely observe and strictly record all adverse events during the study. For
SAE meeting the requirements of laws and regulations, the sponsor shall be notified and reported in
a timely manner, and then detailed and written follow-up reports shall be provided in a timely
manner. The sponsor shall strengthen the collection and analysis of adverse events through
investigators and monitors, identify suspected and unexpected serious adverse reactions (SUSARs)
and submit them according to regulatory requirements; conduct summary analysis on the safety data
of the investigational product on a regular basis, and submit a safety update report to the Center for
Drug Evaluation (CDE) of the NMPA once a year according to regulatory requirements.
Strengthen the follow-up management of subjects, and strengthen the contact for subjects who
withdraw or drop out due to AEs, and correctly complete the corresponding last follow-up content.
In view of the risks of the clinical trial, in order to protect the rights and interests of the subjects,
and to provide timely treatment and handling during the trial due to AEs or SAEs, as well as
reasonable compensation or indemnity, the sponsor will purchase clinical trial liability insurance
covering each subject participating in the clinical trial.
8.6 Reporting procedure
8.6.1 Reporting procedures of serious adverse events
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other documents (such as the Investigator’s Brochure), the investigator shall report all SAEs to the
sponsor (or authorized representative) in writing within 24 hours after learning of the SAE, and then
provide a detailed and written follow-up report in a timely manner. SAE reports and follow-up
reports should indicate the identification code of the subject in the clinical trial, instead of the
subject’s real name, resident ID number, address and other identification information. The time
limit of follow-up report is the same as that of the first report. AEs and abnormal laboratory values
deemed important for safety evaluation, as specified in the trial protocol, should be reported to the
sponsor according to the requirements and time limits outlined in the trial protocol.
For reports involving deaths, the investigator should provide the sponsor and EC with other
required materials, such as autopsy reports and final medical reports.
For all SAEs occurring during the clinical trial, whether in initial or follow-up report, the
investigator must complete the “Serious Adverse Event Report Form” provided by the sponsor, sign
and date it. In the source documents, it should be documented when, how, and to whom the SAEs
be reported.
When reporting an SAE, the following points should be noted:
(1) Potential diagnoses or syndromes should be reported as the primary SAE term rather than
signs or symptoms (signs and symptoms may be described in the narrative).
(2) The event term of “death” should not be reported as an SAE but should be recorded as a result
of the specific SAE term. The event term “death” may be used initially until the actual cause of
death is known. If an autopsy is performed, an autopsy report should be provided.
8.6.2 Reporting procedure for SUSARs
Upon receipt of safety-related information from any source, the sponsor should promptly analyze
and assess it, including severity, relevance to the investigational drug, and whether it is an expected
event. The sponsor shall promptly report suspected and unexpected serious adverse reactions to all
investigators participating in the clinical trial, clinical trial institutions and EC; the sponsor shall
report suspected and unexpected serious adverse reactions to the drug regulatory authorities and the
competent health authorities.
The sponsor shall report to CDE as soon as possible upon first learning about the SUSAR. For
fatal or life-threatening unexpected serious adverse reactions, the report should be reported within 7
days, with follow-up information completion within the subsequent 8 days. For non-fatal or non-
life-threatening unexpected serious adverse reactions, the report should be submitted within 15 days.
The investigator should sign the SUSAR provided by the sponsor and report it to the EC.
The contact information for reporting SUSARs is as following table.
Suspected unexpected serious adverse reactions (SUSAR) reporting unit

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Unit
Contact person
Contact
number
Fax/email
Sponsor: Suzhou Auzone Biological
Technology Co., Ltd.
Hou Xiaolong
15895583778
houxl@szauzone.com
CRO: Guoxin Pharmaceutical Technology
(Beijing) Co., Ltd.
Pharmacovigilance
Center
15201580570
pv@gxcro.com
National Health Commission
010-68792201
saefax@163.com
Center for Drug Evaluation (CDE) NMPA
010-68585566
010-68584181
Note: Center for Drug Evaluation (CDE) NMPA
Address: No. 128, Jianguo Road, Chaoyang District, Beijing, Tel: 010-68585566
8.6.3 Reporting procedures for development safety update reports (DSURs)
The sponsor shall submit the drug development safety update report to CDE on a regular basis
(annually) according to relevant regulatory requirements. The drug development safety update
report provided by the sponsor shall include the assessment of the risks and benefits of the clinical
trial, and relevant information should be informed to all investigators participating in the clinical
trial, clinical trial institutions, and EC.
Note: Provided that the GCP requirements are met, the reporting procedures for SAEs, SUSARs,
and DSURs can be adjusted and implemented according to the safety event reporting requirements
of different sites.
8.6.4 Reporting of pregnancy
If pregnancy occurs in a female subject or female partner of a male subject during the trial, the
investigator should immediately discontinue the subject from the clinical trial and discontinue the
administraction of the investigational drug. The investigator should communicate scientifically and
rigorously with the subject based on the medication information, inform the subject of the possible
effects and risks of the investigational drug on the pregnant woman and fetus, and decide whether to
terminate the pregnancy or continue the pregnancy at the subject's discretion.
Within 24 hours after the occurrence of the confirmed pregnancy, the investigator should fill out
the Pregnancy Report Form upon discovery of the pregnancy, and report to the sponsor (or
authorized representative), drug clinical trial institution and the EC of the hospital within 24 hours,
and record it in the eCRF (if necessary). Pregnancy itself is not considered to be an AE or SAE, but
any complicated situation that occurs during the course of a pregnancy or situations where
pregnancy is terminated for medical reasons will be recorded, reported, and followed up as
specified in the protocol as “adverse event” or “serious adverse event”. If the outcome of the
pregnancy meets the criteria for an SAE, such as spontaneous abortion (including threatened
abortion, inevitable abortion, incomplete abortion, complete abortion, missed abortion, etc.),
stillbirth, neonatal death, or congenital anomaly, the investigator should report it according to the
SAE reporting procedure.
If the subject decides to continue the pregnancy, follow-up is required until the end of the

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pregnancy or for three months post-delivery. The investigator shall complete the pregnancy follow-
up report within 24 hours of each follow-up pregnancy and report to the sponsor, drug clinical trial
institution and the EC of the hospital.
All neonatal deaths that occur within one month of life, regardless of the cause of death, should
be reported as SAE. In addition, any infant death after one month of life should also be reported if
the investigator considers the death to be possibly related to the investigational product.
8.6.5 About lack of efficacy
Lack of efficacy per se cannot be reported as an adverse event and any symptoms/signs or sequelae
resulting from lack of efficacy should only be reported if they meet the criteria for an adverse
event/serious adverse event.
8.6.6 Independent Data Monitoring Committee
One interim analysis will be planned to be conducted at the timing of 50% subjects complete the
trial. Independent Data Monitoring Committee (IDMC) will be established for the assurance of
patient safety and trial integrity and monitoring the effectiveness data. The purpose of IDMC,
IDMC members and their responsibilities, meeting frequency and etc. will be described in the
IDMC Charter.
8.7 Risk control measures for protocol deviations
Strengthen the implementation of the protocol, report the protocol deviation to the EC in time and
strengthen the training for investigators. In case of adverse events, priority should be given to the
rights and safety of the subjects in the treatment. If necessary, deviation from the protocol is
allowed for treatment. For critical procedures such as drug administration, dedicated Standard
Operating Procedures (SOPs) should be developed, and relevant personnel should receive necessary
training to ensure proper execution without deviations, thereby ensuring the scientific integrity of
the protocol implementation.
Strengthen the training and authorization of researchers, especially drug management, to ensure
that special personnel are responsible for each link and provide original records of any one link.
Any change involving the investigator during the study shall be timely trained and authorized
before participating in the clinical trial.
In order to ensure the quality of drugs, a professional cold chain transportation company is
responsible for the whole transportation of drugs and provides temperature records throughout the
process. During the storage period at the study site, the drug should be stored according to the drug
storage conditions, and if necessary, a drug refrigerator meeting the storage conditions should be
provided. Drug management shall be managed by a specially-assigned person.
9. Data Management and Statistical Analyses

