A Prospective, Multicenter, Open-Label, Randomized Controlled Study of Early Intensive Lipid-Lowering in Endovascular Treatment for Acute Ischemic Stroke
Phase: PHASE3
Conditions: Stroke
Sponsor: Shanghai East Hospital

1
Title
A Prospective, Multicenter, Open-Label, Randomized
Controlled Study of Early Intensive Lipid-Lowering in
Endovascular Treatment for Acute Ischemic Stroke
Early Aggressive Strategy for Treatment of Lipid-Lowering in
Acute Ischemic Stroke Delivered with Endovascular Therapy
for Large Artery Occlusion (EAST-LDL)
Study Protocol
Protocol Design Institution: East Hospital Affiliated to Tongji University
Principal Investigator Institution: East Hospital Affiliated to Tongji
University
MA-CVD-Ⅱ-001
Version Number: 2.1
Version Date: April 25, 2025
Address: Department of Neurology, No. 1800 Yuntai Road, Pudong New Area, Shanghai
Tel: 021-38804518-22106
Email: ligang@tongji.edu.cn
Principal Investigator Signature:
Date:

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Contact Information of Principal Investigator
East Hospital Affiliated to Tongji University
Name: Li Gang
Professional Title: Professor, Chief Physician
Address: Department of Neurology, East Hospital Affiliated to Tongji University, No. 1800 Yuntai Road,
Pudong New Area, Shanghai 200127
Tel (Office):
021-38804518-22107
Mobile Phone
13621691786
Email
ligang@tongji.edu.cn
Contact Information of Study Team Members
East Hospital Affiliated to Tongji University
Name: Zhang Yue
Professional Title: Associate Chief Physician
Address: Department of Neurology, East Hospital Affiliated to Tongji University, No. 1800 Yuntai
Road, Pudong New Area, Shanghai 200127
Tel (Office):
021-38804518-22106
Mobile Phone
18602120090
Email
dyuezhang@126.com
East Hospital Affiliated to Tongji University
Name: Huang Zhengyu
Professional Title: Attending Physician
Address: Department of Neurology, East Hospital Affiliated to Tongji University, No. 1800 Yuntai
Road, Pudong New Area, Shanghai 200127
Tel (Office):
021-38804518-22106
Mobile Phone
Email
@126.com
East Hospital Affiliated to Tongji University
Name: Chen Chen
Professional Title: Attending Physician
Address: Department of Neurology, East Hospital Affiliated to Tongji University, No. 1800 Yuntai
Road, Pudong New Area, Shanghai 200127
Tel (Office)
021-38804518-22106

3
Mobile Phone
15921119641
Email
15921119641@163.com
East Hospital Affiliated to Tongji University
Name: Liu Feifeng
Professional Title: Attending Physician
Address: Department of Neurology, East Hospital Affiliated to Tongji University, No. 1800 Yuntai
Road, Pudong New Area, Shanghai 200127
Tel (Office)
021-38804518-22106
Mobile Phone
15121100573
Email
liufeifeng7@163.com
East Hospital Affiliated to Tongji University
Name: Xiao Yaping
Professional Title: Associate Chief Physician
Address: Department of Neurology, East Hospital Affiliated to Tongji University, No. 1800 Yuntai
Road, Pudong New Area, Shanghai 200127
Tel (Office)
021-38804518-22106
Mobile Phone
13916980530
Email
Xiaoyaping2001@163.com
East Hospital Affiliated to Tongji University
Name: Shen Hao
Professional Title: Associate Chief Physician
Address: Department of Neurology, East Hospital Affiliated to Tongji University, No. 1800 Yuntai
Road, Pudong New Area, Shanghai 200127
Tel (Office)
021-38804518-22106
Mobile Phone
15900562941
Email
shenhao717@126.com

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I.
Protocol Synopsis
Protocol Title
A Prospective, Multicenter, Open-Label, Randomized Controlled Study of Early
Intensive Lipid-Lowering in Endovascular Treatment for Acute Ischemic Stroke
Version
No./Version Date
V2.1/April 25, 2025
Study Subjects
Patients with acute ischemic stroke with anterior circulation large vessel occlusion
undergoing endovascular treatment
Study Objectives
Primary Objective:
To compare the rate (%) of good functional outcome at 90 days (modified Rankin
Scale [mRS] score 0-2) in patients with acute ischemic stroke undergoing
endovascular treatment between preoperative intensive lipid-lowering therapy with
PCSK9 inhibitor (PCSK9i) and guideline-recommended standard of care (SoC).
Secondary Objectives
1)
mRS ordinal score at 90 days;
2)
NIHSS score at 14±3 days or before discharge;
3)
Change from baseline in NIHSS score at 14±3 days or before discharge;
4)
LDL-C target attainment rate at 14±3 days or before discharge;
5)
Change from baseline in LDL-C at 14±3 days or before discharge;
6)
Change from baseline in inflammatory markers at 14±3 days or before
discharge;
7)
Rate of severe disability (mRS score 3-5) at 90 days;
8)
Mortality rate (mRS score of 6) at 90 days;
9)
Incidence of recurrent ischemic stroke events within 90 days;
10) Incidence of symptomatic intracranial hemorrhage transformation within
24-48h;
11) Incidence of new hemorrhagic stroke within 90 days;
12) Incidence of major adverse cardiovascular events (MACEs) within 90
days;
13) Safety assessment within 90 days;
14) Quality of life scale (EQ-5D) at 90 days.
Study Design
This study adopts a prospective, national multicenter, open-label, randomized
controlled clinical trial design. Patients meeting eligibility criteria will be allocated
1:1
to
the
PCSK9i
intensive
lipid-lowering
treatment
group
or
the
guideline-recommended SoC group, with the proportion of patients with modified
Rankin Scale (mRS) (0-2) at 90 days as the primary endpoint. A total of 652 patients
are planned for enrollment.
This study will use a stratified block randomization method, with stratification
factors as follows:
1)
Medical center (stratified into 2 subgroups based on the number of patients
who received endovascular treatments for acute ischemic stroke at the
center in the previous year: 50-99 patients/year; ≥100 patients/year)
2)
Time from onset to randomization (0-6h [inclusive]; 6-24h)

5
Study Population
Patients with acute ischemic stroke with anterior circulation large vessel occlusion
undergoing endovascular treatment
Inclusion/Exclusion
Criteria
Inclusion Criteria
(1)
Adults (age 18 years and older);
(2)
Imaging diagnosis of acute ischemic stroke with anterior circulation large
vessel occlusion (including: internal carotid artery, middle cerebral artery M1
and M2, anterior cerebral artery A1 and A2);
(3)
Planned to undergo endovascular intervention within 24 hours of symptom
onset (or last known well time) according to local guidelines;
(4)
Provision of informed consent by the patient or his/her legally authorized
representative (or by an appropriate agent according to local requirements).
Exclusion Criteria
(1)
ASPECTS score ≤5 on cranial CT imaging;
(2)
Pre-existing functional impairment, with mRS score >2;
(3)
Patients who are allergic to PCSK9 inhibitors;
(4)
Patients who have received PCSK9 monoclonal antibody within 1 month prior
to enrollment or PCSK9 siRNA therapy within 6 months prior to enrollment;
(5)
Severe renal insufficiency, defined as estimated glomerular filtration rate
(eGFR) < 15 mL/min/1.73m2 at final screening;
(6)
Active
liver
disease
or
hepatic
dysfunction,
defined
as
aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper
limit of normal;
(7)
Severe, concomitant non-cardiovascular disease expected to reduce life
expectancy to less than 3 months;
(8)
Pregnant or lactating women;
(9)
Patients who are participating in other clinical trials;
(10) Other conditions deemed unsuitable for inclusion in the clinical study by the
investigator.
Study Drugs
Investigational Product:
Drug Name: Recaticimab Injection
Drug Strength: 150mg Recaticimab lyophilized powder for injection

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Method
of
Administration
[Investigational Group]
Recaticimab is added to the guideline-recommended SoC. After randomization and
before endovascular treatment, patients will receive a subcutaneous injection of
Recaticimab. The specific method is: Recaticimab 450mg (3 vials) as a single
subcutaneous injection, until the end of the follow-up for this study.
[Control Group]
Guideline-recommended SoC.
Evaluation
Measures
1.
Baseline: NIHSS score; LDL-C level; blood inflammatory markers (white blood
cell count, CRP);
2.
24-48 hours: NIHSS score; cranial CT assessment for symptomatic intracranial
hemorrhage;
3.
14±3 days or at discharge: NIHSS score; LDL-C level; blood inflammatory
markers (white blood cell count, CRP);
4.
90 ± 7 days: mRS score; recurrent ischemic stroke events within 90 days;
new-onset hemorrhagic stroke events within 90 days; MACEs within 90 days;
adverse events (AEs); EQ-5D scale.
Sample Size
This is a randomized controlled study. According to previous study reports, the
proportion of patients with mRS (0-2) in patients with acute ischemic stroke
receiving endovascular treatment from the control group is approximately 45%.
Based on early study data of the investigational treatment regimen, the
proportion of patients with mRS (0-2) in the investigational group in this study
is expected to reach 58%, with an inter-group difference of approximately 13%.
The significance level α is set at 0.05 (two-sided). Using the Z-test (pooled)
module
of
NCSS
PASS
21
(LLC.
Kaysville,
Utah,
USA,
ncss.com/software/pass) software, it is calculated that approximately 309
subjects need to be enrolled in each group to provide at least 90% power (1-β) to
detect a difference in the proportion of patients with mRS (0-2) between the
investigational
treatment
regimen
and
the
control
treatment
regimen.
Considering 5% dropout and protocol violations, a total of 326 subjects need to
be enrolled in each group for this study, meaning a total of 652 subjects need to
be enrolled for both groups.
Statistical Methods
General Analysis
For continuous data, statistics such as number, mean, standard deviation,
median, minimum, and maximum will be summarized; for categorical data,
statistics
such
as
frequency
and
percentage
will
be
summarized;
for

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time-to-event data, the Kaplan-Meier method will be used to estimate the
survival function and the median time to event occurrence, and survival curves
will be plotted. Efficacy analyses of primary and secondary endpoints will be
conducted in the intent-to-treat (ITT) population, i.e., all randomized patients.
Safety analysis will be performed in the as-treated safety set (SS). All statistical
analyses will be performed using SAS 9.4 software.
Efficacy Analysis
The study's primary efficacy endpoint is the percentage of patients with mRS
(0-2), and a logistic regression model adjusted for stratification factors will be
used to estimate the odds ratio of mRS (0-2) between the investigational group
and the control group, along with the corresponding 95% confidence interval
(CI) and p-value.
For
the
ordinal
mRS
endpoint
among
the
secondary
endpoints,
a
proportional-odds logistic regression model adjusted for stratification factors
will be used to estimate the common odds ratio and its corresponding 95% CI
and p-value. Other binary endpoints will be analyzed using the same regression
model as the primary endpoint.
For event endpoints, the Kaplan-Meier method will be used to estimate the
median value, and the Brookmeyer-Crowley method will be used to estimate the
95% CI for the median time to event. Survival curves will be plotted, and the
stratified Logrank test will be used to compare survival differences between
groups;
Safety Analysis
Safety analysis will primarily be descriptive statistical analysis. All AEs will be
coded using MedDRA and graded according to the NCI-CTCAE version 5.0
grading system. All treatment-emergent AEs, drug-related AEs, serious adverse
events (SAEs), and drug-related SAEs will be listed by the highest severity.
Laboratory test results, vital signs, electrocardiogram (ECG) data, etc. will be
analyzed using conversion tables to compare the baseline and post-baseline
conditions.

