Department of Interventional Neurology, Beijing Tiantan Hospital, Capital Medical University
Phase: EARLY_PHASE1
Conditions: Intracranial Artery Occlusion With Infarction
Sponsor: Feng Gao

Protocol V1.0
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Endovascular Recanalization vs Medical Treatment
for Non-Acute Intracranial Artery Occlusion (ERNA-IAO):
A Multicenter, Prospective, Cohort Study
Study Protocol
Principal Investigator
Feng Gao, MD, Professor of Neurology
Research team
Beijing Tiantan Hospital, Capital Medical University, Beijing, China
China National Clinical Research Center for Neurological Diseases, Beijing, China
Protocol V1.0
20 November 2019

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ERSNAO-IAO Study
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Protocol Signature Page
STUDY TITLE:
Endovascular
Recanalization
vs
Medical
Treatment
for
Non-Acute
Intracranial Artery Occlusion (ERNA-IAO): A Multicenter, Prospective,
Cohort Study
VERSION NUMBER：
V 1.0
VERSION DATE:
20 November 2019
I have read this protocol and agree to conduct this clinical investigation in accordance with the design and
specific provisions outlined herein. I understand the protocol, and I understand I am solely responsible to ensure
the investigation is conducted in accordance with Good Clinical Practices, applicable international regulations,
local regulations, and with the protocol outlined herein. I will conduct this study as outlined therein and will
make reasonable effort to complete the study within the designed time flow.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who will
assist in the conduct of this study. I will discuss this material with them to ensure they are fully informed
regarding the endovascular treatment and the conduct of the study.
I will fulfill the requirements of my Ethics Committee (EC), and/or other oversight committee, to ensure
complete and continual oversight of this clinical investigation. I will use an Informed Consent Document
approved by my reviewing oversight committee(s).
I agree to report all information or data in accordance with the protocol and, in particular, I agree to report any
serious adverse events as defined in this protocol to my reviewing oversight committee, where required. I agree
to permit regulatory authority access to all records relating to the clinical investigation, whether paper-based or
electronic data capture.
The below signature confirms I have read and understood this clinical investigational protocol and its associated
amendments or attachments.
PRINTED OR TYPED NAME
SIGNATURE
DATE
Principal Investigator
PRINTED OR TYPED NAME
SIGNATURE
DATE
Study Statistician

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Table of Contents
List of Abbreviations.................................................................................................................................5
Protocol Synopsis.......................................................................................................................................6
Schedule of assessments............................................................................................................................ 9
1. Background.......................................................................................................................................... 11
2. Study Objective....................................................................................................................................12
3. Methods................................................................................................................................................ 12
3.1 Study Design................................................................................................................................12
3.2 Participants Selection and Enrollment.........................................................................................12
3.3 Participating Center Eligibility....................................................................................................13
3.4 Ethical Issues............................................................................................................................... 13
3.5 Baseline Imaging Evaluation.......................................................................................................13
3.6 Treatments and Study Groups..................................................................................................... 14
3.7 Risk Factor Management.............................................................................................................15
3.8 Follow-up.....................................................................................................................................15
3.9 Outcomes.....................................................................................................................................15
3.10 Data Collection and Management............................................................................................. 16
3.11 Safety and Adverse Events........................................................................................................ 18
3.12 Endpoint Events and Adverse Events Assessment....................................................................19
3.13 Blinding..................................................................................................................................... 20
3.14 Imaging Core Laboratory.......................................................................................................... 20
3.15 Quality Control..........................................................................................................................20
3.16 Statistical Analyses....................................................................................................................20
3.17 Publications................................................................................................................................21
4. References.............................................................................................................................................22
5. Appendix...............................................................................................................................................26
Appendix 1. Modified Rankin Scale................................................................................................. 26
Appendix 2. Modified TICI Scale (mTICI Scale).............................................................................27
Appendix 3. National Institute of Health Stroke Scale (NIHSS)...................................................... 28
Appendix 4. EuroQoL 5D-5L............................................................................................................33
Appendix 5. Heidelberg bleeding classification................................................................................35
Appendix 8. posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS)........... 38