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9.1 Data management
Electronic data management is used for this trial. The main data management processes are listed
below, and other details are detailed in the Data Management Plan (DMP).
As a guidance document for data management, the DMP is written by the data manager (DM)
and approved by the sponsor. The data management will be conducted according to the timing,
content and methods defined in the DMP.
9.1.1 Data management of EDC
Electronic Case Report Form (eCRF): The data manager designs and constructs the eCRF
according to the trial protocol, sets up logical checks based on the Data Validation Plan (DVP),
and releases it for use after testing and sponsor approval.
Data entry: The eCRF data are derived from the source records. The data entry personnel
inputs the subject visit data into EDC in a timely manner according to the eCRF completion
instructions.
Source data verification (SDV): The monitor performs the consistency verification between
eCRF data and source data, and can raise questions if any issues are identified.
Data query and solution: The queries come from the system query generated by EDC logic
check, as well as manual queries from monitor, data manager, etc., and the investigator needs
to answer the questions in time. Data managers and monitors review and respond to queries,
and if necessary, additional queries may be issued until the data is free of discrepancies.
Investigator’s signature: After the data entry is completed and SDV is performed, the
investigator will conduct an electronic signature review and confirmation. After signing, any
data revisions require re-signing.
Database lock: After the principal investigator, sponsor, statistical analysis personnel and data
management personnel jointly sign the database lock application, the data manager will lock
the database.
Database submission: the data manager submits the database to the statistician.
eCRF archiving: A PDF electronic file will be generated for each subject’s eCRF.
EDC closure: After the statistical analysis is completed, the data manager closes the database.
9.1.2 External data transfer
External data transfer agreements will be developed and external data management will be
performed according to the DMP.
9.1.3 Medical coding
Adverse events will be coded using MedDRA (version 26.0 or higher) and concomitant medications
will be coded using WHODD (V2022 SEP or above).

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9.2 Statistical analyses
9.2.1 Statistical hypotheses
The following hypothesis will be tested for the primary efficacy endpoint:

Null hypothesis (H0): PTTYP01 - Pplacebo ≤0

Alternative hypothesis (H1): PTTYP01 - Pplacebo > 0,
P: proportion of subjects who achieved mRS ≤1 on Day 90.
No formal hypothesis tests will be set up for the secondary efficacy endpoints; all the secondary
efficacy endpoints will be just used to provide supportive evidence, and therefore, no adjustments
for multiplicity will be made.
9.2.2 Sample size determination
A sample size of 274 subjects per each treatment group (total of 548 subjects) will provide at least
90% power to detect a difference of 15% (60% in the TTYP01 group versus 45% in the placebo
group) for the primary endpoint the proportion of subjects who achieved mRS ≤1 on Day 90 with a
one-sided α value of 0.025. Assuming drop-out rate of ~20%, 618 subjects (309 in each group) will
be planned to be enrolled for the trial.
9.2.3 General considerations
All statistical analyses will be performed using SAS version 9.4 or above. Detailed statistical
methods will be described in the SAP and finalized prior to database lock.
In general, all study data will be pooled and summarized/analyzed by treatment group: descriptive
statistics (n, mean, median, first quartile (Q1), third quartile (Q3), standard deviation, minimum and
maximum values) will be used for continuous variables; categorical variables will be described
using frequency tables (frequencies and percentages).
All statistical hypothesis tests will use a 2-sided test at α = 0.05 and two-sided 95% confidence
intervals (CIs) will be calculated, unless otherwise specified.
9.2.4 Analysis sets
(1) Full analysis set (FAS): FAS will included all the randomized subjects who receive at least one
dose of investigational drug and who have at least one post-dose primary efficacy assessment
(i.e., mRS).
(2) Per-protocol set (PPS): As the subset of FAS, PPS will include all the subjects who have the
primary efficacy endpoint available on D90, with treatment compliance of 80% to 120% and
who have no major protocol deviations affecting the primary efficacy assessment (e.g. not
meeting important inclusion criteria, use of prohibited medications impacting the primary
efficacy outcomes during the trial).
(3) Safety set (SS): SS will include all the subjects who receive at least one dose of investigational

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drug.
9.2.5 Subject disposition
A summary of the number and percentage of subjects who completed/discontinued study will be
presented respectively by treatment group along with the primary reasons for study withdrawal. In
addition, the number and percentage of subjects included in each analysis set will be presented.
9.2.6 Demographic and baseline characteristics
Demographic data (Age and Age Group (<65, ≥65), Race, Gender, Height, Weight, Body Mass
Index (BMI)) will be analyzed with descriptive statistics as appropriate, respectively. In addition,
baseline disease characteristics including AIS history, time from onset of AIS to treatment, baseline
NIHSS, concomitant illness with AIS (hypertension, diabetes, hyperlipidemia and cardiac disease),
alcohol history, smoking history and etc. will be also summarized.
9.2.7 Extent of exposure and treatment compliance
A descriptive summary of total exposure duration (days), total exposure amount (tablets), and
treatment compliance (%) will be provided:

Exposure duration (days) = date of last dose of study drug - date of first dose of study drug + 1;

Exposure amount = actual total cumulative dose;

Treatment compliance = actual total dose/study planned dose × 100%; planned dose will be
calculated as 28 * 2 * 2 = 112 tablets.
The number of subjects with treatment compliance as <80%, 80% to 120%, >120% will be also
tabulated.
9.2.8 Efficacy analyses
9.2.8.1 Primary efficacy endpoint
The number and percentage of subjects achieving mRS≤1 on Day 90 and the corresponding 95% CI
will be summarized (Clopper-Pearson interval) by treatment group. The treatment group difference
between TTYP01 and placebo group will be tested using Chi-square test, and the 95% CI of the
difference will be estimated. In addition, odds ratio (OR) with the 95% CI as well as p-value will be
also reported using logistic regression. Multiple imputation will be used to account for missing
mRS; Death will be scored as 6 in mRS and thus there will be no missing mRS values due to death.
If the data are applicable, supplementary or sensitivity analyses will be performed to assess the
robustness of the primary analysis results.
Further more, subgroup analyses will be conducted based on the demographic and baseline
characteristics of subjects as applicable.
9.2.8.2 Secondary efficacy endpoints
The shift in Day 90 mRS as a 6-category ordinal scale will be analysed using ordinal logistic

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regression, common OR, the associated 95% CI as well as the p-value will be reported. Similar
statistical methods as the primary endpoint will be applied for binary secondary endpoints including
mRS ≤2 on Day 90, NIHSS improvement ≥4 or NIHSS ≤1 on Day 7, 28 and 90 and etc. For the
continuous secondary outcomes such as change in NIHSS from baseline, the least-square mean
differences with 95% CI between treatment groups will be estimated by analysis of covariance
(ANCOVA) or analysis of variance (ANOVA) as appropriate.
9.2.9 Safety analyses
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA). AE analysis will
be based on TEAE. Based on SS, the number and percentage of subjects in each treatment group
with overall and various types of TEAEs including all TEAEs, all ADRs, CTCAE grade ≥3
TEAEs/ADRs, SAEs, serious ADRs, TEAEs/ADRs that leading to treatment discontinuation will
be counted and also summarized by System Organ Class (SOC) and Preferred Term (PT),
respectively.
The proportions of all AEs, symptomatic intracranial hemorrhage, recurrent symptomatic stroke
(cerebral infarction), all-cause mortality, serious adverse events, discontinuation due to any adverse
event and etc. and the corresponding 95% CI will be summarized by treatment group. The relative
risk of the treatment group compared to the control group and the associated 95% CI will be also
reported.
Cross-tabulation tables before and after treatment will be provided to analyze the post-treatment
changes in the laboratory tests, 12-lead ECG, and other applicable safety parameters. Vital signs
and the changes from baseline will be analyzed using descriptive statistics by treatment group.
9.2.10 Interim analysis
An interim analysis will be planned at the timing of 50% subjects complete D90 or early terminate,
whichever occurs first, for the assurance of patient safety and trial integrity and monitoring the
effectiveness data. To maintain an overall one-sided α of 0.025, the α-spending function to
approximate O'Brien-Fleming will be implemented.
The interim analysis will be monitored by Independent Data Monitoring Committee (IDMC). The
purpose of IDMC, IDMC members and their responsibilities, meeting frequency and etc. will be
described in the IDMC Charter.
10. Quality control and quality assurance
10.1 Clinical monitoring
In accordance with relevant regulations, GCP, and sponsor procedures, the sponsor has
commissioned a CRO to perform all monitoring activities for this clinical study. Monitors will work
according to SOPs established by the sponsor or CRO, and CRO monitors will have the same rights