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II. Table of Contents
I.
Protocol Synopsis.....................................................................................................................4
II.
Table of Contents.....................................................................................................................8
III.
Management Algorithm........................................................................................................ 10
IV.
Study Background................................................................................................................. 10
1. Epidemiology........................................................................................................................10
2. Application of PCSK9i in Lipid Management for Acute Ischemic Stroke...........................11
3. Pleiotropic Effects of PCSK9 Inhibitor Drugs Beyond Lipid Lowering..............................13
V.
Study Objectives.................................................................................................................... 15
1. Primary Objective................................................................................................................. 15
2. Secondary Objectives............................................................................................................15
VI.
Study Methods........................................................................................................................15
1. Overall Design...................................................................................................................... 15
2. Study Design (Flowchart)..................................................................................................... 16
3. Study Population...................................................................................................................16
4. Inclusion and Exclusion Criteria...........................................................................................17
5. Ethical Issues.........................................................................................................................18
6 Randomization....................................................................................................................... 20
7 Interventions...........................................................................................................................21
8. Withdrawal and Removal Criteria....................................................................................22
9. Study Endpoints.................................................................................................................... 24
10. Data Collection and Follow-up........................................................................................ 24
VII. Study Flow Chart...................................................................................................................30
VIII. SAEs........................................................................................................................................30
1. Definition:............................................................................................................................. 30
2．Recording and Reporting of Serious Adverse Events....................................................31
3．Monitoring of Serious Adverse Events...............................................................................32
4．Monitoring of Suspected Unexpected Serious Adverse Reactions.....................................32
IX.
Quality Assurance..................................................................................................................32
1．Preservation and Monitoring of Source Documents/Files.................................................. 33
2．Pre-Study Activities............................................................................................................ 33
3．Site Staff Training...............................................................................................................34
4．Study Monitoring................................................................................................................ 34
5．Audits and Inspections by Government Regulatory Agencies........................................... 34
6．Source Data.........................................................................................................................35

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7．Archiving of Study Documents...........................................................................................35
8．Study Progress.....................................................................................................................35
X.
Data Management..................................................................................................................35
XI.
Statistical Plan........................................................................................................................35
1.
Statistical Analysis.......................................................................................................... 35
2.
Sample Size Estimation...................................................................................................36
XII. Publication and Reporting....................................................................................................37
XIII. Organizations......................................................................................................................... 38
XIV. Funding...................................................................................................................................38
XV.
Timeline.................................................................................................................................. 38
XVI. References...............................................................................................................................39
XVII.Appendices..............................................................................................................................42
1. Modified Rankin Scale (mRS)..............................................................................................42
2. NIH Stroke Scale...................................................................................................................44
3. European Quality of Life Scale (EQ-5D)..............................................................................50
4. Glasgow Coma Scale (GCS).................................................................................................53

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III.Management Algorithm
Protocol History Record
Version No.
Version Date
Revision Summary
1.0
January 20, 2025
Initial Version
2.0
March 12, 2025
1. Added quality of life assessment at 90 days using the EQ-5D scale.
2. Added lipid profile testing at 90 days.
3. Adjusted PCSK9i administration time to before endovascular
treatment.
2.1
April 25, 2025
Added supplementary explanation for the selection of study drug
administration regimen
IV. Study Background
1. Epidemiology
Stroke is a global health problem and the second leading cause of death worldwide.
Furthermore, there are currently over 80 million stroke survivors globally. Among these
survivors, half are left with moderate to severe neurological deficits, and one-quarter require
assistance from others in their daily lives. Stroke is now the third leading cause of disability in
adults worldwide1. China also faces the world's largest stroke challenge. Results from the
global burden of disease (GBD) study show that in 2019, there were 3.94 million new stroke
cases in China, the number of stroke patients reached 28.76 million, and the number of stroke
deaths was 2.19 million2. Furthermore, in the coming decades, the family and societal burden
of stroke is expected to increase further due to population aging, the continued high
prevalence of risk factors (such as hypertension), and inadequate management3.
Stroke can be divided into ischemic stroke and hemorrhagic stroke based on its nature, with
approximately 80% of strokes being ischemic stroke2. Acute ischemic stroke (AIS) refers to a
clinical syndrome characterized by acute cerebral blood supply disorders due to various
causes, leading to local brain tissue ischemia, hypoxic necrosis, and corresponding
neurological deficits. It is mostly caused by thrombosis or embolism obstructing cerebral
blood vessels supplying specific brain regions. Particularly, acute ischemic stroke with large
vessel occlusion (LVO) accounts for about 30% of all AIS. Due to the large area supplied by
the occluded vessel, ischemia can lead to extensive cerebral infarction, resulting in higher
mortality and disability rates than other ischemic stroke subtypes3. In recent years,
endovascular interventional treatment, by rapidly opening occluded large arteries early and

11
quickly restoring blood flow to brain tissue, has been proven to benefit some patients with
ischemic stroke with large artery occlusion4. Endovascular interventional treatment has
become the preferred treatment for selected patients with stroke with anterior circulation large
vessel occlusion. Data from the CNIS China Thrombectomy Quality Control Registry show
that the number of emergency thrombectomies in China reached 88,131 in 2023. Combined
with 77,299 cases in 2022 and 67,147 cases in 2021, the national number of emergency
thrombectomies is expected to maintain an annual growth rate of around 10,000 cases in the
next 2-3 years. However, even with this effective treatment, only about 40% of patients who
successfully achieve vascular recanalization through reperfusion therapy achieve a good
prognosis5.
This
phenomenon,
where
functional
recovery
is
poor
despite
vascular
recanalization, is known in the medical field as "futile recanalization"6, and its causes are
currently unclear. In recent years, growing evidence suggests that neuroinflammation and the
presence of microthrombi may be among the key mechanisms underlying futile recanalization
after reperfusion therapy for ischemic stroke7,8. However, effective drugs for targeted
treatment are currently lacking. Therefore, medical researchers and clinicians urgently need to
find effective solutions.
2. Application of PCSK9i in Lipid Management for Acute Ischemic Stroke
Therapies to lower low-density lipoprotein cholesterol have been proven to reduce the risk of
recurrence after acute ischemic stroke, and statins are the main representative drugs for
lowering LDL-C levels, forming the cornerstone of secondary prevention therapy for
ischemic stroke4,9. Although the mainstream clinical drugs for lowering LDL-C are statins
(cholesterol synthesis inhibitors). Moderate statin therapy can reduce LDL-C levels by 25% ~
50%, but doubling the dose only increases the LDL-C lowering effect by an additional 6%,
while increasing potential side effects such as liver damage, myopathy, and new-onset
diabetes31. LDL-C control in China is not ideal. Among individuals with established ASCVD,
the LDL-C control target achievement rate is only 6.8%31. Furthermore, the Chinese
population has poorer tolerance to high-dose statins compared to European and American
populations, further exacerbating the treatment dilemma. In recent years, the emergence of
proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has ushered in a new era of
lipid-lowering therapy. The 2023 "Chinese Guidelines for Lipid Management" recommend,
on the basis of lifestyle intervention, initiating treatment with moderate-intensity statins, and
if necessary, using a treat-to-target strategy by combining cholesterol absorption inhibitors
and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors31.

12
PCSK9 is the 9th member of the proprotein convertase subtilisin/kexin family, is a serine
protease encoded by the PCSK9 gene, mainly produced in liver cells, and is expressed in
various cells throughout the body. In 2003, Abifadel et al. first revealed the correlation
between PCSK9 gene mutations and autosomal dominant familial hypercholesterolemia10.
Subsequent studies further found that loss-of-function mutations in PCSK9 can enhance the
liver's lipid metabolism capacity, thereby lowering blood LDL-C levels11. Further exploration
of its mechanism revealed that PCSK9 protein can participate in the degradation of the
low-density lipoprotein receptor (LDLR). When LDLR on the cell surface binds to free
LDL-C in the blood and mediates its endocytosis into the cell, it is further degraded and
metabolized intracellularly, while LDLR is transported back to the cell membrane for
recycling.
The
PCSK9
molecule
can
bind
to
LDLR
extracellularly,
forming
a
PCSK9-LDLR-LDL-C complex. This complex is transported to lysosomes for degradation,
blocking the process of LDLR returning to the cell membrane for recycling, thereby inhibiting
the cell's clearance of LDL-C and leading to abnormally elevated LDL-C levels in the blood.
12
Drugs targeting PCSK9 have been a research hotspot in recent years, including monoclonal
antibodies, antisense nucleotides, small interfering RNAs, and small molecule inhibitors.
Their function is to neutralize or inhibit the PCSK9 protein, block its mediated LDLR
degradation process, and upregulate cell surface LDLR levels, thereby enhancing the body's
ability to metabolize LDL-C. Among these, PCSK9 monoclonal antibody (PCSK9 mAb), as a
representative drug of PCSK9i, was the first to enter clinical application and is characterized
by strong targeting, high specificity, and low toxic side effects. During 2017-2018, two
high-quality clinical studies demonstrated that when used in combination with statins, PCSK9
inhibitors can further reduce low-density lipoprotein (LDL) cholesterol levels and decrease
the incidence of vascular events, including ischemic stroke and myocardial infarction13,14.
Precisely because of the evidence from these two pivotal trials, authoritative guidelines both
domestically and internationally, such as the 2019 European Society of Cardiology (ESC)
dyslipidemia management guidelines, recommend the combined use of PCSK9 inhibitors for
secondary prevention in high-risk atherosclerotic cardiovascular disease (ASCVD) patients if
lipid levels remain poorly controlled despite high-dose statin and ezetimibe combination
therapy15.
However, in the early management of acute ischemic stroke, the correlation between lipid
levels and patients' neurological functional prognosis remains unclear. In recent years, there
has been increasing attention on the impact of lipid levels and intensive lipid-lowering