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List of Abbreviations
ADP
Adenosine Diphosphate
AE
Adverse Event
aHR
Adjusted Hazard Ratio
ALT
Alanine Aminotransferase
APTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
ASTIN/SIR
American Society of Therapeutic and Interventional Neuroradiology /Society of
Interventional Radiology
ASPECTS
Alberta Stroke Program Early CT Score
BA
Basilar Artery
BMI
Body Mass Index
BP
Blood Pressure
CI
Confidence Interval
CICAS
The Chinese Intracranial Atherosclerosis (study)
CRF
Case Report Form
CT
Computed Tomography
CTA
Computed Tomography Angiography
CTP
Computed Tomography Perfusion Imaging
DWI
Diffusion Weighted Imaging
DSA
Digital Subtraction Angiography
EC
Ethics Committee
EC-IC
Extracranial-Intracranial
OEAC
Outcome Event Arbitration Committee
EVT
Endovascular Treatment
ER
Endovascular Recanalisation
ERNA-IAO
The Endovascular Recanalization for Non-Acute Intracranial Artery Occlusion
(study)
EQ-5D
EuroQOL-Five-Dimensions
FIB
Fibrinogen
GCS
Glasgow Coma Scale
HbA1c
Glycated Hemoglobin
HDL
High Density Lipoprotein
HI1
Hemorrhagic Infarction 1
HI2
Hemorrhagic Infarction 2
HR
Hazard Ratio

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IAO
Intracranial Artery Occlusion
ICA
Internal Carotid Artery
ICF
Informed Consent Form
ICH
Intracranial Hemorrhage
IFU
Instructions for Use
IQR
Interquartile Range
LDL
Low Density Lipoprotein
INR
International Normalized Ratio
IVH
Intraventricular Hemorrhage
MCA
Middle Cerebral Artery
MRA
Magnetic Resonance Angiography
MRI
Magnetic Resonance Imaging
mRS
Modified Rankin Scale
mTICI
Modified Thrombolysis In Cerebral Infarction Score
NA-IAO
Non-Acute Intracranial Artery Occlusion
NIHSS
National Institute of Health Stroke Scale
OR
Odds Ratio
pc-ASPECTS
Posterior Circulation Alberta Stroke Program Early CT Score
PH1
Parenchymal Hemorrhage 1
PH2
Parenchymal Hemorrhage 2
PMI
Pons-Midbrain Index
PSM
Propensity Score Matching
PT
Prothrombin Time
PWI
Perfusion Weighted Imaging
RAPID
Rapid Processing of Perfusion and Diffusion
RIH
Ischemic Field
SAE
Serious Adverse Event
SAH
Subarachnoid Hemorrhage
SD
Standard Deviation
sICH
Symptomatic Intracranial Hemorrhage
sNA-IAO
Symptomatic Non-Acute Intracranial Artery Occlusion
TIA
Transient Ischemic Attack
TT
Thrombin Time
VA
Vertebral Artery

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Protocol Synopsis
Title
Endovascular Recanalization vs Medical Treatment for Non-Acute Intracranial
Artery Occlusion (ERNA-IAO): A Multicenter, Prospective,Cohort Study
Sponsor
Beijing Tiantan Hospital, Capital Medical University
Study period
Enrollment from January 1,2020 to October 31, 2023 (and 1 year follow-up)
Study Centers
Interventional Neuroradiology, Department of Neurology, Beijing Tiantan Hospital,
Capital Medical University;
Department of Neurology, Beijing Liangxiang Hospital;
Department
of
Neurointerventional
Radiology,
Beijing
Fengtai
You’anmen
Hospital;
Department of Neurology, Ordos Central Hospital;
Department of Neurology, Jingjiang People's Hospital Affiliated to Yangzhou
University;
Department of Neurology, Taizhou first people's Hospital.
Study Objectives
The primary objective of this study is to investigate whether endovascular
recanalisation (ER) plus medical treatment is superior to medical treatment alone
for symptomatic non-acute intracranial artery occlusion (sNA-IAO) in the primary
outcome.
Study Design
multicenter, prospective, cohort study
Study Population
Patients with sNA-IAO, with the time from the latest ischemic event (ischemic
stroke or transient ischemic attack) in the territory of the qualifying artery to
enrollment being beyond 24 hours and within 90 days, as confirmed by computed
tomography angiography (CTA) or digital subtraction angiography (DSA).
Inclusion Criteria