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and responsibilities as sponsor monitors. The monitor will establish and maintain regular contact
between the investigator and the sponsor.
At the time of contact, the monitor will:
Check the progress of the trial;
Review the collected data;
Perform source document verification;
Identify and resolve the issues.
This is to confirm that:
The data are authentic, accurate, and complete;
The safety and rights of the subjects are protected;
The study is conducted in compliance with the currently approved protocol (and any
supplements), GCP, and all relevant regulatory requirements;
The investigator agrees to allow the monitor to check all relevant documents directly and
arranges personal and staff time to discuss findings and all relevant issues with the monitor.
10.2 Audit
The audit shall be conducted by relevant personnel not directly involved in this trial. When the
relevant personnel conduct the audit, the trial site must timely provide the materials to be inspected.
10.3 Quality assurance of the clinical trial process
To ensure the quality of the trial, a clinical study protocol will be jointly discussed and prepared by
the sponsor and the investigators before the formal start of the trial. Before the start of the clinical
trial, the investigator should carry out the training of the trial protocol to have a full understanding
and awareness of the clinical trial protocol. GCP training is required for all relevant study personnel
participating in the trial. During the trial, the investigator should carefully perform clinical
operations and other work in accordance with the institutional SOPs and trial protocol requirements,
and record it in a true, timely, complete and standardized manner. Quality control personnel shall
check the basic conditions of the clinical trial to ensure that the conditions of clinical trial can meet
the requirements of the protocol. Quality control personnel conduct quality checks on the trial
process and corresponding source records. After the trial, the study unit sorts out the corresponding
project documents, and archives them after checking by the quality control personnel. The quality
assurance department of the clinical research unit performs quality control on the implementation of
the test. When non-conformities are identified, the investigator and the head of the unit for
correction ahould be notified promptly and the status of the correction should be tracked.
Each site must manage investigational drug according to SOPs, including receipt, storage,
dispensing, retrieval, and destruction, as applicable. In accordance with GCP guidelines, necessary

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steps will be taken during the design and implement of the study to ensure that the data collected are
accurate, consistent, complete, and credible. All observed results and abnormal findings in the
clinical trial should be verified and recorded in a timely manner to ensure the reliability of the data.
The instruments, equipment, reagents, standards, etc. used for various inspection items in the
clinical trial shall meet relevant requirements and ensure that they work under normal conditions.
The drug regulatory authorities, Institutional Review Board or Independent EC, monitor and/or
auditor of the sponsor may systematically check the clinical trial related activities and documents to
determine whether the trial is conducted in accordance with the trial protocol, SOPs and relevant
regulations, and whether the trial data are accurate, true and complete.
10.4 Recording and retention of study data
In accordance with the principles of GCP, the investigator should keep all the detailed source
documents of the subjects, including the contents of the trial process, medication administration,
laboratory test data, safety data and efficacy evaluation, and the recorded data should be complete,
timely and clear. Source documents, medical records and other relevant documents should be clear,
detailed and easily identifiable by the personnel participating in the clinical trial.
Any modifications to the original data collection sheet and source data must not obliterate the
source data. The correct modification method is to draw a single line on the original data, and then
write the modified data next to the original data, and sign the date and the name or initials of the
person who modified it.
The sponsor shall keep the clinical trial data related to the sponsor, and other data obtained by
some relevant units participating in the clinical trial shall also be kept in the essential documents of
the clinical trial as sponsor-specific data.
If the principal investigator moves or retires, or ceases to perform his or her study duties, the
sponsor must be notified so that appropriate measures can be taken regarding the trial data.
10.5 Storage, management and archiving of test data
In order to ensure the evaluation and supervision of the clinical trial by the NMPA and the sponsor,
the investigator shall agree to keep the original study data of all subjects participating in the trial,
including the confirmation of the subjects (can effectively check different records, such as eCRF
and original records of the hospital), the original signed informed consent form, and the detailed
records of drug distribution, etc. The paper and electronic documents generated in the clinical study
shall be properly kept to ensure timely traceability, and shall be kept for at least 5 years after the
investigational drug is approved for marketing. All materials of this clinical trial are owned by
Suzhou Auzone Biological Technology Co., Ltd., and the investigator shall not provide to any third
party in any form without the written consent of the sponsor, except as required by the NMPA. If

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otherwise specified in the contract, it shall be executed in accordance with the contract.
11. Ethical and Regulatory Requirements
11.1 GCP and ethical requirements
This trial is conducted in accordance with the Good Clinical Practice (2020), Declaration of
Helsinki, relevant laws and regulations of China, and the opinions of the EC of this drug clinical
trial institution.
Before the start of the trial, the investigator/trial institution should obtain the written approval
opinion from EC of the investigator’s members, investigator’s brochure, trial protocol/protocol
amendment, informed consent form, subject recruitment procedures, etc. During the clinical
investigation, any modifications to the trial protocol and informed consent form must be approved
or documented by the EC. After the end of the trial, the EC should be notified that the trial has
ended.
11.2 Informed consent procedure
The principal investigator at each site will:
Ensure that each subject or his/her guardian is provided with comprehensive information,
orally or in writing, about the nature, purpose, possible risks and benefits of the study;
Ensure that each subject or his/her guardian is informed that he/she may voluntarily
discontinue participation in the study at any time;
Ensure that each subject or his/her guardian is given the opportunity to ask questions and allow
sufficient time to consider the information provided;
Ensure that each subject or his/her guardian provides a signed and dated informed consent
form (ICF) before any study-related procedures are performed;
Ensure that the original signed ICF is maintained in the investigator study file;
Ensure a copy of the signed ICF is provided to the subject;
Ensure that any benefits to the subjects participating in the study as well as harm may occur to
the subject are described in the ICF approved by the EC.
11.3 Protocol deviation
If a protocol deviation occurs, the investigator must inform the monitor and the significance of the
deviation must be reviewed and discussed. Any protocol deviation must be documented either as a
response to a query in the eCRF, or in the protocol violation report, or a combination of both. The
protocol deviation report form will be kept by the sponsor. Protocol deviation reports with
supporting documentation must be retained in the investigator site file.
11.4 Suspension or termination of study/ closure of site
The sponsor reserves the right to close the site or terminate the study at any time for any reason, if

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appropriate. The party suspending or terminating the study shall provide written notification to the
subjects, investigators, and the regulatory authorities of the clinical trial (NMPA, clinical trial
institutions of the investigational site and the EC), and shall record the reasons for the suspension or
termination of the study. If the investigator prematurely terminates or suspends the study, the
principal investigator shall promptly inform the subjects, the EC, and the sponsor with the reason
for the termination or suspension. If applicable, the investigator should contact the subject and
notify the change in the visit schedule. Reasons for suspension or termination of the study/site
closure include, but are not limited to, the following:
(1) Major errors in the clinical trial protocol are found in the trial, making it difficult to evaluate
the drug;
(2) Determination of an unexpected, significant, or unacceptable risk to subjects;
(3) Inability to comply with the requirements of the protocol;
(4) Data are incomplete and/or insufficient for evaluation;
(5) Determination that the primary endpoint has been met;
(6) Due to reasons related to the sponsor itself or changes in national pharmaceutical
development policies;
(7) The request of the drug regulatory authority or EC to terminate an approved study.
The suspension may be temporary or permanent. The study can only resume if issues related to
safety, protocol compliance, and data quality are addressed and meet the requirements of the
sponsor, EC, NMPA. Once the decision is made to terminate/close an investigational site, the
sponsor shall properly handle the relevant matters after terminating/closing the investigational site,
and promptly notify the investigational site, EC or NMPA. After the decision is made to
terminate/close the investigational site, the archived study records specified in GCP shall be
retained for future inspection, and other relevant study materials (including completed, partially
completed and blank study materials and investigational medicinal products, etc.) shall be delivered
to the sponsor according to the relevant requirements in GCP.
11.5 Confidentiality and privacy
The informed consent form may contain elements that comply with relevant data protection and
privacy rights. In some cases, these will be documented in a separate companion document.
Participant privacy will be kept strictly confidential to the investigator, staff involved in the study,
the sponsor and the respective treatments. The protocol, records, data, and all other information
generated will be kept in strict confidence. Study information or data will not be divulged to any
unauthorized third party without the written consent of the sponsor.
All study activities should be conducted in as private a location as possible.