13
therapy on neurological functional outcomes in acute ischemic stroke. Observational studies
have found that among patients with acute ischemic stroke, those whose LDL-C levels
increased during hospitalization had a higher proportion of unfavorable outcomes at discharge
compared to those whose LDL-C levels decreased16. The latest high-quality RCT study found
that in patients with acute ischemic stroke, early initiation of intensive statin therapy within
72 hours, compared to delayed intensive statin lipid-lowering therapy, can reduce the risk of
recurrent stroke within 90 days and improve patients' neurological functional prognosis
without increasing the risk of hemorrhage17. Another retrospective clinical study found that
for patients with ischemic stroke with large artery occlusion undergoing mechanical
thrombectomy, those who received early PCSK9i lipid-lowering therapy had lower NIHSS
scores at discharge and a higher proportion of mRS ≤3 compared to the control group.
Although there was no significant statistical difference in the proportion of good prognosis at
3 months between the two groups, there was no risk of early neurological deterioration or
hemorrhage18. Preliminary analysis from a small-sample observational study previously
conducted at our center also found that patients with large vessel occlusion who received
PCSK9 inhibitors after thrombectomy had better mRS scores at 3 months compared to the
control group. In summary, the use of intensive lipid-lowering therapy in the early stage of
acute ischemic stroke may be safe and has the potential value of improving neurological
functional outcomes. As a novel lipid-lowering drug that has emerged in recent years,
PCSK9i achieves a greater degree of intensive lipid-lowering than statins and other oral
lipid-lowering drugs. Therefore, its impact on neurological function when used for early
lipid-lowering therapy in patients with acute ischemic stroke is highly worthy of further
exploration, and the underlying mechanisms also warrant further investigation.
3. Pleiotropic Effects of PCSK9 Inhibitor Drugs Beyond Lipid Lowering
In fact, in addition to regulating lipid components such as LDL-C, PCSK9 inhibitors may also
be involved in processes such as anti-inflammatory immune regulation, and antithrombotic
effects in arteries and veins, exerting pleiotropic effects.
Studies have found that PCSK9 can lead to the upregulation of receptors such as SR-A, CD36,
and LOX-1 on the surface of macrophages, activating downstream inflammation-related
pathways and promoting the occurrence of inflammatory responses19. PCSK9 siRNA, by
regulating inflammation-related transcription factors, can inhibit nuclear factor-kappa B
(NF-kB) and suppress the secretion of inflammatory factors such as interleukin-1α (IL-1α),
IL-6, and tumor necrosis factor α (TNF-α) induced by oxidized low-density lipoprotein
(ox-LDL), exerting anti-inflammatory functions in mice20. In PCSK9 gene knockout mice,

14
while plaque volume and intimal thickness were reduced, the levels of inflammatory factors
within the plaques also decreased21. There is also evidence that inhibiting PCSK9 can
eliminate ox-LDL-mediated inflammatory responses in pro-inflammatory T cells and
dendritic cells, including downregulation of co-stimulatory molecules (CD83, CD86, and
HLA-DR) and scavenger receptors (LOX-1 and CD36) on the cell membrane, as well as
inhibition of T cell polarization towards Th1 and Th17 subsets22. After PCSK9 mAb
treatment, the expression of chemokine (C-C motif) receptor 2 (CCR2) on the surface of
monocytes can be reduced, thereby significantly decreasing monocyte infiltration in the
vascular wall23. Previous studies at our center found that after injecting PCSK9 inhibitor into
ischemia-reperfusion model mice, neurological dysfunction was alleviated compared to the
control group, and it was also found that the GPNMB/CD44 pathway-mediated inflammatory
response was inhibited24. In summary, a large amount of cellular and animal experimental
data currently supports the anti-inflammatory effects of PCSK9 inhibitors, but corresponding
clinical data to confirm this is still lacking. Although there has been some exploration in
studies of acute cardiovascular events, research on patients with ischemic stroke is still almost
nonexistent.
In addition to inflammatory responses, PCSK9 may also be involved in the formation of
arterial and venous thrombi. Studies have found that in in vitro experiments, after activation
by agonists, indicators of platelet interaction from human and mouse sources, such as
P-selectin and glycoprotein IIb/IIIa, are further elevated25,26. Additionally, in a carotid artery
injury mouse model with PCSK9 knockout, using ferric chloride to stimulate thrombus
formation, it was found that compared to wild-type mice, PCSK9 knockout mice took longer
to form arterial thrombi, and the volume of the thrombi formed was also smaller26. These
findings all suggest a correlation between PCSK9 and platelet activation reactivity. Similar
findings have also been observed in human populations. Navarese et al. found that in patients
with acute coronary syndrome, those with higher PCSK9 concentrations exhibited stronger
platelet aggregation responses after activation by adenosine diphosphate27. Barale et al. found
that after treating hypercholesterolemia patients with PCSK9i, their platelet activity
significantly decreased and their responsiveness to aspirin increased. Factors reflecting
platelet function, such as P-selectin and platelet factor 4, showed a significant decline28. A
meta-analysis including the FOURIER and ODYSSEY studies found no significant
correlation between baseline LDL-C levels and the extent of reduction in venous
thromboembolism risk. However, the use of PCSK9 inhibitors significantly reduced the risk
of venous thromboembolism (HR=0.69, 95% CI: 0.53~0.90, P=0.007)29.

15
In summary, PCSK9 can directly activate platelets on the one hand, and on the other hand, it
can lead to abnormal lipid and inflammatory states, indirectly causing a hypercoagulable state
in the body. Both of these enhance platelet function when PCSK9 levels are elevated. This
also suggests that, in addition to lowering lipid levels, PCSK9 inhibitors have the potential for
combined use with traditional drugs such as aspirin in patients requiring antiplatelet or even
anticoagulant therapy, thereby enhancing patients' responsiveness to antiplatelet drugs and
improving prognosis30.
V. Study Objectives
1. Primary Objective
To explore the effect of preoperative early intensive lipid-lowering therapy with PCSK9
inhibitor on good functional outcome at 90 days (modified Rankin Scale [mRS] score 0-2) in
patients with acute ischemic stroke with anterior circulation large vessel occlusion undergoing
endovascular treatment.
2. Secondary Objectives
Compared to the control group receiving guideline-recommended SoC, the effects of adding
PCSK9 inhibitor on the following aspects in patients with acute ischemic stroke with anterior
circulation large vessel occlusion undergoing endovascular treatment: mRS ordinal score at
90 days; NIHSS score at 14±3 days or before discharge; change from baseline in NIHSS
score at 14±3 days or before discharge; LDL-C target attainment rate at 14±3 days or before
discharge; change from baseline in LDL-C at 14±3 days or before discharge; change from
baseline in inflammatory markers (white blood cell count, CRP) at 14±3 days or before
discharge; rate of severe disability (mRS 3-5) at 90 days; mortality rate (mRS 6) at 90 days;
incidence of recurrent ischemic stroke events within 90 days; incidence of symptomatic
intracranial hemorrhage transformation within 48h; incidence of new-onset hemorrhagic
stroke within 90 days; incidence of MACEs within 90 days; incidence of SAEs within 90
days; European quality of life scale (EQ-5D) at 90 days.
VI. Study Methods
1. Overall Design:
This is a prospective, multicenter, open-label, randomized controlled clinical study. This
study will enroll 652 patients with acute ischemic stroke with anterior circulation large vessel

16
occlusion undergoing endovascular treatment from approximately 10+ clinical sites in China.
Patients will be randomly assigned 1:1 to the PCSK9 inhibitor treatment group and the SoC
control group. The study design is shown in the figure below (Study Design Flowchart).
2. Study Design (Flowchart)
3. Study Population
All patients with acute ischemic stroke with anterior circulation large vessel occlusion who
are planned to undergo endovascular reperfusion therapy at participating sites can be
considered for this study. The principal investigator at each site bears the primary
responsibility for patient enrollment. Because enrollment is recommended before stroke
patients receive endovascular treatment, successful enrollment is expected to require the
active participation of relevant physicians at each site. The following reasons are expected to
limit the enrollment rate:

The absolute number of patients receiving endovascular treatments;

Compliance with inclusion/exclusion criteria;

Obtaining informed consent, and conducting baseline assessments.
All patients with AIS with anterior circulation large
vessel occlusion who are planned to undergo
endovascular treatment
Meeting inclusion/exclusion criteria
1:1 randomization
Baseline blood sample
collection, preoperative NIHSS
score
Guideline-recommended SoC + one
subcutaneous injection of 450mg
Recaticimab
Guideline-recommended SoC
Control
Group
PCSK9i Group
Endovascular interventional
treatment
24-48 hours
Neuroimaging: Cranial CT
NIHSS score
NIHSS score
Blood sample collection
14 ± 3 days or at discharge
90 ± 7 days
mRS score at 90 days;
Within 90 days:
Recurrent ischemic stroke events;
New-onset hemorrhagic stroke events;
MACEs;
Safety evaluation:
EQ-5D scale

17
4. Inclusion and Exclusion Criteria
To meet the inclusion criteria for this study, patients must meet the local standard criteria for
endovascular treatment of acute ischemic stroke with anterior circulation large vessel
occlusion, and the attending physician must consider the clinical uncertainty for each patient,
weighing the potential benefits and risks of neuroprotective therapy, as follows:
4.1 Inclusion Criteria
[1] Adults (age 18 years and older);
[2] Imaging diagnosis of acute ischemic stroke with anterior circulation large vessel occlusion
(including: internal carotid artery, middle cerebral artery M1 and M2, anterior cerebral artery
A1 and A2);
[3] Planned to undergo endovascular intervention within 24 hours of symptom onset (or last
known well time) according to local guidelines;
[4] Provision of informed consent by the patient or his/her legally authorized representative
(or by an appropriate agent according to local requirements).
4.2 Exclusion Criteria
[1] ASPECTS score ≤5 on cranial CT imaging;
[2] Pre-existing functional impairment, with mRS score >2;
[3] Patients who are allergic to PCSK9 inhibitors;
[4] Patients who have received PCSK9 monoclonal antibody within 1 month prior to
enrollment or PCSK9 siRNA therapy within 6 months prior to enrollment;
[5] Severe renal insufficiency, defined as estimated glomerular filtration rate (eGFR) < 15
mL/min/1.73m2 at final screening;
[6] Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST)
or alanine aminotransferase (ALT) > 3 times the upper limit of normal;
[7] Severe, concomitant non-cardiovascular disease expected to reduce life expectancy to less
than 3 months;
[8] Pregnant or lactating women;
[9] Patients who are participating in other clinical trials;
[10] Other conditions deemed unsuitable for inclusion in the clinical study by the investigator.

18
5. Ethical Issues
This study adheres to the principles outlined in the Declaration of Helsinki of the World
Medical Association.
5.1 Ethics Committee Approval
Before patient enrollment begins, each participating site must obtain written approval from
the Ethics Committee (e.g., Institutional Review Board [IRB]). The principal investigator at
each study site is responsible for any amendments to the study protocol, reporting of serious
adverse events (SAEs), and routine reports to the IRB.
5.2 Informed Consent
Most patients presenting with acute ischemic stroke with large artery occlusion require
emergency treatment, including endovascular interventional therapy. However, the acute
nature of this condition means that patients may be unable to understand the information that
must be conveyed during the informed consent process due to their medical condition. To
avoid delays in emergency treatment, informed consent needs to be obtained promptly. The
optional informed consent procedures for this study are detailed below, and local Ethics
Committee regulations should be adhered to.
5.2.1 Patient Informed Consent
Whenever possible, the patient should provide written informed consent. A clinician familiar
with the study protocol will explain the situation to the patient and the implications of
consenting to participate in this study.
5.2.2 Legally Authorized Representative Informed Consent
If the patient is unable to provide informed consent, for example, due to a decreased level of
consciousness or confusion, the patient's legally authorized representative may provide
informed consent on his/her behalf.
5.2.3 Withdrawal of Informed Consent
The informed consent information provided to the patient and/or his/her legally authorized
representative will clearly state that the patient may withdraw from the study at any time
without explanation, and the patient will not be prejudiced or disadvantaged as a result. This
should be documented in the patient's file. If the patient withdraws consent only related to the

19
use of PCSK9i, data collection may continue, and this situation will be recorded in the
patient's file.