(1) Age ranging between 18 and 80 years.

(2) sNA-IAO defined as：
①Time from latest ischemic event (ischemic stroke or TIA) in territory of
the qualifying artery to enrollment is beyond 24 hours and within 90 days.
②Occlusion of intracranial internal carotid artery, M1 segment of middle
cerebral artery, intracranial vertebral artery (with contralateral vertebral
artery hypoplasia or occlusion) or basilar artery confirmed by computed
CTA or DSA.

(3) Computed tomographic (CT) or magnetic resonance imaging (MRI)
demonstrating ASPECTS ≥6 (for anterior circulation), or pc-ASPECTS ≥6 and

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pons-midbrain index (PMI) <3 (for posterior circulation).

(4) Modified Rankin Scale (mRS) score 0-2 at the time of enrollment.

(5) Technical feasibility of endovascular recanalization for the qualifying artery
evaluated by two experienced interventional neuroradiologists.

(6) More than one risk factor for atherosclerosis.

(7) Signed informed consent form.
Exclusion Criteria

(1) Severe stenosis or occlusion of other arteries, or tandem stenosis proximal
to the qualifying artery.

(2) Intracranial hemorrhagic diseases such as definite Intracranial tumors, any
intracranial vascular malformations, hemorrhagic transformation of infarction,
spontaneous intracranial hemorrhage (cerebral parenchymal, subarachnoid,
subdural, or epidural) within 30 days.

(3)
Non atherosclerotic
intracranial arterial disease:
arterial dissection,
moyamoya
disease
or
moyamoya
syndrome
demonstrated
by
imaging
examination, or a definite medical history of autoimmune vasculitis.

(4) Evidence of cardioembolic embolism such as atrial fibrillation, prosthetic
valve(s), infective endocarditis, mitral stenosis, atrial myxoma, intracardiac clot
or vegetation, left ventricular aneurysms and so on.

(5) Known unstable angina or myocardial infarction within the last 6 months.

(6) Intolerance or allergic reaction to any treatment-related medication,
including aspirin, clopidogrel, heparin, and local or general anesthetics.

(7) History of life-threatening allergy to contrast dye.

(8) Severe liver impairment (AST or ALT > 3 times normal, cirrhosis), serum
creatinine > 3.0 mg/dl.

(9) Past history of EC-IC bypass surgery or EVT.

(10) Major surgery (including open femoral, aortic, or carotid surgery) within
previous 30 days or planned in the next 90 days after enrollment.

(11) Late-stage malignant tumors, cachexia, or other serious diseases and an
expected life expectancy of less than 1 year.

(12) Pregnant, perinatal stage or lactating women.
Treatments
and
Study
Groups
The technical feasibility of ER for all sNA-IAO patients in this study will be
collaboratively evaluated by two experienced interventional neuroradiologists. The
decision to select either medical treatment alone or additional ER is made by the
patients themselves or their legal representatives. Patients are subsequently divided
into two groups based on selection of treatment approach: the medical group and
the ER group.