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The study monitor, authorized representatives of the sponsor, representatives of EC, regulatory
authorities, or the pharmaceutical company supplying investigational drug may inspect all
documents and records required to be maintained by the investigator, including, but not limited to,
medical records (clinic, outpatient, or hospital) and drug records of study subjects. The clinical site
will allow the above-mentioned individuals to access to these records.
Study subject contact information will be kept strictly by each clinical site for internal use during
the study. At the end of the study, all records will continue to be kept in a secure location for a
period determined by the EC, site policy or sponsor requirements.
11.6 Revision of study protocol and informed consent form
Study procedures may be modified only after mutual consultation between the principal investigator
and the sponsor.
If there are any significant changes to the protocol, these changes must be documented in a
protocol amendment to the most recent version of the clinical study protocol, if required. The
amendment should be approved by the appropriate EC and, if applicable, the national regulatory
authority prior to implementation. The sponsor will distribute the most current version of the
protocol and any amendments to each principal investigator.
If a protocol amendment requires changes to the central ICF, the sponsor and the central EC will
approve the ICF amendment before the amendment can be used. Any administrative changes should
be communicated to and approved by each EC.
12. Right to Publish Privacy
All data provided by Suzhou Auzone Biological Technology Co., Ltd. and all data generated during
the course of the study (except the subject’s medical records) should be kept confidential by the
investigator and other study site personnel. Neither the investigator nor other staff at the study site
may use the materials, data, or records for any purpose other than those related to the study. These
restrictions do not apply to: (1) Data that has been publicly disclosed not due to errors by the
investigator or research center staff; (2) Data that must be disclosed for the purpose of academic or
EC review to assess this study; (3) Data that must be disclosed to provide appropriate healthcare to
participants in the study.
The summary, submission and publication by the research institution must be reviewed by the
sponsor and the principal investigator of the clinical research institution.

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13. References
[1]
Jivan, K, Ranchod, K and Modi, G, Management of ischaemic stroke in the acute setting:
review of the current status. Cardiovasc J Afr,2013.24(3):86-92.
[2]
Chinese Society of Neurology; Cerebrovascular Disease Group, Chinese Society of
Neurology. Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke 2018
[J]. Chinese Journal of Neurology, 2018,51(9):666-682.
[3]
Wang Y, Dai D, Fan YW et al. Clinical progress in thrombolytic therapy for acute cerebral
infarction. Progress in Modern Biomedicine, 2017.26:57+204-206.
[4]
Toyoda, K, Fujii, K, Kamouchi, M, et al., Free radical scavenger, edaravone, in stroke with
internal carotid artery occlusion. J Neurol Sci,2004.221(1-2):11-17.
[5]
Gong Siwen. Treatment of Acute Brain Infarction with Edaravone, a novel brain protective
drug. JOURNAL OF MEDICAL INFORMATION (mid-month issue, 2011.09:672-673.
[6]
Pharmacology review of Radicava®.2017.
[7]
Review report of Edaravone from PMDA.2001.
[8]
Clinical Pharmacology and Biopharmaceutics Review(s) of Radicava®.2017.
[9]
Package Insert of Edaravone Injection - 1-Feb-2015.
[10] Kaste,M,Murayama,S,Ford,GA,et al.,Safety, tolerability and pharmacokinetics of MCI-186
in patients with acute ischemic stroke: new formulation and dosing regimen. Cerebrovasc
Dis,2013.36(3):196-204.
[11] Label for Radicava®.2021.
[12] A
Phase
I,
single-center,
randomized,
double-blind,
placebo-controlled,
single-
administration dose-escalation pharmacokinetic and safety study of TTYP01 in healthy adult
subjects (Part A), a randomized, open, four-cycle crossover comparative bioavailability
study of the two dosage forms [TTYP01, edaravone intravenous solution (Radicut®)] (Part B)
and a TTYP01 a randomized, open, crossover food effect study (Part C).
[13] Edaravone Acute Infarction Study, G, Effect of a novel free radical scavenger, edaravone
(MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study
at multicenters. Cerebrovasc Dis,2003.15(3):222-229.
[14] Watanabe, T, Tahara, M and Todo, S, The novel antioxidant edaravone: from bench to
bedside. Cardiovasc Ther,2008.26(2):101-114.
[15] Kobayashi, S, Fukuma, S, Ikenoue, T, et al., Effect of Edaravone on Neurological
Symptoms in Real-World Patients with Acute Ischemic Stroke. Stroke,2019.50(7):1805-
1811.

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14. Appendix
14.1 Appendix 1. Modified Rankin Scale (mRS)
The modified Rankin Scale is used to measure functional recovery after stroke. Formal definitions
for each level are shown in bold. Further guidance is given in italics with a view to minimizing
possible errors between different observers, but there are no requirements for the structure of the
interview. Please note that only symptoms that have occurred since the stroke are considered. A
person is considered to be able to walk independently if he or she can walk without outside help and
with the help of some assistive device.
If both levels appear to be equally applicable to the patient, and further questioning is unlikely to
make an absolutely correct choice, the more severe level should be selected.
Patient’s condition
Scoring
Criteria
No symptoms
0
No significant disability despite symptoms: able to carry out all usual duties and activities
1
Slight disability: unable to carry out all previous activities, but able to look after own affairs
without assistance
2
Moderate disability: requiring some help, but able to walk without assistance
3
Moderately severe disability: unable to walk without assistance, unable to attend to needs
without assistance
4
Severe disability: bed-ridden, incontinent, and requiring constant nursing care and attention
5
Note:
0 - No symptoms
Although there may be mild symptoms, the patient has not noticed any newly occurring functional
limitations or symptoms since the stroke.
1 - No significant disability despite symptoms: able to carry out all usual duties and activities
The patient has certain symptoms caused by the stroke, either physical or cognitive (e.g., affecting
speech, reading, or writing; or body movement; or sensation; or vision; or swallowing; or emotion),
but can continue to engage in all the work, social, and leisure activities that he or she was engaged
in before the stroke. The key question used to differentiate between Levels 1 and 2 (see below)
could be, “Are there things you used to do regularly, but you can no longer do them until after the
stroke?” Activities that are more frequent than once a month are considered “frequent”.
2 - Slight disability: unable to carry out all previous activities, but able to look after own affairs
without assistance
Certain activities that could be accomplished before the stroke (such as driving, dancing, reading, or
working) can no longer be performed by the person after the stroke, but the person is still able to
take care of himself/herself on a daily basis without assistance. The patient is able to dress, walk,
eat, go to the bathroom, prepare simple food, shop, and travel locally without assistance. The patient
lives without supervision. It is envisioned that patients at this level could be left alone in their

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homes unattended for a week or more.
3 - Moderate disability: requiring some help, but able to walk without assistance
At this level, the patient can walk (with the aid of walking machinery), dress, go to the bathroom,
eat, etc. independently, but more complex tasks need to be done with assistance. For example, other
people are required to do shopping, cooking, or cleaning instead, and to visit the patient more than
once a week to ensure completion of these activities. Assistance is needed not only to take care of
the body, but also to give advice: for example, patients at this level will need supervision or
encouragement to handle finances.
4 - Moderately severe disability: unable to walk without assistance, unable to attend to needs
without assistance
The patient needs someone else to help with daily life, whether walking, dressing, going to the
bathroom, or eating. The patient needs to be cared for at least once a day, usually two or more times
a day, or must live in close proximity to the caregiver. To distinguish between levels 4 and 5 (see
below), consider whether the patient is able to routinely live alone for an appropriate amount of
time during the day.
5 - Severe disability: bed-ridden, incontinent, and requiring constant nursing care and attention
Although trained nurses are not required, someone will need to attend to them several times
throughout the day and night.