20
5.2.4 Confidentiality and Privacy
Patient privacy should be respected during the conduct of the study. To ensure patient privacy,
submitted data will be de-identified. However, during the monitoring of data quality and
adherence to the study protocol, clinical research associates (CRAs) may access medical
records at participating hospitals.
6 Randomization
6.1 Randomization Procedure
Eligible patients will be randomly assigned 1:1 according to a stratified block randomization
method to ensure balance between groups and within groups over time.
Stratification Factors:
1)
Medical center (stratified into 2 subgroups based on the number of patients who received
endovascular treatments for acute ischemic stroke at the center in the previous year:
50-99 patients/year; ≥100 patients/year)
2)
Time from onset to puncture (0-6h [inclusive]; 6-24h)
Procedure for Handling Patients Incorrectly Enrolled or Randomly Assigned
Under no circumstances should patients who do not meet the eligibility criteria be enrolled in
this study or undergo randomization. This principle must be adhered to in all situations.
If a patient who does not meet the eligibility criteria has already been enrolled in this study,
the following procedure should be followed:
1) The investigator or CRA should immediately notify the study team physician, with patient
safety as the top priority.
2) If continuing the study treatment may jeopardize the patient's safety, the study treatment
must be discontinued. After discussion between the study team physician and the investigator,
a decision will be made on whether to discontinue the study drug. The reason for
discontinuing study treatment must be clearly documented. The patient should undergo
follow-up according to the prescribed study procedures, including follow-up for endpoint
events, until the end of the study. This is consistent with the intention-to-treat principle.
3) If continuing the study is deemed not to pose a safety risk to the patient and not to affect
the treatment of the disease, the reason for continuing the study should be clearly documented.

21
The patient should continue to undergo follow-up according to the prescribed study
procedures.
6.2 Blinded Follow-up
Follow-up assessment scales, event occurrences, and imaging evaluations, etc., will be
analyzed, assessed, and recorded by a trained professional designated by each site or arranged
by the study coordinating site, who is unaware of the patient's treatment group assignment.
6.3 Blinded Review
After blinded review and confirmation of the correctness of the established database, the data
will be locked by the principal investigator and statistical analysts. Locked data files will not
be modified further.
7 Interventions
7.1 Study Drugs
7.1.1 PCSK9i Drug Selection
Drug Name: Recaticimab
Drug Strength: Lyophilized powder for injection, 150 mg/vial
7.2 Dosage and Method of Administration
Investigational Group: Recaticimab is added to the guideline-recommended SoC. After
randomization and before endovascular interventional treatment, patients will receive a
subcutaneous injection of Recaticimab. The specific method is: Recaticimab 450mg (3 vials)
as a single subcutaneous injection, until the end of the follow-up for this study.
The Phase III registration studies of Recaticimab, REMAIN-1 and REMAIN-2, have
confirmed good lipid-lowering efficacy and safety of Recaticimab 450mg SC Q12W (every
12 weeks). Considering that most acute stroke patients have limited mobility, to improve
subject follow-up compliance and ensure study quality, the 450mg SC Q12W dosing regimen
is chosen.
Control
Group:
Guideline-recommended
SoC,
including
but
not
limited
to
oral
lipid-lowering drugs, antiplatelet aggregation drugs, anticoagulant drugs, antihypertensive
drugs, etc. It is to be determined by the investigator based on the subject's treatment needs.
7.3 Drug Management

22
Drug management will be carried out in accordance with the package insert and the standard
operating procedures for pharmacy management at each hospital.
7.4 Surgical Method:
The surgical method for endovascular interventional reperfusion therapy is not restricted.
7.5 Prohibited Medications in the Study:
Any drugs targeting PCSK9 (including PCSK9 mAb or PCSK9 siRNA) or non-drug
lipid-lowering therapies (such as lipid filtration, etc.) are prohibited.
8. Withdrawal and Removal Criteria
8.1 Withdrawal at the Investigator's Discretion
If a situation arises during the study where it is inappropriate for an enrolled subject to
continue, the investigator will decide to withdraw the case from the study.
1)
Occurrence of allergic reactions or SAE, where the physician judges that the subject
should be withdrawn from the study.
2)
The patient's symptoms worsen after medication for which, to protect the subject, he/she
will be withdrawn from the study to receive other effective treatments.
3)
During the study, the subject develops certain comorbidities, complications, or special
physiological changes that affect the assessment of efficacy and safety.
4)
During the study, the subject has poor compliance, with drug usage less than 70% or
more than 130% of the prescribed amount.
5)
During the study, cases of unblinding for any reason;
6)
Other situations where the investigator deems it inappropriate to continue the study.
8.2 Withdrawal at the Subject's Discretion
According to the provisions of the informed consent form (ICF), subjects have the right to
withdraw from the study midway, or if a subject, although not explicitly withdrawing, is lost
to follow-up by no longer accepting medication and assessments, this is also considered
"withdrawal" (or "dropout").
Patients are free to withdraw from the study at any time (e.g., permanently discontinuing
study medication and withdrawing from study assessments) without affecting their further
treatment (withdrawal of informed consent). Withdrawal of informed consent from this study
must be confirmed by the investigator and recorded on the case report form (CRF) and the

23
ICF. If possible, the patient and the investigator should re-sign and date the ICF. These
patients should be asked the reason for withdrawal and whether any AEs are present. The
reason for permanent discontinuation of study drug treatment and the date of the last dose of
study drug must be recorded in the CRF.
Patients who permanently discontinue study medication should receive standard treatment, if
applicable, and should be asked to continue participating in visits. If the patient refuses any
additional study follow-up and formally withdraws informed consent (including whether they
consent to the continued use of collected de-identified clinical data), the study coordinating
site should be notified. If the patient and his/her family refuse the use of any clinical data for
the study, after notifying the study coordinating site, the database will be contacted to delete
all data for that patient.
At the end of the planned follow-up period for all patients (90 days ± 7 days
post-randomization), for patients who have withdrawn informed consent, their survival status
will be collected from public data sources to the extent permitted by local regulations after
their withdrawal of consent.
To ensure the validity of study data, it is important to collect as much data as possible during
the study period, especially survival status (dead or alive). Therefore, investigators should
attempt at the end-of-treatment visit and study closure visit to collect survival status
information for all patients who have withdrawn informed consent from public data sources.
Withdrawn subjects cannot be replaced.
8.3 Criteria for Case Removal
Subjects who should not have been enrolled but are enrolled, or who, although completing the
study, have violated certain provisions of the study protocol during the process and are
deemed by the investigator to warrant removal, include:
1)
Those who have never received study medication;
2)
Those with no assessment records after study medication;
3)
Those for whom efficacy and safety evaluation is impossible due to the use of a
prohibited medication.
At the blinded review meeting, the principal investigator and statisticians will decide whether
a case is to be removed and into which dataset it will be entered. The reasons for removing
cases should be stated, and their study medical records should be retained for inspection.

24
9. Study Endpoints:
Primary Endpoint:
1)
To compare the rate (%) of good functional outcome at 90 days (mRS 0-2) in patients
with acute ischemic stroke undergoing endovascular treatment between preoperative
intensive
lipid-lowering
therapy
with
PCSK9
inhibitor
(PCSK9i)
and
guideline-recommended standard of care (SoC).
Secondary Endpoints:
1)
mRS ordinal score at 90 days;
2)
NIHSS score at 14±3 days or before discharge;
3)
Change from baseline in NIHSS score at 14±3 days or before discharge;
4)
LDL-C target attainment rate at 14±3 days or before discharge;
5)
Change from baseline in LDL-C at 14±3 days or before discharge;
6)
Change from baseline in inflammatory markers at 14±3 days or before discharge;
7)
Rate of severe disability (mRS score 3-5) at 90 days;
8)
Mortality rate (mRS score of 6) at 90 days;
9)
Incidence of recurrent ischemic stroke events within 90 days;
10) Incidence of symptomatic intracranial hemorrhage transformation within 24-48h;
11) Incidence of new hemorrhagic stroke within 90 days;
12) Incidence of MACEs within 90 days;
13) Safety assessment;
14) Quality of life scale (EQ-5D).
10. Data Collection and Follow-up
Study sites need to collect all patient and study-related information at the following time
points: Baseline (after randomization, before treatment); treatment period (Day 0, day of
randomization); 24-48 hours post-randomization, Day 14±3 days or at discharge, and Day
90±7 days follow-up. Assessments at each follow-up time point will be conducted
face-to-face or by telephone by a trained physician designated by each study site or the study

25
coordinating site, who is blinded to the patient's treatment group assignment. The content of
the follow-up conversations must be audio-recorded and saved. For results of blood test
indicators at baseline and each follow-up time point, laboratory reports should be collected for
retention. Brain imaging data will be collected by each site. The study coordinating site will
assist each site with uploading imaging data. After uploading, a trained professional
designated by the study coordinating site, who is blinded to the patient's treatment group
assignment, will be responsible for imaging analysis. All data must be entered into the
database or recorded on paper CRFs and retained as source data.
All randomized patients will be followed up for 90 days ± 7 days. If death occurs before 90
days ± 7 days, follow-up will be performed until patient death. Patients who do not adhere to
the protocol and/or discontinue their assigned treatment regimen also need to be followed up
for 90 days ± 7 days, as their data will be analyzed according to the "intention-to-treat"
principle. The study flowchart lists the types of data to be collected and the schedule during
the study. The study coordinating site will provide paper versions of the CRFs and an
operations manual for reference, as well as CRF completion guidelines and definitions of
terms.
10.2 Randomization Assessment
For all patients undergoing endovascular treatment for acute ischemic stroke, the attending
physician will use an inclusion/exclusion criteria checklist to assess the patient's suitability for
enrollment in this study. This checklist needs to be kept with the patient's study file in a
locked filing cabinet at each participating study site.
Specifically, it includes:

Inclusion and exclusion criteria.

Medical center information: Name; Number of patients who underwent endovascular
treatments for acute ischemic stroke at the center in the previous year.

Patient information: Initials, sex, date of birth, time of onset (last known well time),
pre-stroke mRS score.

Imaging information: ASPECTS score on cranial CT, responsible vessel indicated by
CTA/MRA imaging.

Randomization stratification information: Hospital stratification, time from onset to
randomization.