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Follow-up schedule
Baseline, 30±7 days, 90±7 days, 1 year±30 days
Primary Outcome
The primary outcome is a composite outcome as follows:

Any stroke or death within 30 days after enrollment

Ischemic stroke in the territory of the qualifying artery form 30 days to 1 year
after enrollment.
Secondary Endpoints
Secondary outcomes as follows:

Mortality within 1 year;

Ischemic stroke outside the territory of the qualifying artery within 1 year;

Disabling stroke within 1 year;

TIA in the territory of the qualifying artery within 1 year;

Unplanned revascularization (EC-IC bypass surgery or ER) of the qualifying
artery within 1 year;

Myocardial infarction within 1 year;

Composite vascular events within 1 year, including any stroke, myocardial
infarction, and unplanned revascularization;

Quality of life assessment (EuroQol-5-Dimensions scale questionnaire) at 1
year;

mRS score at 1 year;

Periprocedural outcomes;

Restenosis or reocclusion (symptomatic or asymptomatic).
Statistical Methods

Categorical variables will be compared between treatment groups using χ² or
Fisher's exact test. Continuous variables or ordinal variables will be compared
between treatment groups using t-test or Wilcoxon-Mann-Whitney test.

The primary and time-to-event secondary outcomes will be compared between
the groups using log-rank test.

Kaplan-Meier curves wil be used to show the incidence of outcomes over time.

The hazard ratio (HR) and adjusted hazard ratio (aHR) between groups, along
with their 95% CIs, will be determined using univariate and multivariate Cox
proportional hazards regression models.

Propensity score matching (PSM) will be performed to reduce the possible
influence of selection bias and confounders on the outcomes.

A 2-sided P value less than 0.05 is considered to demonstrate a statistically
significant difference.

All analyses will be performed with using SAS Version 9.4.

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Schedule of assessments
Table 1: Summary of Study Treatment and Study Assessments
Study Requirements
Screening
and Baseline
Endovascular recanalisation
Discharge
Follow-up Visits
Pre-procedure
Intra-procedure
Post-procedure
30-Day
(±7 days)
90-Day
(±7 days)
1-Year
(±30 days)
Inclusion/Exclusion
X
X
Informed Consent
X
Clinical Assessment, Vital Signs, and Physical
Exam
X
X
X
X
X
X
Laboratory tests
X
X
X
X
NIHSS (blinded to treatment)
X
X
X
mRS (blinded to treatment)
X
X
X
X
X
EQ-5D (blinded to treatment)
X
X
X
mTICI assessment
X
X
X
CT/MRI
X
X
X
X
CTP/PWI
X
X
X
CTA/DSA
X
X
X
Protocol Deviations
X
X
X
X
X
X
X
Medication review and patient compliance survey
X
X
X
X
X
X
X
X
Primary and secondary outcomes
X
X
X
X
X
X

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Figure 1. Study design and treatment grouping flowchart