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14.2Appendix 2. National Institutes of Health Stroke Scale (NIHSS)
Note that for each NIHSS score, record the actual time of rating, score according to the table, and
record the results. Do not change the score. The score reflects the patient's actual condition, not
what the doctor thinks the patient should be. Quick check and record results. Do not train the patient
(e.g., repeatedly ask the patient to make a certain effort) unless necessary instructions are given. If
some items are not rated, they should be detailed on the form.
Items
Scale Definition
Score
1a
Level of consciousness:
The investigator must choose a response, even if a
full evaluation is prevented by such obstacles as an
endotracheal
tube,
language
barrier,
orotracheal
trauma/bandages. A 3 is scored only if the patient
makes no movement (other than reflexive posturing)
in response to noxious stimulation.
0 = Alert; keenly responsive
1 = Not alert, but arousable by
minor stimulation to obey,
answer, or respond
2 = Not alert, requires repeated
stimulation to attend, or is
obtunded and requires strong or
painful stimulation to make
movements (not stereotyped)
3 = Responds only with reflex
motor or autonomic effects or
totally unresponsive, flaccid,
areflexic
___
1b
LOC Questions:
The patient is asked the month and his/her age. The
answer must be correct - there is no partial credit for
being close. Aphasic and stuporous patients who do
not comprehend the questions will score 2. Patients
unable to speak because of endotracheal intubation,
orotracheal trauma, severe dysarthria from any
cause, language barrier or any other problem not
secondary to aphasia are given a 1. It is important
that only the initial answer be graded and that the
examiner not "help" the patient with verbal or non-
verbal cues.
0 = Answers both questions
correctly.
1 = Answers one question correctly.
2 = Answers neither question
correctly.
___
1c
LOC Commands:
The patient is asked to open and close the eyes and
then to grip and release the non-paretic hand.
Substitute another one step command if the hands
cannot be used. Credit is given if an unequivocal
attempt is made but not completed due to weakness.
If the patient does not respond to command, the task
should be demonstrated to them (pantomime) and
score the result (i.e., follows none, one or two
commands). Patients with trauma, amputation, or
other physical impediments should be given suitable
one-step commands. Only the first attempt is scored.
0 = Performs both tasks correctly
1 = Performs one task correctly
2 = Performs neither task correctly
___
2
Best gaze:
Only
horizontal
eye
movements
were
tested.
Voluntary
or
reflexive
(oculocephalic)
eye
movements will be scored but caloric testing is not
done. If the patient has a conjugate deviation of the
eyes that can be overcome by voluntary or reflexive
activity, the score will be 1. If a patient has an
0 = Normal
1 = Partial gaze palsy. This score is
given when gaze is abnormal in
one or both eyes, but where
forced deviation or total gaze
paresis are not present.
2 = Forced deviation, or total gaze
___

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Items
Scale Definition
Score
isolated peripheral nerve paresis (CN III, IV or VI)
score a 1. Gaze is testable in all aphasic patients.
Patients with ocular trauma, bandages, pre-existing
blindness or other disorder of visual acuity or fields
should be tested with reflexive movements and a
choice made by the investigator. Establishing eye
contact and then moving about the patient from side
to side will occasionally clarify the presence of a
partial gaze palsy.
paresis not overcome by the
oculocephalic maneuver.
3
Visual:
Visual fields (upper and lower quadrants) are tested
by confrontation, using finger counting or visual
threat as appropriate. Patient must be encouraged,
but if they look at the side of the moving fingers
appropriately, this can be scored as normal. If there
is unilateral blindness or enucleation, visual fields in
the remaining eye are scored. Score 1 only if a clear-
cut asymmetry, including quadrantanopia is found. If
patient is blind from any cause score 3. Double
simultaneous stimulation is performed at this point.
If there is extinction patient receives a 1 and the
results are used to answer question 11.
0 = No visual loss
1 = Partial hemianopia
2 = Complete hemianopia
3 = Bilateral hemianopia (blind
including cortical blindness)
___
4
Facial Palsy:
Ask, or use pantomime to encourage the patient to
show teeth or raise eyebrows and close eyes. Score
symmetry of grimace in response to noxious stimuli
in the poorly responsive or noncomprehending
patient. If facial trauma/bandages, orotracheal tube,
tape or other physical barrier obscures the face, these
should be removed to the extent possible.
0 = Normal symmetrical movement
1 = Minor paralysis (flattened
nasolabial fold, asymmetry on
smiling)
2 = Partial paralysis (total or near
total paralysis of lower face)
3 = Complete paralysis of one or
both sides (absence of facial
movement in the upper and
lower face)
___
5
Motor Arm:
The limb is placed in the appropriate position:
extend the arms (palms down) 90 degrees (if sitting)
or 45 degrees (if supine). Drift is scored if the arm
falls before 10 seconds. The aphasic patient is
encouraged
using
urgency
in
the
voice
and
pantomime but not noxious stimulation. Each limb is
tested in turn, beginning with the non-paretic arm.
Only in the case of amputation or joint fusion at the
shoulder, should it be recorded as untestable (NT),
and the examiner must clearly write the explanation.
0 = No drift, limb holds 90 (or 45)
degrees for full 10 seconds
1 = Drift, Limb holds 90 (or 45)
degrees, but drifts down before
full 10 seconds; does not hit bed
or other support
2 = Some effort against gravity,
limb cannot get to or maintain
(if cued) 90 (or 45) degrees,
drifts down to bed, but has some
effort against gravity
3 = No effort against gravity, limb
falls
4 = No movement
UN = Amputation, joint fusion
explains:
__________________
5a Left
Arm
___
5b Right
Arm
___
6
Motor Leg:
The limb is placed in the appropriate position: the
leg 30 degrees (always tested supine). Drift is scored
if the leg falls before 5 seconds. The aphasic patient
is encouraged using urgency in the voice and
0 = No drift, leg holds 30 degrees
position for full 5 seconds
1 = Drift, leg falls by the end of the
5 second period but does not hit
6a Left
leg
___
6b Right

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Items
Scale Definition
Score
pantomime but not noxious stimulation. Each limb is
tested in turn, beginning with the non-paretic leg.
Only in the case of amputation or joint fusion at the
hip, should it be recorded as untestable (NT), and the
examiner must clearly write the explanation.
bed
2 = Some effort against gravity; leg
falls to bed by 5 seconds, but
has some effort against gravity
3 = No effort against gravity, leg
falls to bed immediately
4 = No movement
UN = Amputation, joint fusion
explains:
__________
leg
___
7
Limb Ataxia:
This item is aimed at finding evidence of a unilateral
cerebellar lesion. Test with eyes open. In case of
visual defect, insure testing is done in intact visual
field. The finger-nose-finger and heelshin tests are
performed on both sides, and ataxia is scored only if
present out of proportion to weakness. Ataxia is
absent in the patient who cannot understand or is
paralyzed. Only in the case of amputation or joint
fusion, should it be recorded as untestable (NT), and
the examiner must clearly write the explanation. In
case of blindness test by touching nose from
extended arm position.
0 = Absent
1 = Present in one limb
2 = Present in two limbs
UN = Amputation, joint fusion
explains:
___
8
Sensory:
Sensation or grimace to pin prick when tested, or
withdrawal from noxious stimulus in the obtunded or
aphasic patient. Only sensory loss attributed to
stroke is scored as abnormal and the examiner
should test as many body areas [arms (not hands),
legs, trunk, face] as needed to accurately check for
hemisensory loss. A score of 2, "severe or total,"
should only be given when a severe or total loss of
sensation can be clearly demonstrated. Stuporous
and aphasic patients will therefore probably score 1
or 0. The patient with brain stem stroke who has
bilateral loss of sensation is scored 2. If the patient
does not respond and is quadriplegic score 2.
Patients in coma (item 1a=3) are arbitrarily given a 2
on this item.
0 = Normal; no sensory loss
1 = Mild to moderate sensory loss;
patient feels pinprick is less
sharp or is dull on the affected
side; or there is a loss of
superficial pain with pinprick
but patient is aware he/she is
being touched
2 = Severe to total sensory loss;
patient is not aware of being
touched in the face, arm, and leg
___
9
Best Language:
A great deal of information about comprehension
will be obtained during the preceding sections of the
examination. The patient is asked to describe what is
happening in the attached picture, to name the items
on the attached naming sheet, and to read from the
attached list of sentences. Comprehension is judged
from responses here as well as to all of the
commands in the preceding general neurological
exam. If visual loss interferes with the tests, ask the
patient to repeat, and produce speech. The intubated
patient should be asked to write. The patient in coma
(question 1a=3) will arbitrarily score 3 on this item.
The examiner must choose a score in the patient with
stupor or limited cooperation but a score of 3 should
0 = No aphasia: normal
1 = Mild to moderate aphasia; some
obvious loss of fluency or
facility of comprehension,
without significant limitation on
ideas expressed or form of
expression. Reduction of speech
and/or comprehension, however,
makes conversation about
provided material difficult or
impossible. For example, in
conversation about provided
materials examiner can identify
picture or naming card from
patient's response
___