Randomization result: Investigational group or control group.

26
10.3 Baseline Data
(1) Patient basic information and general condition: Height, body weight.
(2) History of present illness and physical examination: Time of arrival at hospital, blood
pressure on admission, heart rate, blood glucose, NIHSS score on admission, GCS score,
(3) Acute phase drug treatment information:
a) Whether intravenous thrombolysis is performed, name of thrombolytic drug (rtPA,
TNK, other, time of administration, dose);
b) Antithrombotic drugs used in the acute phase: Drug names: Aspirin, Clopidogrel,
Ticagrelor, Cilostazol, and Tirofiban, other, specific time of administration, dose.
(4) Past
medical
history:
Hypertension,
diabetes
mellitus,
stroke or
TIA,
cerebral
hemorrhage, ischemic heart disease, hyperlipidemia, arrhythmia, valvular heart disease,
history of smoking, history of alcohol consumption.
(5) Prior
medications: Anticoagulant drugs, antiplatelet drugs, lipid-lowering drugs,
including statins, ezetimibe, etc. Whether PCSK9i-related drugs have been used
previously, record name and time of use.
(6) Hematological parameters:
a)
Lipids:
Total
cholesterol,
low
density
lipoprotein
cholesterol,
high-density
lipoprotein cholesterol, triglycerides, lipoprotein (a), apolipoprotein B;
b)
Hematology: Red blood cell count, white blood cell count, hematocrit, hemoglobin,
platelet count;
c)
Blood chemistry: Renal function: Creatinine, uric acid; Liver function: Aspartate
aminotransferase, alanine aminotransferase; Glucose;
d)
Coagulation function tests: APTT, INR;
e)
Blood inflammatory response markers: CRP;
(7) Brain imaging: Study sites with necessary capability may complete brain tissue perfusion
assessment (record the time): Cranial CTP or PWI, etc., record core infarct volume,
hypoperfusion volume, and name of assessment software.
(8) ECG: Record the time, presence of atrial fibrillation.
10.4 Medication Information (Preoperative)

27
(1) PCSK9i use information, including drug information for PCSK9i (Recaticimab) (e.g.,
number), time of subcutaneous injection, and dose injected; Ensure patient adherence to
the assigned PCSK9i use regimen. If the dose deviates from the protocol, record the
reason.
(2) Other lipid-lowering therapy information, including oral lipid-lowering drugs such as
statins, fibrates, ezetimibe, etc. Record drug name, dose, time of administration, time of
discontinuation.
10.5 Interventional and Perioperative Treatment Information
(1) Endovascular treatment information: Arterial puncture time, time of first angiography,
number of thrombectomy attempts, mTICI grade of blood flow status before and after
thrombectomy, end of procedure time, whether angioplasty is performed (if yes, select:
simple balloon angioplasty, or balloon angioplasty + stent implantation).
10.6 Follow-up Data
10.6.1 24-48 Hours
(1) Neurological function assessment: GCS score and NIHSS score;
(2) Brain imaging:
Plain cranial CT: Assess for intracranial hemorrhage.
(3) Record presence of symptomatic intracranial hemorrhage transformation (Yes/No):
Symptomatic intracranial hemorrhage is defined as any apparent intracerebral or intracranial
hemorrhage associated with clinical deterioration. Specifically, it refers to hemorrhage that
leads to neurological deterioration, indicated by an increase of 4 points or more on the NIHSS
score compared to baseline or the lowest value, or hemorrhage that leads to death and is
identified as the primary cause of neurological deterioration.
10.6.2 Assessment Form at Day 14±3 or Discharge
On Day 14±3 postoperatively or on the day of discharge, confirm and record the detailed
contact information of the patient or his/her caregiver to facilitate future follow-up
assessments.
The following needs to be recorded:
(1) Assessment time, discharge (death) time

28
(2) Neurological function assessment: NIHSS score, mRS score, GCS score
(3) Ischemic stroke type (TOAST classification)
(4) Information on other treatments received during hospitalization:
a)
Whether decompressive craniectomy is performed
b)
Whether mechanical ventilation >24h is received
c)
Whether infection requiring antibiotics occurs
(5) Hematological parameters:
a)
Lipids:
Total
cholesterol,
low
density
lipoprotein
cholesterol,
high
density
lipoprotein cholesterol, triglycerides, lipoprotein (a), apolipoprotein B;
b)
Hematology: Red blood cell count, white blood cell count, hematocrit, hemoglobin,
platelet count;
c)
Blood chemistry: Renal function: Creatinine, uric acid; Liver function: Aspartate
aminotransferase, alanine aminotransferase; Glucose;
d)
Coagulation function tests: APTT, INR;
e)
Blood inflammatory response markers: CRP;
(6) Calculate and record whether current LDL-C is <1.8 mmol/L (70 mg/dL).
10.6.3 Day 90±7
The following needs to be recorded:
(1) mRS score
(2) Clinical events
a)
Recurrent ischemic/hemorrhagic stroke events
Adjudication of recurrent stroke events requires confirmation based on patient-provided
medical history, signs and symptoms, and imaging examinations, such as head CT or
MRI, to confirm the presence of new infarcts (ischemic stroke) or hemorrhages
(hemorrhagic stroke). All cases of suspected recurrent stroke should be confirmed by
imaging whenever possible to ensure the accuracy of new stroke events. The above will
be adjudicated by an Event Adjudication Committee, and original materials will be

29
collected and retained.
b)
Major adverse cardiovascular events (MACEs)
MACE is defined as a composite endpoint, including:
a)
Recurrent stroke (ischemic or hemorrhagic)
b)
Acute coronary syndrome
c)
New-onset or worsening peripheral vascular disease
d)
Cardiovascular death
Adjudication of MACEs requires confirmation based on patient-provided medical history,
signs and symptoms, imaging examinations, etc., adjudicated by the Event Adjudication
Committee, and original materials will be collected and retained.
(3) Safety assessment: Record potentially common adverse reactions, such as injection site
reactions, abnormal biochemical indicators, etc., and the investigator's determination of
their relevance to the study.
(4) Quality of life scale (EQ-5D).
(5) Lipids: Total cholesterol, low density lipoprotein cholesterol, high-density lipoprotein
cholesterol, triglycerides, lipoprotein (a), apolipoprotein B.
10.6.4 Death
If a patient dies before the planned follow-up time points listed above, documents regarding
the cause of death, including the date and time of death, must be collected. Copies of autopsy
reports, admission records, or death certificates should be kept with the subject contact
information form for monitoring by the study coordinating site.
10.7 Discontinuation of Assigned Treatment and Protocol Deviations
The study coordinating site will provide a form to record the date and specific circumstances
of protocol deviations or missed assessments.
10.8 Informed Consent
The informed consent process should be recorded in the patient's medical record and CRF,
and the type of informed consent obtained should be recorded in the database.
10.9 Serious Adverse Events
All SAEs should be recorded on the SAE form and reported to the study coordinating site via
fax or email within the specified timeframe. Supplementary information regarding the event

30
and outcome may be requested.
VII.
Study Flow Chart
Assessment Contents
Baseline
(Screening
and
Enrollment)
Administration
Within 24-48
hours
Day 14±3 or at
discharge
Day 90±7
(Endpoint Visit)
Signing ICF
X
Demographic
characteristics
X
Current medical
history
X
Past medical history
X
Concomitant
medications
X
X
Vital signs
X
X
X
X
Laboratory tests
X
X
X
Check
inclusion/exclusion
criteria
X
Randomization
X
Imaging examinations
X
X
PCSK9i medication
information
X
Information on
lipid-lowering drugs in
standard treatment
X
X
X
X
Endovascular
treatment information
X
mRS score
X
X
X
NIHSS score
X
X
X
Stroke or TIA events
X
MACE events
X
AEs
X
X
X
X
X
VIII.
SAEs
1. Definition:
The mechanism for notifying and reporting SAEs is based on guidelines adopted by the

31
International Council for Harmonization of Technical Requirements for Pharmaceuticals for
Human Use (ICH) - Good Clinical Practice (GCP) (ICH-GCP). According to the definition
made by WHO International Drug Monitoring Centre (1994), an SAE refers to any untoward
medical occurrence that:
1) Results in death;
2) Is life-threatening (i.e., the subject is at risk of death at the time of the event; it does not
refer to an event which hypothetically might have caused death if it were more severe);
3) Requires inpatient hospitalization or prolongation of existing hospitalization;
4) Results in persistent or significant disability or incapacity;
5) Results in a congenital anomaly or birth defect (please note, women in the study population
may be postmenopausal);
6) Is a medically important event that may not be immediately life-threatening or result in
death or hospitalization but may jeopardize the patient or may require intervention to prevent
one of the other outcomes listed in the definition above. These should also usually be
considered serious.
Since the primary endpoint of this study includes hemorrhagic transformation for any reason,
all post-infarction hemorrhagic transformations (any definition) in this study are considered
medically important events by the investigator and must be reported as SAEs.
Note: The following situations are not reported as SAEs:
1) Elective surgery planned before signing the ICF for this study;
2) Hospitalization required for routine health check-ups (e.g., routine colonoscopy, etc.);
3) Hospitalization solely for the purpose of neurological rehabilitation.
Unexpected adverse reaction (UAR) is an adverse reaction inconsistent with the package
insert. Suspected unexpected serious adverse reaction (SUSAR) is any unexpected adverse
reaction at any dose that:
1) Results in death
2) Is life-threatening (the patient is at risk of death at the time of the event; it does not refer to
an event that might have caused death if it were more severe)
3) Requires hospitalization or prolongation of current hospitalization
4) Results in persistent or significant disability or incapacity
5) Results in a congenital anomaly or birth defect
2．Recording and Reporting of Serious Adverse Events
Details of the event must be recorded on the SAE form, including a complete description of
the event, classification of the event according to the definitions above, the principal

32
investigator's judgment of the causal relationship between the randomized treatment group
and the SAE, and the onset time of the SAE. All SAEs must be reported to the study
coordinating site as soon as possible within 24 hours of becoming aware of them. To obtain
further information, the principal investigator may need to submit follow-up reports to
document the outcome of the SAE. The principal investigator is responsible for reporting
SAEs to the Ethics Committee according to local regulations.
Details of the event must be recorded on the SUSAR form, including a complete description
of the event, classification of the event according to the definitions above, the principal
investigator's judgment of the causal relationship between the SUSAR and the suspected drug,
and detailed information about the suspected drug. All SUSARs must be reported to the study
coordinating site as soon as possible within 24 hours of becoming aware of them. The
principal investigator may need to provide additional detailed information to supplement the
initial report of the SAE, and the outcome of the SUSAR must also be recorded. The principal
investigator is responsible for reporting SUSARs to the IRB or regulatory authorities
according to local regulations or administrative requirements.
3．Monitoring of Serious Adverse Events
The study coordinating site will closely monitor all SAEs to understand the relationship
between SAEs and study procedures and protocol, or the occurrence of clusters of similar
events at a specific site. If an excessive number of special SAEs related to the protocol occur,
the study protocol may need to be revised or the study terminated prematurely. In addition,
outside of planned interim analysis meetings, the study coordinating site will submit all
SUSARs to the Data Safety Monitoring Board (DSMB) for review.
4．Monitoring of Suspected Unexpected Serious Adverse Reactions
The study coordinating site will closely monitor all SUSARs to understand the relationship
between SUSARs and study procedures and protocol, or the occurrence of clusters of similar
events at a specific clinical study site. In addition, the study coordinating site will report
according to the requirements of the Ethics Committees of each participating site.
IX. Quality Assurance
The study will be conducted in hospitals with acute stroke units that can perform
thrombectomy and have experience in thrombectomy. CRAs will conduct data verification at
each study site and monitor the execution of the study. The first monitoring visit will take