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1. Background
Intracranial large artery atherosclerotic stenosis or occlusion constitutes one of the major etiologies of
ischemic stroke worldwide.1,2 Previous studies have showed that ischemic stroke among Asian populations,
African Americans, and Hispanic populations are primarily attributable to intracranial large artery stenosis
and occlusion.3,4 The Chinese Intracranial Atherosclerosis (CICAS) Study revealed that in the Chinese
population, 33%-50% of ischemic strokes and over 50% of transient ischemic attacks (TIAs) were caused by
intracranial artery stenosis or occlusion.5 Furthermore, patients with intracranial artery occlusion (IAO)
exhibit higher mortality rates, stroke incidence, and recurrence rates.5 Beyond this, a series of studies have
consistently demonstrated that the most common location for IAO is in the anterior circulation, with middle
cerebral artery occlusion being the most prevalent, while in the posterior circulation, basilar artery occlusion
is frequently observed.6,7
Endovascular treatment (EVT) has been proven to be an effective treatment option within the established
time window for acute ischemic stroke attributable to IAO.8,9,10,11,12 Additionally, the relevant clinical trials
have collectively established the extension of the therapeutic window for EVT in acute IAO to 24 hours.13,14
However, a significant number of patients with acute ischemic stroke attributable to IAO frequently fail to
achieve endovascular recanalisation (ER) during the acute phase due to delays in reaching a qualified stroke
center in time after symptom onset.15 Consequently, these patients were compelled to transition into the
non-acute phase. Currently, there is no definite definition for non-acute intracranial artery occlusion. To
distinguish the therapeutic time window for acute occlusion, previous studies has defined occlusion with a
duration exceeding 24 hours as non-acute occlusion.16,17 In patients with symptomatic non-acute intracranial
artery
occlusion
(sNA-IAO),
severe
hemodynamic
compromise
resulting
from
chronic
cerebral
hypoperfusion has emerged as a significant contributor to both initial occurrence and recurrence of ischemic
stroke, demonstrating strong correlation with adverse functional outcomes.1,18 Nevertheless, the optimal
therapeutic approach for sNA-IAO beyond 24 hours after symptom onset continues to pose a significant
clinical challenge.
Clinical experience suggests that for sNA-IAO patients presenting with significant clinical manifestations or
experiencing symptom progression/recurrence despite receiving optimal medical management, ER or
extracranial-intracranial (EC-IC) bypass surgery may be considered as therapeutic options. With respect to
EC-IC bypass surgery, previous studies have failed to demonstrate superior efficacy compared to medical
treatment in patients with symptomatic atherosclerotic large artery occlusion accompanied by severe
hemodynamic compromise.19,20,21 Regrettably, large-scale prospective controlled studies specifically
investigating the potential superiority of endovascular recanalization for patients with sNA-IAO remain
scarce. Notably, a collection of case series reports and small retrospective analyses have demonstrated that
ER for carefully selected sNA-IAO patients beyond the 24-hour window seems feasible and may represent a
promising therapeutic option.16,17,22,23,24,25,26,27,28,29,30 Nonetheless, this studies were single arm, small sample
size, retrospective studies. While ER may represent a potential therapeutic alternative for sNA-IAO patients
refractory to medical treatment, there is a paucity of controlled studies establishing its definitive superiority
over medical management. Furthermore, compared to EVT in acute IAO, recanalization procedures in
non-acute cases are associated with elevated procedure-related risks and increased susceptibility to
symptomatic intracranial hemorrhage, raising substantial safety concerns.

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Consequently, We conducted a multicenter, prospective, cohort study to investigate whether ER combined
with medical treatment is superior to medical treatment alone for sNA-IAO.
2. Study Objective
The primary objective of this study is to investigate whether ER plus medical treatment is superior to
medical treatment alone for sNA-IAO in the primary outcome (any stroke or death within 30 days after
enrollment or ischemic stroke in the territory of the qualifying artery beyond 30 days through 1 year after
enrollment).
3. Methods
3.1 Study Design
The Endovascular Recanalization for Non-Acute Intracranial Artery Occlusion (ERNA-IAO) study is a
multicenter, prospective, cohort study, this cohort prospectively will enroll consecutive patients with
radiologically confirmed sNA-IAO at 6 comprehensive stroke centers in China from January 1,2020 to
October 31, 2023. All participants or their legal representatives provide written informed consent before
enrollment. The primary objective of this study is to evaluate whether ER plus medical treatment is superior
to medical treatment alone for patients with sNA-IAO presenting beyond 24 hours after symptom onset. All
study centers complied with the Expert Consensus on Standardized Diagnosis and Treatment in China,
ensuring consistent data acquisition across sites. The study protocol was approved by the Institutional Ethics
Committee of Beijing Tiantan Hospital (approval number: KY2020-114-02), and each subcenter, and will
follow the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline.
3.2 Participants Selection and Enrollment
Patients eligible for initial study screening are those who present with occlusion in the intracranial internal
carotid artery (ICA), M1 segment of middle cerebral artery (MCA), intracranial vertebral artery (VA) or
basilar artery (BA), presenting beyond 24 hours of symptom onset. All such patients who meet all eligibility
criteria as follows and with informed consent will be enrolled in the study.
3.2.1 Inclusion criteria
Patient eligibility for study enrollment is determined based on the following inclusion criteria:
(1) Age ranging between 18 and 80 years.
(2) sNA-IAO defined as：
①Time from latest ischemic event (ischemic stroke or TIA) in territory of the qualifying artery to
enrollment is beyond 24 hours and within 90 days.
②Occlusion of intracranial ICA, M1 segment of MCA, intracranial VA (with contralateral VA
hypoplasia or occlusion) or BA confirmed by computed tomographic angiography (CTA) or
digital subtraction angiography (DSA).
(3) Computed tomographic (CT) or magnetic resonance imaging (MRI) demonstrating Alberta Stroke
Program Early CT Score (ASPECTS) ≥6 (for anterior circulation) or Posterior Circulation Alberta Stroke
Program Early CT Score (pc-ASPECTS) ≥6 and pons-midbrain index (PMI) <3 (for posterior circulation).
(4) Modified Rankin Scale (mRS) score 0-2 at the time of enrollment.
(5) Technical feasibility of endovascular recanalization for the qualifying artery evaluated by two
experienced interventional neuroradiologists.
(6) More than one risk factor for atherosclerosis.