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Items
Scale Definition
Score
be used only if the patient is mute and follows no
one step commands.
2 = Severe aphasia; all
communication is through
fragmentary expression; great
need for inference, questioning,
and guessing by the listener.
Range of information that can
be exchanged is limited; listener
carries burden of
communication. Examiner
cannot identify materials
provided from patient response
3 = Mute, global aphasia; no usable
speech or auditory
comprehension
10
Dysarthria:
If patient is thought to be normal an adequate sample
of speech must be obtained by asking patient to read
or repeat words from the attached list. If the patient
has severe aphasia, the clarity of articulation of
spontaneous speech can be rated. Only if the patient
is
intubated
or
has
other
physical
barrier
to
producing speech, it be recorded as untestable (UN),
and the examiner must clearly write an explanation
for not scoring. Do not tell the patient why he/she is
being tested.
0 = Normal
1 = Mild to moderate; patient slurs
at least some words and, at
worst, can be understood with
some difficulty.
2 = Severe; patient's speech is so
slurred as to be unintelligible in
the absence of or out of
proportion to any dysphasia, or
is mute/anarthric
UN = Intubated or other physical
barrier, explain: __________
___
11
Neglect:
Sufficient information to identify neglect may be
obtained during the prior testing. If the patient has a
severe
visual
loss
preventing
visual
double
simultaneous stimulation, and the cutaneous stimuli
are normal, the score is normal. If the patient has
aphasia but does appear to attend to both sides, the
score is normal. The presence of visual spatial
neglect or anosagnosia may also be taken as
evidence of abnormality. Since the abnormality is
scored only if present, the item is never untestable.
0 = No abnormality
1 = Visual, tactile, auditory, spatial,
or personal inattention or
extinction to bilateral
simultaneous stimulation in one
of the sensory modalities
2 = Profound hemi-inattention or
hemi-inattention to more than
one modality. Does not
recognize own hand or orients to
only one side of space
___
Total
Scores
___

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14.3 Appendix 3. Barthel Index (BI) of Activities of Daily Living
Scale
Definition
Scoring and Rationale
Independent
Minor help
Major help
Dependent
Fedding
10 points
Able to eat independently
5 points
Minor help
0 point
Requires major
assistance or total
dependence on
others, or requires
modified diet
Bathing
5 points
Once the bathwater is ready,
they can independently
complete the bathing process
0 point
Need help during
bathing
Grooming
5 points
Can independently complete
0 point
Need help during
grooming
Dressing
10 points
Able to dress independently
5 points
Minor help
0 point
Requires major
assistance or total
dependence on
others
Bowels
10 points
Continent
5 points
Occasional accident
or need prompts
from others
0 point
Incontinent
Bladder
10 points
Continent
5 points
Occasional accident
or need prompts
from others
0 point
Incontinent, or
indwelling catheter
Toilet Use
10 points
Able to dress independently
5 points
Minor help
0 point
Requires major
assistance or total
dependence on
others
Transfer
(bed
to
chair
and
back)
15 points
Able to dress independently
10 points
Minor help
5 points
Major help
0 point
Completely
dependent on others
Mobility
(on
level
surfaces)
15 points
Able to walk independently
on flat ground for 45 m
10 points
Minor help
5 points
Major help
0 point
Completely
dependent on others
Stairs
10 points
Able to independently go up
and down 8 flights of stairs
5 points
Minor help
0 point
Requires major
assistance or total
dependence on
others

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14.4 Appendix 4. Montreal Cognitive Assessment Scale (MoCA) (Beijing version)
The Montreal Cognitive Assessment (MoCA) was designed as a rapid screening instrument for mild
cognitive dysfunction. It assesses different cognitive domains: attention and concentration,
executive functions, memory, language, visuoconstructional skills, abstraction, calculations, and
orientation. Time to administer the MoCA is approximately 10 minutes. The total possible score is
30 points; a score of 26 or above of the original English version is considered normal.
1: Alternating Trail Making
Administration: " The examiner instructs the subject: "Please draw a line going from anumber to a
letter in ascending order. Begin here [point to (1)] and draw a line from 1then to A then to 2 and so
on. End here [point to (E)].”
Scoring: One point is allocated if the subject successfully draws the following pattern:1- A- 2- B-
3- C- 4- D- 5- E, without drawing any lines that cross. Any error that is not immediately self-
corrected earns a score of 0.
2: Visuoconstructional Skills (Cube):
Administration: pointing to the cube: “Copy this drawing as accurately as you can, in the space
below”.
Scoring: One point is allocated for a correctly executed drawing.
●Drawing must be three-dimensional
●All lines are drawn
●No line is added
●Lines are relatively parallel and their length is similar (rectangular prisms are accepted)
A point is not assigned if any of the above-criteria are not met.
3: Visuoconstructional Skills (Clock):
Administration: “Draw a clock. Put in all the numbers and set the time to 10 past 11”.
Scoring: One point is allocated for each of the following three criteria:
●Contour (1 pt.): the clock face must be a circle with only minor distortion acceptable (e.g.,
slight imperfection on closing the circle);
●Numbers (1 pt.): all clock numbers must be present with no additional numbers; numbers
must be in the correct order and placed in the approximate quadrants on the clock face; Roman
numerals are acceptable; numbers can be placed outside the circle contour;
●Hands (1 pt.): there must be two hands jointly indicating the correct time; the hour hand
must be clearly shorter than the minute hand; hands must be centred within the clock face with
their junction close to the clock centre. A point is not assigned for a given element if any of the
above-criteria are not met.

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4: Naming
Administration: Beginning on the left, point to each figure and say: “Tell me the name of this
animal”.
Scoring: One point each is given for the following responses: (1) lion (2) rhinoceros or rhino (3)
camel or dromedary.
5: Memory
Administration: The examiner reads a list of 5 words at a rate of one per second, giving the
following instructions: “This is a memory test. I am going to read a list of words that you will have
to remember now and later on. Listen carefully. When I am through, tell me as many words as you
can remember. It doesn’t matter in what order you say them”. Mark a check in the allocated space
for each word the patient produces on this first trial. When the patient indicates that (s)he has
finished (has recalled all words), or can recall no more words, read the five words again with the
following instructions: “I am going to read the same list for a second time. Try to remember and tell
me as many words as you can, including words you said the first time.” Put a check in the allocated
space for each word the patient recalls after the second trial.
At the end of the second trial, inform the patient that (s)he will be asked to recall these words
again by saying, “I will ask you to recall those words again at the end of the test.”
Scoring: No points are given for Trials One and Two.
6: Attention
Forward Digit Span: Administration: Give the following instruction: “I am going to say some
numbers and when I am through, repeat them to me exactly as I said them”. Read the five number
sequence at a rate of one digit per second.
Backward Digit Span: Administration: Give the following instruction: “Now I am going to say
some more numbers, but when I am through you must repeat them to me in the backwards order.”
Read the five number sequence at a rate of one digit per second.
Scoring: Allocate one point for each sequence correctly repeated, (N.B.: the correct response for
the backwards trial is 2-4-7).
Vigilance: Administration: The examiner reads the list of letters at a rate of one persecond, after
giving the following instructions: “I am going to read a sequence of letters.Every time I say the
letter A, tap your hand once. If I say a different letter, do not tapyour hand.”.
Scoring: One point is allocated if there is zero to one error (an error is a tap on a wrongletter or a
failure to tap on letter A).
Serial 7s: Administration: The examiner gives the following instructions: “Now, I willask you to
count by subtracting 7 from 60, and then, keep subtracting 7 from your answeruntil I tell you to