33
place after the first few patients have been randomized at the study site, followed by
monitoring at least twice a year based on the number of enrolled patients. Monitoring will
ensure that investigators strictly adhere to the protocol and GCP requirements, guarantee the
authenticity and reliability of data, and ensure that all conclusions in the clinical study are
derived from source data.
1．Preservation and Monitoring of Source Documents/Files
Source documents are the basis for verifying the actual existence of subjects and the
credibility of collected data. Source documents should be kept at each study site.
Data on the CRF are derived from source documents and should be consistent with them. Any
discrepancies should be explained.
All other data (i.e., written or electronic text records without data) can be directly recorded on
the CRF and are recognized as source data.
Investigators must allow the sponsor to conduct monitoring and audits, the Ethics Committee
to review, and relevant regulatory authorities to conduct inspections, and allow the
aforementioned personnel to access all relevant source documents/files.
The CRF and all source data, including photocopies of laboratory tests and other medical
examination results, must be readily available for review by the clinical monitor designated
by the sponsor. CRAs should verify all CRFs and ICFs to confirm the accuracy of the data in
the documents.
2．Pre-Study Activities
Before the first subject is enrolled in the study, a representative of the study sponsor should
visit the study site to:
(1) Determine if the study site's facilities are adequate;
(2) Determine if the study site has suitable patients for enrollment;
(3) Discuss with the investigator/head of the study site (and other study-related personnel)
their responsibilities regarding the study protocol and the responsibilities of the study
sponsor or its representative, and document this in the clinical study agreement between
the study sponsor and the investigator/head of the study site.

34
3．Site Staff Training
Before the first study subject is enrolled, the leading site will provide standardized training
and assessment for the principal investigators and all investigators at the sub-sites. Sub-site
study initiation can only proceed after passing the assessment. The principal investigator must
ensure that all study personnel receive study-related training and that training records are
maintained.
The principal investigator will maintain a record of all study-related personnel (doctors,
nurses, and other staff).
4．Study Monitoring
During the study, the study sponsor will regularly contact the study site, including:
(1) Visiting the study site to provide information and support for the study to the
investigators
(2) Confirming that facilities still meet requirements
(3) Confirming that all study-related personnel are adhering to the study protocol, data on the
CRF are recorded promptly and accurately, and study drug accountability has been
verified
(4) Conducting source data verification (SDV) (comparing data on the CRF with the
subject's hospital records and other study-related records), which includes reviewing the
informed consent of study subjects. Direct access to all source records (e.g., inpatient
medical records) for each patient is required
If investigators or other staff at the study site require information or advice regarding study
implementation, they may contact the study sponsor during follow-up intervals.
Upon study completion, CRAs must ensure that each site has a plan for long-term (15 years)
retention of relevant materials and source documents.
5．Audits and Inspections by Government Regulatory Agencies
Additionally, the study may be audited by third-party organizations and by auditors
dispatched by government regulatory agencies. During and after the study, all study sites must
ensure that CRFs, source documents, and other study documents are accessible during audits

35
and inspections.
6．Source Data
The leading site will retain all original records and source data.
7．Archiving of Study Documents
Investigators should adhere to the principles outlined in the clinical study agreement.
8．Study Progress
If study procedures at an individual study site are not conducted according to the study
protocol, or if the recruitment period is excessively long, this study at that site may be
terminated. The study sponsor may also prematurely terminate this study due to safety
concerns in this study or other studies of PCSK9 inhibitor injections.
X. Data Management
Data entry will be completed by each participating site via a password-protected
internet-based data management system developed under commission by the study
coordinating site. Paper CRFs will be provided to sites that wish to use them for initial data
collection.
XI. Statistical Plan
1.
Statistical Analysis
General Analysis
For continuous data, statistics such as number, mean, standard deviation, median, minimum,
and maximum will be summarized; for categorical data, statistics such as frequency and
percentage will be summarized; for time-to-event data, the Kaplan-Meier method will be used
to estimate the survival function and the median time to event occurrence, and survival curves
will be plotted. Efficacy analyses of primary and secondary endpoints will be conducted in
the intent-to-treat (ITT) population, i.e., all randomized patients. Safety analysis will be
performed in the as-treated safety set (SS). In addition, a per-protocol set (PPS) will be also
established in this study: including all subjects who have completed the protocol-specified
treatment or do not have serious violations of the study protocol. The exact definition of
serious protocol violations will be finalized during data review and may generally include

36
(but is not limited to) the following situations: serious violation of eligibility criteria, presence
of treatment that seriously interferes with efficacy evaluation after enrollment, serious
violation of the medication regimen, lack of evaluation of primary efficacy endpoints, etc.
All statistical analyses will be performed using SAS 9.4 software or a later version.
Efficacy Analysis
The primary efficacy endpoint of this study is the percentage of mRS (0-2). A logistic
regression model adjusted for stratification factors will be used to estimate the odds ratio of
mRS (0-2) between the investigational group and the control group, along with the
corresponding 95% CI and p-value.
For the ordinal mRS endpoint among the secondary endpoints, a proportional-odds logistic
regression model adjusted for stratification factors will be used to estimate the common odds
ratio and its corresponding 95% CI and p-value. Other binary endpoints will be analyzed
using the same regression model as the primary endpoint.
For event endpoints, the Kaplan-Meier method will be used to estimate the median value, and
the Brookmeyer-Crowley method will be used to estimate the 95% CI for the median time to
event. Survival curves will be plotted, and the stratified Logrank test will be used to compare
survival differences between groups;
Safety Analysis
Safety analysis will primarily be descriptive statistical analysis. All AEs will be coded using
MedDRA and graded according to the NCI-CTCAE version 5.0 grading system. All
treatment-emergent AEs, drug-related AEs, serious adverse events (SAEs), and drug-related
SAEs will be listed by the highest severity.
Laboratory test results, vital signs, electrocardiogram (ECG) data, etc. will be analyzed using
conversion tables to compare the baseline and post-baseline conditions.
2.
Sample Size Estimation
This study is a randomized controlled trial. According to previous study reports, the
proportion of patients with mRS (0-2) in patients with acute ischemic stroke receiving
endovascular treatment from the control group is approximately 45%. Based on early study
data of the investigational treatment regimen, the proportion of patients with mRS (0-2) in the
investigational group in this study is expected to reach 58%, with an inter-group difference of
approximately 13%. The significance level ɑ is set at 0.05 (two-sided). Using the Z-test

37
(pooled) module of NCSS PASS 21 (LLC. Kaysville, Utah, USA, ncss.com/software/pass)
software, it is calculated that approximately 309 subjects need to be enrolled in each group to
provide at least 90% power (1-β) to detect a difference in the proportion of patients with mRS
(0-2) between the investigational treatment regimen and the control treatment regimen.
Considering 5% dropout and protocol violations, a total of 326 subjects need to be enrolled in
each group for this study, meaning a total of 652 subjects need to be enrolled for both groups.
XII.
Publication and Reporting
The main report will be published in the name of the principal investigator of this study. A
writing committee approved by the steering committee will fully manage the writing of the
report.
Investigators have the right to publish or present the study results. However, given that this is
a multicenter academic study, investigators agree not to publish or publicly report any interim
results of this study without the prior written consent of the steering committee. Investigators
agree to provide the steering committee with a copy of any abstract or manuscript reporting
study results (including but not limited to, text and slide presentations, any other
dissemination manuscripts or media presentations) for review at least 30 days prior to
submission.
The steering committee has the right to review and evaluate publications, abstracts, slides, and
manuscripts from the perspectives of information accuracy, protection of individual rights,
and ensuring that presentations are appropriately balanced and comply with relevant
regulations.
If there is disagreement among parties regarding the appropriateness of data analysis and
presentation, and/or confidentiality, investigators agree to meet with members of the steering
committee at the clinical site or an agreed-upon location before submission for publication, to
make every effort to discuss and resolve any such issues or disagreements in good faith.
The writing committee will be composed of members from various committees, statisticians,
researchers, and investigators, with credit attributed to collaborating investigators and other
study personnel.
Authors of publications must meet the following guidelines for authorship from the
International Committee of Medical Journal Editors:
1 Authors must have made substantial contributions to the conception and design of the study,
the acquisition of data, or the analysis and interpretation of results;

38
2 Authors must have drafted the publication or contributed to important revisions of the
manuscript (data analysis, interpretation, or other important intellectual content) during the
manuscript review process and received approval from other authors;
3 Authors must provide approval of the final draft manuscript before the article is submitted
to a journal for publication.
In accordance with the ICMJE guidelines for acknowledgments, if the journal permits, all
contributors who do not meet the above 3 criteria for authorship will be listed in the
acknowledgments section of the publication.
XIII.
Organizations
This study is an investigator-initiated and executed study, managed by Shanghai East Hospital
as the study coordinating site.
Participating Sites
Neurology Ward / Department of Neuroscience / Acute Stroke Unit / Neurosurgery
Responsibilities: Overall management of the study at their respective hospitals, ensuring
adherence to the study protocol; recruiting and training study nurses; introducing the protocol
to colleagues, enrolling patients, collecting data, resolving data queries, liaising with the local
hospital EC/IRB in accordance with local ethical guidelines and relevant reporting
requirements, and reporting adverse events to the local hospital EC/IRB and the study
coordinating site according to the protocol.
Data Safety Monitoring Board
This study will establish a DSMB, which will periodically review unblinded data during study
follow-up and monitor dropout rates and event incidence. A detailed statistical analysis plan
will be completed and archived before the enrollment of 50 patients, which will detail the
stopping rules to be used.
XIV.
Funding
Partial funding is provided by the New Clinical Medicine Specialty (Special Disease) under
the Construction of Peak and Plateau Disciplines in Pudong New Area in 2024
(2024-PWXZ-17) and the Key Discipline of Shanghai East Hospital (2024-DFZD-003).
Jiangsu Hengrui Pharmaceuticals Co., Ltd. provides partial funding, details as specified in the
contract.
XV.
Timeline

39
Central ethics submission: April 2025
Kick-off meeting, screening and enrollment: May 2025
End of follow-up: June 2028
Statistical analysis, publication: December 2028
XVI.
References
1.
Global, regional, and national burden of neurological disorders, 1990-2016: a systematic
analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18(5): 459-80.
2.
Wang Y-J, Li Z-X, Gu H-Q, et al. China Stroke Statistics: an update on the 2019 report
from the National Center for Healthcare Quality Management in Neurological Diseases,
China National Clinical Research Center for Neurological Diseases, the Chinese Stroke
Association, National Center for Chronic and Non-communicable Disease Control and
Prevention, Chinese Center for Disease Control and Prevention and Institute for Global
Neuroscience and Stroke Collaborations. Stroke Vasc Neurol 2022; 7(5): 415-50.
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Wang Y, Zhao X, Liu L, et al. Prevalence and outcomes of symptomatic intracranial
large artery stenoses and occlusions in China: the Chinese Intracranial Atherosclerosis
(CICAS) Study. Stroke 2014; 45(3): 663-9.
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Powers WJ, Rabinstein AA, Ackerson T, et al. 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. Stroke 2019; 50(12): e344-e418.
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Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after
large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised
trials. The Lancet 2016; 387(10029): 1723-31.
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Aguiar de Sousa D, von Martial R, Abilleira S, et al. Access to and delivery of acute
ischaemic stroke treatments: A survey of national scientific societies and stroke experts in 44
European countries. Eur Stroke J 2019; 4(1): 13-28.
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Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation.
Nature Medicine 2011; 17(7): 796-808.
8.
Xu S, Lu J, Shao A, Zhang JH, Zhang J. Glial Cells: Role of the Immune Response in
Ischemic Stroke. Front Immunol 2020; 11: 294.