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(7) Signatured informed consent form.
3.2.2 Exclusion criteria
Patients are deemed ineligible for study participation if they meet any of the following exclusion
criteria:
(1) Severe stenosis or occlusion of other arteries, or tandem stenosis proximal to the qualifying artery.
(2) Intracranial hemorrhagic diseases such as definite Intracranial tumors, any intracranial vascular
malformations, hemorrhagic transformation of infarction, spontaneous intracranial hemorrhage (cerebral
parenchymal, subarachnoid, subdural, or epidural) within 30 days.
(3) Non atherosclerotic intracranial artery disease: arterial dissection, moyamoya disease or moyamoya
syndrome demonstrated by imaging examination, or a definite medical history of autoimmune vasculitis.
(4) Evidence of cardioembolic embolism such as atrial fibrillation, prosthetic valve(s), infective endocarditis,
mitral stenosis, atrial myxoma, intracardiac clot or vegetation, left ventricular aneurysms, etc.
(5) Known unstable angina or myocardial infarction within the last 6 months.
(6) Intolerance or allergic reaction to any treatment-related medication, including aspirin, clopidogrel,
heparin, and local or general anesthetics.
(7) History of life-threatening allergy to contrast dye.
(8) Severe liver impairment (AST or ALT > 3 times normal, cirrhosis), serum creatinine > 3.0 mg/dl.
(9) Past history of EC-IC bypass surgery or EVT.
(10) Major surgery (including open femoral, aortic, or carotid surgery) within previous 30 days or planned in
the next 90 days after enrollment.
(11) Late-stage malignant tumors, cachexia, or other serious diseases and an expected life expectancy of less
than 1 year.
(12) Pregnant, perinatal stage or lactating women.
3.3 Participating Center Eligibility
To minimize selection bias, all participating centers are mandated to systematically enroll consecutive
eligible patients according to predefined protocol criteria. To be fully eligible for participation in this study,
participating centers selection are required to meet the following minimum criteria:(1) all study centers are
required to have performed at least 120 endovascular procedures annually, including at least 40 cases of
intracranial artery endovascular procedures; (2) the interventional neuroradiologists at these centers had each
performed over 100 endovascular procedures..
3.4 Ethical Issues
All the patients gave written informed consent to participate. The study protocol was approved by the
Institutional Ethics Committee of Beijing Tiantan Hospital (approval number: KY2020-114-02), and the
respective institutional review boards of all participating centers. Participation in the study did not alter the
standard clinical care protocols for enrolled patients.
3.5 Baseline Imaging Evaluation
All participants will have baseline imaging (MRI or CT to rule out ICH and exclude major infarction, and
CTA/DSA to confirm an occlusion in the MCA, BA, intracranial ICA or VA), performed as part of
institutional standard of care procedures for stroke management. All imaging data of this baseline imaging
(including raw data) must be provided to the imaging core laboratory for assessment of collateral