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stop.” The subject must perform a mental calculation, therefore, (s) he may not use his/her fingers
nor a pencil and paper to execute the task. The examiner maynot repeat the subject’s answers. If the
subject asks what her/his last given answer was orwhat number (s) he must subtract from his/her
answer, the examiner responds byrepeating the instructions if not already done so.
Scoring: This item is scored out of 3 points. Give no (0) points for no correctsubtractions, 1 point
for one correct subtraction, 2 points for two or three correctsubtractions, and 3 points if the subject
successfully makes four or five correctsubtractions. Each subtraction is evaluated independently;
that is, if the subject respondswith an incorrect number but continues to correctly subtract 7 from it,
each correctsubtraction is counted. For example, a subject may respond “52 - 45 - 38 - 31 –
24”where the “52” is incorrect, but all subsequent numbers are subtracted correctly. This isone error
and the task would be given a score of 3.
7: Sentence repetition
Administration: The examiner gives the following instructions: “I am going to read you asentence.
Repeat it after me, exactly as I say it [pause]: The child walked his dog in thepark after midnight.”
Following the response, say: “Now I am going to read you anothersentence. Repeat it after me,
exactly as I say it [pause]: The artist finished his painting atthe right moment for the
exhibition.”Scoring: One point is allocated for each sentence correctly repeated. Repetitions must
beexact. Be alert for omissions (e.g., omitting "right"), substitutions/additions (e.g.,substituting
"after" for "at"), grammar errors/altering plurals (e.g. "his painting" for "hispaintings"), etc.
8: Verbal fluency
Administration: The examiner gives the following instructions: “Now, I want you to tellme as many
words as you can think of that begin with the letter B. I will tell you to stopafter one minute. Proper
nouns, numbers, and different forms of a verb are not permitted.Are you ready? [Pause] [Time for
60 sec.] Stop.” If the subject names two consecutive words that begin with another letter of the
alphabet, the examiner repeats the target letterif the instructions have not yet been repeated.
Scoring: One point is allocated if the subject generates 11 words or more in 60 seconds.The
examiner records the subject’s responses in the margins or on the back of the testsheet.
9: Abstraction
Administration: The examiner asks the subject to explain what each pair of words has incommon,
starting with the example: “I will give you two words and I would like you totell me to what
category they belong to [pause]: an orange and a banana.” If the subjectresponds correctly the
examiner replies: ‘‘Yes, both items are part of the categoryFruits.’’ If the subject answers in a
concrete manner, the examiner gives one additionalprompt: “Tell me another category to which
these items belong to.” If the subject doesnot give the appropriate response (fruits), the examiner

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83
says: “Yes, and they also bothbelong to the category Fruits.” No additional instructions or
clarifications are given.After the practice trial, the examiner says: “Now, a hammer and a
screwdriver.”Following the response, the examiner administers the second trial by saying:
“Now,matches and a lamp.” A prompt (one for the entire abstraction section) may be given ifnone
was used during the example.
Scoring: Only the last two pairs are scored. One point is given for each pair correctlyanswered.
The following responses are acceptable:
- hammer- screwdriver = tools, carpentry, construction, work instruments,
- matches- lamp = light, lighting, illumination
The following responses are not acceptable:
- hammer- screwdriver = instruments, have handles, metallic objects,
- matches- lamp = fire, hot objects, produce heat
10: Delayed recall
Administration: The examiner gives the following instructions: “I read some words toyou earlier,
which I asked you to remember. Tell me as many of those words as you canremember.” The
examiner makes a check mark (√) for each of the words correctlyrecalled spontaneously without
any cues, in the allocated space.
Scoring: One point is allocated for each word recalled freely without any cues.
Memory index score (MIS):
Administration: Following the delayed free recall trial, the examiner provides a category (semantic) cue for each
word the subject was unable to recall. Example: ‘‘I will give you somehints to see if it helps you remember the
words, the first word was a body part.’’ If the subject isunable to recall the word with the category cue, the
examiner provides him/her with a multiplechoice cue. Example: “Which of the following words do you think it
was, HAND, LEG, orFACE?” All non-recalled words are prompted in this manner. The examiner identifies the
wordsthe subject was able to recall with the help of a cue (category or multiple-choice) by placing acheck mark
(√) in the appropriate space. The cues for each word are presented below:
Category and/or multiple-choice hint
FACE: part of the body: nose, face, hand
VELVET: type of fabric: cotton, denim, velvet
CHURCH: type of building: church, school, hospital
DAISY: type of flower: rose, daisy, peony
RED: a colour: red, blue, green
Scoring: No points are allocated for words recalled with a cue. A cue is used for clinical information purposes
only and can give the test interpreter additional information about the type of memory disorder. For memory
deficits due to retrieval failures, performance can be improved with a cue. For memory deficits due to encoding
failures, performance does not improve with a cue.
11: Orientation
Administration: The examiner gives the following instructions: “Tell me today’s date.” Ifthe subject
does not give a complete answer, the examiner prompts accordingly bysaying: “Tell me the [year,
month, exact date, and day of the week].” Then the examinersays: “Now, tell me the name of this
place, and which city it is in.”

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Scoring: One point is allocated for each item correctly answered. The date and place (name
ofhospital, clinic, office) must be exact. No points are allocated if the subject makes an error ofone
day for the day and date
TOTAL SCORE: Sum all subscores listed on the right-hand side. Add one point for subject whohas
12 years or fewer of formal education, for a possible maximum of 30 points. A final totalscore of 26
and above is considered normal. There is no Chinese and Beijing norm and reliability and validity
analysis. Therefore, the original boundary value can be referred to temporarily.

Phase III Clinical Trial Protocol of TTYP01 Tablets
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85
Montreal Cognitive Assessment (MoCA) Beijing
Version
Date of birth:
Education:
Name:
Sex:
Date:
VISUOSPATIAL
/
EXECUTIVE
Draw CLOCK (Ten past eleven) (3
points)
POINTS
[ ]
Contour
[ ]
Numbers
[ ]
Hands
_/5
NAMING
_/3
MEMORY
Read list of words,
patient must repeat
them. Do 2 trials, even
if 1st trial is successful
Do a recall after 5
minutes
FACE
VELVET
CHURCH
DAISY
RED
NO
POINTS
1st
TRIAL
2nd
TRIAL
ATTENTION
Read list of digits and ask the patient
repeated
(1 digit / sec.).
Patient has to repeat them
in the forward order
[ ]21854
Patient has to repeat them
in the backward order
[ ]742
_/2
Read list of numbers. The patient must tap with his hand when number 1 appears. No points if ≥2 errors
[ ]52139411806215194511141905112
_/1
Serial 7
subtraction
starting at 100
[ ]93 [ ] 86 [ ] 79 [ ] 72 [ ]65
4 or 5 correct subtractions: 3 pts, 2 or 3 correct: 2 pts, 1 correct: 1 pt, 0 correct: 0 pt
_/3
LANGUAGE
Repeat: All I know is that Zhang Liang has come to help [ ]
The cat always hid under the couch when dogs were in the room [ ]
_/2
Language Fluency. Name maximum number of animals in one minute
[ ] _______ (N≥11 names)
_/1
ABSTRACTION
Similarity between e.g. banana - orange = fruit [ ] train - bicycle [ ] watch - ruler
_/2
DELAYED
RECALL
Has to recall
words with no
cue
FACE
[ ]
VELVET
[ ]
CHURCH
[ ]
DAISY
[ ]
RED
[ ]
Points
for
uncued
recall
only
_/5
Options
Category hint
multiple-choice
hint
ORIENTATION
[ ] Date
[ ] Month [ ] Year
[ ] Day of Week
[ ] Place [ ] City
-/6
© Z.Nasreddine MD Version November 7,2004
Beijing version 26 August,2006 translated by Wei Wang & Hengge Xie
www.mocatest.org
Total Scores
-/30
Copy
Cube
End
Start
A
B
C
D
E