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9.
Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of
Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the
American Heart Association/American Stroke Association. Stroke 2021; 52(7): e364-e467.
10. Abifadel M, Varret M, Rabès J-P, et al. Mutations in PCSK9 cause autosomal dominant
hypercholesterolemia. Nature Genetics 2003; 34(2): 154-6.
11. Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A. PCSK9 R46L,
low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent
studies and meta-analyses. Journal of the American College of Cardiology 2010; 55(25):
2833-42.
12. Barale C, Melchionda E, Morotti A, Russo I. PCSK9 Biology and Its Role in
Atherothrombosis. Int J Mol Sci 2021; 22(11).
13. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in
Patients with Cardiovascular Disease. The New England Journal of Medicine 2017; 376(18):
1713-22.
14. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after
Acute Coronary Syndrome. The New England Journal of Medicine 2018; 379(22): 2097-107.
15. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to
reduce cardiovascular risk. Atherosclerosis 2019; 290: 140-205.
16. Yuan HW, Yang YN, Chen HF, et al. Rise in Low-Density Lipoprotein Cholesterol
during Hospitalization is Related with Poor Outcome at Discharge in Patients with Acute
Ischemic Stroke. Cerebrovasc Dis 2020; 49(1): 88-96.
17. Gao Y, Jiang L, Pan Y, et al. Immediate- or Delayed-Intensive Statin in Acute Cerebral
Ischemia: The INSPIRES Randomized Clinical Trial. JAMA Neurol 2024; 81(7): 741-51.
18. Kim J, Hong U, Yoon CW, Bae JW, Rha J-H, Park H-K. PCSK9 inhibitor in acute
ischemic stroke patient receiving mechanical thrombectomy: early outcomes and safety.
Front Neurol 2024; 15: 1375609.
19. Ding Z, Liu S, Wang X, et al. PCSK9 regulates expression of scavenger receptors and
ox-LDL uptake in macrophages. Cardiovasc Res 2018; 114(8): 1145-53.
20. Tang Z, Jiang L, Peng J, et al. PCSK9 siRNA suppresses the inflammatory response
induced by oxLDL through inhibition of NF-κB activation in THP-1-derived macrophages.
Int J Mol Med 2012; 30(4): 931-8.

41
21. Ferri N, Marchianò S, Tibolla G, et al. PCSK9 knock-out mice are protected from
neointimal formation in response to perivascular carotid collar placement. Atherosclerosis
2016; 253: 214-24.
22. Liu A, Frostegård J. PCSK9 plays a novel immunological role in oxidized LDL-induced
dendritic cell maturation and activation of T cells from human blood and atherosclerotic
plaque. J Intern Med 2018.
23. Bernelot Moens SJ, Neele AE, Kroon J, et al. PCSK9 monoclonal antibodies reverse the
pro-inflammatory profile of monocytes in familial hypercholesterolaemia. European Heart
Journal 2017; 38(20): 1584-93.
24. Zheng Y, Zhu T, Li G, Xu L, Zhang Y. PCSK9 inhibitor protects against ischemic
cerebral
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GPNMB/CD44
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25. Akram ON, Bernier A, Petrides F, Wong G, Lambert G. Beyond LDL cholesterol, a new
role for PCSK9. Arterioscler Thromb Vasc Biol 2010; 30(7): 1279-81.
26. Camera M, Rossetti L, Barbieri SS, et al. PCSK9 as a Positive Modulator of Platelet
Activation. Journal of the American College of Cardiology 2018; 71(8): 952-4.
27. Navarese EP, Kolodziejczak M, Winter M-P, et al. Association of PCSK9 with platelet
reactivity in patients with acute coronary syndrome treated with prasugrel or ticagrelor: The
PCSK9-REACT study. International Journal of Cardiology 2017; 227: 644-9.
28. Barale C, Bonomo K, Frascaroli C, et al. Platelet function and activation markers in
primary hypercholesterolemia treated with anti-PCSK9 monoclonal antibody: A 12-month
follow-up. Nutr Metab Cardiovasc Dis 2020; 30(2): 282-91.
29. Marston NA, Gurmu Y, Melloni GEM, et al. The Effect of PCSK9 (Proprotein
Convertase Subtilisin/Kexin Type 9) Inhibition on the Risk of Venous Thromboembolism.
Circulation 2020; 141(20): 1600-7.
30. Deoker A, Lehker A, Mukherjee D. Updates in Anti-anginal and Anti-ischemic Therapies
for Acute Coronary Syndromes. Curr Cardiol Rep 2020; 22(10): 126.
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2023,38(3):237-271.

42
XVII. Appendices
1. Modified Rankin Scale (mRS)
The modified Rankin scale is used to measure the status of neurological function recovery in
patients after stroke. Bold text shows the formal definition of each level, while italicized text
provides further guidance to reduce potential errors between different observers, but there are
no requirements for the structure of the interview. Please note to consider only symptoms that
have occurred since the stroke. If the patient does not require external help and can walk with
the aid of certain assistive devices, they are considered able to walk independently.
If two levels seem equally applicable to the patient, and further questioning is unlikely to lead
to an absolutely correct choice, the more severe level should be chosen.
0 No symptoms at all
Although there may be minor symptoms, the patient has not noticed any new 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 some symptoms caused by the stroke, whether physical or cognitive (e.g.,
affecting speech, reading, writing; or physical movement; or sensation; or vision; or
swallowing; or emotions), but can continue to perform all work, social, and leisure activities
they engaged in before the stroke. The key question to distinguish between level 1 and level 2
(see below) can be, "Are there some things you used to do regularly that you can no longer do
since the stroke?" Activities with a frequency of more than once a month are considered usual
activities.
2 Slight disability; unable to carry out all previous activities, but able to look after own
affairs without assistance
Certain activities that could be performed before the stroke (such as driving, dancing, reading,
or working) can no longer be performed by the patient after the stroke, but they can still take
care of themselves daily without assistance from others. The patient is able to dress, walk, eat,
go to the toilet, prepare simple food, shop, and travel locally without the help of others. The
patient does not require supervision in their daily life. It is envisioned that patients at this
level can live alone at home for a week or longer without care.
3 Moderate disability; requires some help, but able to walk without assistance
At this level, the patient can walk independently (possibly with the aid of assistive walking

43
devices), and can independently dress, go to the toilet, eat, etc., but more complex tasks
require assistance from others. For example, requiring others to do shopping, cooking, or
cleaning, and visiting the patient more than once a week to ensure these activities are
completed. Assistance needed is not only for physical care but also for advice, for example:
patients at this level will require supervision or encouragement to manage finances.
4 Moderately severe disability; unable to walk without assistance and unable to attend
to own bodily needs without assistance
The patient requires help from others to manage daily life, whether it is walking, dressing,
going to the toilet, or eating. The patient needs to be looked after at least once a day, usually
twice or more, or must live very close to a caregiver. To distinguish between level 4 and level
5 (see below), consider whether the patient can routinely live alone for an appropriate period
during the day.
5 Severe disability; bedridden, incontinent, and requiring constant nursing care and
attention
Although a trained nurse is not required, someone needs to look after them throughout the day
and several times at night.
6. Dead

44
2. NIH Stroke Scale
Instructions
Scale Definition
Score
1a Level of Consciousness (LOC):
The examiner must choose a response 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 = Drowsy, arousable by minimal stimulation to
obey commands, answer questions, or respond
2 = Stuporous or obtunded, requires strong or
repeated stimulation or painful stimulation to make
non-stereotyped responses
3 = Responds only with reflex motor or autonomic
effects or is totally unresponsive, flaccid, and
areflexic
1b LOC Questions: (Score only the first
answer, examiner should not prompt)
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.
0 = Answers both questions correctly
1 = Answers one question correctly
2 = Answers neither question correctly or unable
to speak
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 (e.g., stick out tongue) if the
hands cannot be used. Only the first
attempt is scored. 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, and then the score
is
recorded.
Patients
with
trauma,
amputation, or other physical impediments
should
be
given
suitable
one-step
commands.
0 = Performs both tasks correctly
1 = Performs one task correctly
2 = Performs neither task correctly

45
2 Best Gaze:
Only horizontal eye movements will be
tested.
Voluntary
or
reflexive
(oculocephalic) eye movements will be
scored. If the patient has a conjugate
deviation of the eyes that can be overcome
by voluntary or reflexive activity, score 1.
If the patient has an isolated peripheral
nerve paresis (Cranial Nerve (CN) III, IV,
V), score 1. Gaze is testable in aphasic
patients. In patients with ocular trauma,
bandages, blindness, or other disorder of
visual acuity or fields, the examiner should
choose
a
reflexive
movement
to
test.
Establish eye contact and then move from
one
side
to
the
other,
which
may
occasionally reveal gaze palsy.
0 = Normal
1 = Partial gaze palsy (gaze is abnormal in one or
both eyes, but forced deviation or total gaze
paresis is not present)
2 = Forced deviation, or total gaze paresis not
overcome by the oculocephalic maneuver
3 Visual Fields
Test upper and lower quadrant visual fields
by confrontation, using finger counting or
visual threat, as appropriate. If the patient
can see fingers in the lateral fields, score as
normal. If one eye is blind or enucleated,
test the other eye. Score 1 if there is
clear-cut
asymmetry,
including
quadrantanopia. If patient is bilaterally
blind (any cause), score 3. Stimulate both
eyes
simultaneously.
If
the
patient
is
moribund, score 1; the result is used for
question 11.
0 = No visual loss
1 = Partial hemianopia
2 = Complete hemianopia
3 = Bilateral hemianopia (blind, including cortical
blindness)
4 Facial Palsy:
Ask patient, or use pantomime, to show
teeth, raise eyebrows, and close eyes. In
the
poorly
responsive
or
non-comprehending
patient,
score
symmetry of grimace to noxious stimuli. If
facial trauma/bandages, orotracheal tube,
tape or other physical barriers obscure the
face, these should be removed to the extent
possible for assessment.
0 = Normal
1 = Minor (flattened nasolabial fold, asymmetry on
smiling)
2 = Partial (total or near-total paralysis of lower
face, central palsy)
3 = Complete (paralysis of one or both sides,
absence of facial movement in the upper and lower
face, peripheral palsy)