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compensation, location of the occlusion and determination of ASPECTS (pc-ASPECTS for posterior
circulation), etc.
3.6 Treatments and Study Groups
The technical feasibility of endovascular recanalization for all sNA-IAO patients in this study will be
collaboratively evaluated by two experienced interventional neuroradiologists. The decision to select either
medical treatment alone or additional ER is made by the patients themselves or their legal representatives.
Patients are subsequently divided into two groups according to the treatment they received: the medical
group and the endovascular recanalization (ER) group. Patients in ER group will receive endovascular
recanalisation procedure (details in procedure part below) plus medical treatment (same as the control
group).
3.6.1 Endovascular recanalisation (ER)
For patients presenting with ICA or MCA M1 segment occlusion, ipsilateral cerebral hemodynamic
compromise is rigorously evaluated through computed tomography perfusion (CTP) or magnetic resonance
perfusion imaging prior to enrollment according to a previous study.31 Moreover, the non-contrast and
perfusion scans are additionally transferred to the Rapid Processing of Perfusion and Diffusion (RAPID)
system, providing analysis of perfusion source images with respect to the DEFUSE 3 criteria13.
All patients who are scheduled to undergo ER should receive dual antiplatelet therapy (aspirin 100 mg per
day and clopidogrel 75 mg per day) for at least three days before the procedure.
All procedures are performed under general anesthesia by an experienced interventional neuroradiologist.
After placement of sheath introducers, heparin is given intravenously to maintain the coagulation time
between 200 and 300 s. The 6- or 8- French guiding catheter is located distal to the occluded artery as much
as possible. Under the route map, the micro guidewire in combination with a microcatheter and the
microcatheter are used to carefully pass through the occluded segment. Angiography with the microcatheter
should confirm that the guidewire is in the true lumen. The exchange micro guidewire is then sent into the
micro catheter, and the microcatheter is exchanged out. The balloon catheter is advanced smoothly into the
occluded segment along the exchange micro guidewire. After the occluded segment is dilated with the
balloon, angiography with a guiding catheter is performed. Stents are deployed in cases of residual severe
stenosis, vascular dissection and failure to maintain forward flow (according to the judgment of the
neuroradiologist to select the stent). If one stent cannot completely cover the lesion, multiple stents can be
implanted. Successful recanalization was defined as achieving a modified Thrombolysis in Cerebral
Infarction (mTICI)32 grade of 2b or higher, coupled with residual arterial stenosis less than 50% in
immediate post-procedural DSA imaging..
After the procedure, if there are no evidence of hemorrhagic complications on the head CT scan, dual
antiplatelet therapy is systematically continued. Aspirin 100 mg per day must be used for the entire duration
of follow-up, and clopidogrel 75 mg per day (or ticagrelor 90mg twice a day) must be used for 90 days after
procedure. After 90 days, the decision to whether to continue clopidogrel therapy will be based on the
patient's clinical condition and the investigator's assessment.
3.6.2 Medical treatment