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14.5 Appendix 5. Hamilton Depression Rating Scale (HDRS)
Hamilton Depression Rating Scale - 21-item scale
1. DEPRESSED MOOD (sadness,
hopeless, helpless, worthless)
0 - Absent
1 - These feeling states indicated only on questioning
2 - These feeling states spontaneously reported verbally
3 - Communicates feeling states non-verbally, i.e. through facial
expression, posture, voice and tendency to weep
4 - Patient reports virtually only these feeling states in his/her
spontaneous verbal and non-verbal communication (facial expressions,
gestures)
2. FEELINGS OF GUILT
0 - Absent
1 - Self reproach, feels he/she has let people down
2 - Ideas of guilt or rumination over past errors or sinful deeds
3 - Present illness is a punishment. Delusions of guilt
4 - Hears accusatory or denunciatory voices and/or experiences
threatening visual hallucinations
3. SUICIDE
0 - Absent
1 - Feels life is not worth living
2 - Wishes he/she were dead or any thoughts of possible death to self
3 - Ideas or gestures of suicide
4 - Attempts at suicide
4. INSOMNIA (EARLY IN THE
NIGHT)
0 - No difficulty falling asleep
1 - Complains of occasional difficulty falling asleep, i.e. more than 1⁄2
hour
2 - Complains of nightly difficulty falling asleep
5. INSOMNIA (MIDDLE OF THE
NIGHT)
0 - No difficulty falling asleep
1 - Patient complains of being restless and disturbed during the night
2 - Waking during the night – any getting out of bed for any reason
except for purposes of voiding
6. INSOMNIA (EARLY HOURS OF
THE MORNING)
0 - No difficulty falling asleep
1 - Waking in early hours of the morning but goes back to sleep
2 - Unable to fall asleep again if he/she gets out of bed
7. WORK AND ACTIVITIES
0 - No difficulty falling asleep
1 - Thoughts and feelings of incapacity, fatigue or weakness related to
activities, work or hobbies
2 - Loss of interest in activity, hobbies or work – either directly
reported by the patient or indirect in listlessness, indecision and
vacillation (feels he/she has to push self to work or activities)
3 - Decrease in actual time spent in activities or decrease in
productivity. If the patient does not spend at least three hours a day in
activities (job or hobbies) excluding routine chores
4 - Stopped working because of present illness. If patient engages in no
activities except routine chores, or if patient fails to perform routine
chores unassisted
8. RETARDATION (slowness of
thought and speech, impaired ability to
concentrate, decreased motor activity)
0 - Normal speech and thought
1 - Slight retardation during the interview
2 - Obvious retardation during the interview
3 - Interview difficult
4 - Complete stupor (unable to answer questions)
9. AGITATION
0 - Absent
1 - Fidgetiness
2 - Playing with hands, hair, etc.
3 - Moving about, can’t sit still
4 - Hand wringing, nail biting, hair-pulling, biting of lips
10. ANXIETY PSYCHIC
0 - Absent
1 - Subjective tension and irritability

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2 - Worrying about minor matters
3 - Apprehensive attitude apparent in face or speech
4 - Fears expressed without questioning
11. ANXIETY SOMATIC
(Physiological concomitants of anxiety, such as: gastro-intestinal – dry
mouth, abdominal distension, indigestion, diarrhea, cramps, eructation;
cardio-vascular
–
palpitations,
headaches;
respiratory
–
hyperventilation, sighing; pollakiuria; sweating)
0 - Absent
1 - Mild
2 - Moderate
3 - Severe
4 - Incapacitating (Significantly impacting daily life and activities)
12. SOMATIC SYMPTOMS
GASTRO-INTESTINAL
0 - None
1 - Loss of appetite but eating without staff encouragement
2 - Difficulty eating without staff urging
13. GENERAL SOMATIC
SYMPTOMS
0 - Absent
1 - Heaviness in limbs, back or neck. Backaches, headaches, muscle
aches. Loss of energy and fatigability
2 - Any clear-cut symptom
14. GENITAL SYMPTOMS
(symptoms such as loss of libido,
menstrual disturbances)
0 - Absent
1 - Mild
2 - Severe
15. HYPOCHONDRIASIS
0 - Absent
1 - Self-absorption (bodily)
2 - Preoccupation with health
3 - Frequent complaints, requests for help, etc.
4 - Hypochondriacal delusions
16. INSIGHT
0
-
Acknowledges
being
depressed
and
ill,
or
currently
not
experiencing depression
1 - Acknowledges illness but attributes cause to bad food, climate,
overwork, virus, need for rest, etc.
2 - Denies being ill at all
17. LOSS OF WEIGHT (based on
medical history score)
0 - No weight loss
1 - Probable weight loss associated with present illness
2 - Definite (according to patient) weight loss
18. WEIGHT FLUCTUATION
PATTERN (up during the day, down at
night)
0 - Absent
1 - Mild
2 - Severe
19. DEPERSONALIZATION AND
DEREALIZATION
0 - Absent
1 - nihilistic ideas
2 - feelings of unreality
3 - Feel unreal
4 - Feeling like one is not living as a person in the world
20. PARANOID SYMPTOMS
0 - Absent
1 - Suspicion or doubt
2 - Speculating that others intend to harm him/her
3 - Delusion that others intend to harm him/her and are actively trying
to do so
4 - Fantasy that others are attempting to harm him/her
21. OBSESSIONAL SYMPTOMS
0 - Absent
1 - Admitting to having these symptoms
2 - Obsessive thoughts and compulsions against which the patient
struggles
Total score:
Severe depression with a score of >30
Moderate depression with a score of >20
Mild depression with a score of >17

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14.6 Appendix 7. Protocol Version Development and Amendment Schedule
Version No.
Version Date
Description of Change and
Brief Rationale
V1.0
October 28, 2022
V2.0
June 30, 2023
1. Dosing Regimen is improved: The first dose should
be given within 1 hour after randomization and
remaining doses should be administrated within 30–
60 minutes before breakfast or dinner. In case of
postprandial randomization, the second dose should
not be earlier than 6 hours after the first dose.
2. The inclusion criteria No. 3 is improved: “Patients
who refuse thrombolysis or thrombectomy, or do not
meet
the
indications
for
thrombolysis
or
thrombectomy;”.
3. The inclusion criteria No. 4 is improved: “Patients
who are within ≤24 hours after the symptom onset.
For patients with uncertain onset time due to wake-up
stroke, aphasia, consciousness disorders, etc., the last
known asymptomatic time is considered as the onset
time;”.
4. The exclusion criteria for dementia patients No. 5 is
improved: “Patients who are unable or unwilling to
cooperate with the study due to comorbidity such as
severe
mental
disorders,
depression,
Alzheimer's
disease,
Parkinson's
dementia,
and
Louis
body
dementia;”.
5. The withdrawal criteria No.7 is improved: (7)
Subjects who participate in another intervention study
during this trial.
6. IQCODE score is deleted, as this assessment will not
be performed in the trial.
7. In study procedure, “Continued administration of
the investigational drug treatment” is deleted from
V1, V2 and V3. The description is modified due to
ambiguity.
8. The blood chemistry text parameters-schedule of
activities note 10 and 11 are improved:”. 1) “or blood
urea nitrogen (BUN)” is added; 2) “Assessments of
high-density
lipoprotein
(HDL),
low-density
lipoprotein (LDL) and D-dimer will be performed on
D1, D7, D28 + 3 and D90 ± 5 or upon early
withdrawal” is added.
9.
The
relevant
provision
on
urinalysis
is
supplemented-schedule of Activities note 9: If results
of the urine routine test are not available due to
emergency, investigatonal drugs can be administered
first. If the subject has no urine temporarily, the test
results of first urine sample collected upon admission
will serve as baseline data.
10. According to the actual clinical execution: “V3
(D28 ± 3)” is revised as “V3 (D28 + 3)” throughout the
text.