46
5 Motor Arm
Arm extension: 90º if sitting, 45º if supine.
Ask to hold for 10 seconds; encourage
aphasic patients with language or gestures,
do not use noxious stimuli. The assessor
can lift the patient's upper limb to the
required position and encourage the patient
to hold it.
0 = Arm holds required position for 10 seconds
with no drift
1 = Arm can be lifted but cannot be maintained for
10 seconds, drifts down without hitting bed or
other support
2 = Some effort against gravity, but arm cannot
reach or maintain 90º (sitting) or 45º (supine),
drifts down to bed fairly quickly
3 = No effort against gravity, arm falls rapidly
4 = No movement
9 = Amputation or joint fusion
5a Left Arm
5b Right Arm
6 Motor Leg
Leg raised 30º in supine position, hold for
5 seconds; encourage aphasic patients with
language or gestures, do not use noxious
stimuli. The assessor can lift the patient's
upper limb to the required position and
encourage the patient to hold it.
0 = Holds required position for 5 seconds, no drift
1 = Drifts down by end of 5 seconds, does not hit
bed
2 = Falls to bed fairly quickly within 5 seconds,
but some effort against gravity
3 = Falls to bed immediately, no effort against
gravity
4 = No movement
9 = Amputation or joint fusion
6a Left Leg
6b Right Leg
7 Limb Ataxia:
This item is aimed at finding evidence of
a unilateral cerebellar lesion. Test with
eyes open. If there is visual loss, ensure
testing is done in intact visual field.
Bilateral finger-nose and heel-shin tests.
Score if ataxia is present and out of
proportion to weakness. Do not score if
patient
cannot
understand
or
limb
is
paralyzed. Blind patients touch nose with
extended
arm.
If
amputation
or
joint
fusion, score 9 (untestable [UN]) and
explain clearly.
0 = Absent
1 = Present in one limb
2 = Present in two limbs
If ataxia is present;
Left arm 1 = Yes 2 = No
9 = Amputation or joint fusion
Right arm 1 = Yes 2 = No
9 = Amputation or joint fusion
Left leg 1 = Yes 2 = No
9 = Amputation or joint fusion
Right leg 1 = Yes 2 = No
9 = Amputation or joint fusion
8 Sensory:
Examine
with
a
pin.
During
testing,
observe sensation and facial expression in
0 = Normal, no sensory loss
1 = Mild to moderate; pinprick sensation is less
sharp or dull on the affected side, or patient is

47
stuporous or aphasic patients by pinprick
stimulation and withdrawal. Score only
sensory loss attributed to stroke. Patients
with
hemisensory
loss
require
precise
examination; test multiple body areas:
arms (not hands), legs, trunk, face. Severe
or total sensory loss, score 2. Aphasic
patients can be scored 1 or 0. Bilateral
sensory loss in brainstem stroke, score 2.
Unresponsive and quadriplegic patients,
score 2. Comatose patients (1a=3), score 2.
aware of being touched
2 = Severe to total sensory loss; patient is not
aware of being touched in the face, arm, and leg
9 Best Language
Naming, reading tests. Ask patient to name
items,
read
listed
sentences.
Judge
comprehension from patient's responses
and responses to commands in the general
neurological
examination.
If
visual
impairment interferes with testing, have
the patient identify items placed in the
hand,
repeat,
and
articulate.
Intubated
patients
should
write
answers.
For
comatose patients (1a=3), score 3. Choose
a score for stuporous or uncooperative
patients, but score 3 only for patients who
are mute or do not follow commands at all.
0 = Normal, no aphasia
1 = Mild to moderate aphasia: some loss of
fluency or comprehension, but expression is not
significantly limited.
2 = Severe aphasia; communication is through
fragmented
expression;
listener
must
infer,
question, and guess. Range of information that can
be
exchanged
is
limited;
examiner
feels
communication is difficult.
3 = Mute or global aphasia; no usable speech or
auditory comprehension
10 Dysarthria:
Do not tell the patient why this test is being
done.
Read or repeat words from the attached
list. If the patient has severe aphasia, assess
clarity of articulation during spontaneous
speech. If patient is intubated or has other
physical barriers preventing speech, score
9 (UN). Also note the reason.
0 = Normal
1 = Mild to moderate; at least some slurring but
can be understood with some difficulty
2 = Speech is so slurred as to be unintelligible
9 = Intubated or other physical barrier
11 Extinction and Inattention (formerly
Neglect):
If
severe
visual
loss
interferes
with
bilateral visual simultaneous examination,
and cutaneous stimuli are normal, score as
normal. If the patient is aphasic but does
0 = No neglect
1 = Visual, tactile, auditory, spatial, or personal
inattention; or extinction to bilateral simultaneous
stimulation in any sensory modality
2 = Profound hemi-inattention; more than one
modality of hemi-inattention; does not recognize

48
demonstrate attention to both sides, score
as normal.
Assess for neglect by testing the patient's
ability
to
recognize
simultaneous
cutaneous sensory and visual stimuli on the
right and left sides. Show the standard
picture to the patient and ask them to
describe it. If the patient cannot recognize
parts of the picture on one side, it is
considered abnormal. Then, the physician
asks the patient to close their eyes and tests
bilateral cutaneous sensation by pinprick
on the upper or lower limbs separately. If
the patient has unilateral sensory neglect, it
is abnormal.
own hand or orients to one side of space only
Total
Notes:
Score according to the table, record the results. Do not change the score; the score reflects the patient's
actual condition, not what the physician thinks the patient should be. Perform a rapid examination and
record the results simultaneously. Unless necessary for pointing, do not train the patient (e.g., by repeatedly
asking the patient to make an effort).
If some items are not assessed, explain in detail in the form.
Appendix: Chart for Items 9 and 10 Examination
Reading Test Picture 1
Reading Test Picture 2
Reading Test Picture 3
Please read the following sentences:
Know
Go downstairs
Go home to cook
Review at school
Deliver a wonderful speech
Reading Test Picture 4
Please read the following words:
Mama
Earth
Airplane
Silk
Start work on time
Eat grapes but do not spit out
grape skins

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Basic Principles and Precautions for NIHSS Scoring
Basic Principles for NIHSS Scoring:
Record the patient's first response, even if subsequent responses may be better;
Note to record only what the patient does, not what you think they are capable of doing;
Record while examining, and try to avoid leading the patient;
For items that cannot be evaluated, please record the score as "9"; computer statistical
processing will automatically treat it as a missing value;
"Consistency" principle: Maintain consistent evaluation criteria during multiple follow-ups.
How to Assess NIHSS Score in Comatose Patients?
For patients with a score of less than 3 on item 1a, each item should be assessed individually.
Item 1a is scored 3 only when the patient has no response to any noxious stimuli (sternal rub,
supraorbital pressure, etc.), only reflex activity.
If 1a = 3 points, other items should be assessed as follows:
1b - LOC Questions: 2 points
1c - LOC Commands: 2 points
2 - Best Gaze: Assessed based on whether it can be overcome by the oculocephalic maneuver.
If it can be overcome, score 1 point; if not, score 2 points.
3 - Visual Fields: Assessed using visual threat.
4 - Facial Palsy: 3 points
5, 6 - Limb Movement: 4 points for each limb
7 - Limb Ataxia: Score only if ataxia is present. If the patient's muscle strength is reduced and
they cannot complete tests like finger-nose or heel-shin, score 0 points.
8 - Sensory: 2 points
9 - Best Language: 3 points
10 - Dysarthria: 2 points
11 - Extinction and Inattention: Coma implies loss of all cognitive abilities, so score 2 points.
How to Calculate the Total NIHSS Score?
When calculating the total score, the following items should not be included in the total score:
Items 5 and 6 - Limb Movement: "9 = amputation or joint fusion"
Item 7 - Limb Ataxia: The items for determining the location of ataxia, i.e., "Left arm 1 = Yes
2 = No 9 = amputation or joint fusion, explain:" (not required for registration).

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3. European Quality of Life Scale (EQ-5D)
The following are various descriptions of your health today. Please tick the most accurate and
appropriate item in each group:
1. Mobility
Thinking carefully about your health today, which of the following best describes your
mobility?
□I have no problems in walking about
□I have some problems in walking about
□I am confined to bed
2. Self-Care
Thinking carefully about your health today, which of the following best describes your
self-care?
□I have no problems with self-care
□I have some problems washing or dressing myself
□I am unable to wash or dress myself
3. Usual Activities
Thinking carefully about your health today, which of the following best describes your
usual activities (e.g., work, study, housework, family or leisure activities)?
□I have no problems performing my usual activities
□I have some problems performing my usual activities
□I am unable to perform my usual activities
4. Pain/Discomfort
Thinking carefully about your health today, which of the following best describes any
pain or discomfort you may be currently experiencing?
□I have no pain or discomfort
□I have moderate pain or discomfort
□I have extreme pain or discomfort
5. Anxiety/Depression

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The best health
you can imagine
The worst health
you can
imagine
Thinking carefully about your health today, which of the following best describes any
anxiety or depression you may be currently experiencing?
□I am not anxious or depressed
□I am moderately anxious or depressed
□I am extremely anxious or depressed
To help you indicate how good or ba
d your health is, we have drawn a sc
ale (rather like a thermometer).
On this scale, 100 represents the best
health you can imagine, and 0 repre
sents the worst health you can imagin
e.
Please mark an “×” on the scale to indicate how your he
alth is today.
Please write the number you marked on the scale in the l

52
ine below: ________

[Enter here]
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4. Specific Criteria for Glasgow Coma Scale (GCS) Scoring:
Eye Opening Response: Spontaneous: 4 points
To speech: 3 points
To pain: 2 points
No response to any stimuli: 1 point
Eyes cannot be opened due to swelling, fracture, etc.: C
Verbal Response: Oriented (correctly oriented, can clearly state name, etc.): 5 points
Confused (disoriented, answers incorrectly): 4 points
Inappropriate words: 3 points
Incomprehensible sounds: 2 points
No response: 1 point
Endotracheal intubation or tracheostomy preventing normal speech: T
Motor Response: Obeys commands: 6 points
Localizes pain: 5 points
Withdraws from pain: 4 points
Flexion to pain (decorticate posturing): 3 points
Extension to pain (decerebrate posturing): 2 points
No response: 1 point