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Medical treatment will be identical in both groups. Both groups are prescribed with an medical treatment
(includes aspirin 100 mg per day for the entire follow-up and clopidogrel 75mg per day for the first 90 days
after enrollment). In instances where clopidogrel pharmacogenetic resistance testing is performed, and the
results demonstrate either a loss-of-function CYP2C19 allelic variant or an adenosine diphosphate
(ADP)-induced platelet aggregation rate exceeding 40%, alternative antiplatelet agents such as ticagrelor or
cilostazol may be strategically implemented as therapeutic substitutes. Atorvastatin will be administered at a
dosage of 20 mg to 80 mg per day for one year following enrollment, with the continuation of treatment
thereafter contingent upon the patient's condition.
3.7 Risk Factor Management
Risk factor management is based on 2014 American Heart Association/American Stroke Association
guidelines33 for the clinical management of cerebrovascular disorders. Medical management of risk factors
consists of normalizing low-density lipoprotein (LDL-C) (target LDL-C: <2.59 mmol/L [100mg/dL]),
hypertension (systolic pressure <140 mmHg and a diastolic pressure <90 mmHg; patients with
diabetes
should be controlled with a blood pressure of <130/80 mmHg), diabetes (hemoglobin A1c [HbA1c] <6.5%),
and lifestyle modification(include encompassing smoking cessation, alcohol consumption reduction[up to 2
drinks per day for men and half for women], and targeted weight management interventions [BMI <25
kg/m2], moderate physical exercise [at least 40 minutes per session, 3-4 times per week]).
At each research site, neurologists and study investigators will be principally entrusted with comprehensive
management of patients' cerebrovascular risk factors. Should a patient fail to achieve the target goals for risk
factor management, a face-to-face clinical consultation with the local neurologist will be required to adjust
the patient's medical management.
3.8 Follow-up
All participants will be followed up by the neurologists at 30±7 days, 90±7 days, 1 year ±30 days. The
preferred follow-up modality is to implement face-to-face clinical evaluations. At every scheduled follow-up
visit, the participants’ medication regimens, laboratory tests, risk factor management (as previously outlined),
and potential adverse clinical events/outcomes are evaluated by an experienced neurologist and/or
neurointerventionalist.When patients are unable to attend on-site clinical follow-ups, a remote telephonic
follow-up will be utilized as an alternative method of patient assessment.During the 1-year follow-up period,
all patients are required to undergo a neurovascular imaging examination including DSA, CTA or MRA.
For perioperative patients in ER group, a clinical examination including the National Institutes of Health
Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS) will be carried out at 24-72 hours after the
procedure. Meanwhile, patients will undergo CT to assess the cerebral hemorrhage at 24-72 hours, if
possible, supplementary assessment of vessel recanalization status will be conducted through CTA or MRA.
At the one-week post-intervention assessment, a clinical evaluation will be conducted,including patients’
clinical status, NIHSS score, GCS score, and adverse events.
3.9 Outcomes
3.9.1 Primary outcome
The primary outcome is a composite of any stroke or death within 30 days after enrollment or ischemic
stroke in the territory of the qualifying artery from 30 days to 1 year after enrollment.

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Ischemic stroke is defined as a new focal neurological deficit of sudden onset persisting for at least 24 hours
and confirm by cerebral infarction on CT or MRI. Ischemic stroke are further classified as being either in or
out of the territory of the qualifying artery. We regard ischemic stroke either in or out of the territory of the
qualifying artery within 30 days after enrollment as a primary outcome, but beyond 30 days through 1 year,
only ischemic stroke in the territory of the qualifying artery is considered as a primary outcome. We define
symptomatic intracranial hemorrhage (sICH) as parenchymal, intraventricular, or subarach noid hemorrhage
identified on brain MRI or CT, which led to new emergence or worsening of neurological symptoms lasting
more than 24 hours or a seizure. Death is categorized as vascular-related or non-vascular-related, and
all-cause death is considered a primary outcome within 30 days.
Ischemic stroke and intracranial hemorrhage will be determined by core-lab assessment of imaging, and
neurological assessment will be performed at the study site by independent neurologist certified in NIHSS,
adjudication of outcomes will be done by an outcome adjudication committee.
3.9.2 Secondary outcomes
Secondary outcomes as follows:

Mortality within 1 year;

Ischemic stroke outside the territory of the qualifying artery within 1 year;

Disabling stroke within 1 year;

TIA in the territory of the qualifying artery within 1 year;

Unplanned revascularization (EC-IC bypass surgery or ER) of the qualifying artery within 1 year;

Myocardial infarction within 1 year;

Composite vascular events within 1 year;

Quality of life assessment (EuroQol -Five-Dimensions [EQ-5D] scale questionnaire) at 1 year;

mRS score at 1 year;

Periprocedural outcomes;

Restenosis or reocclusion (symptomatic or asymptomatic).
Disabling stroke is defined by any of the following: (1) an mRS score of 3 or more, (2) an increase of at
least 1 point in the mRS score from prestroke baseline, (3) a score on the composite NIHSS of 7 or more, or
(4) an increase of at least 4 points in the NIHSS score from pre-stroke baseline.
TIA is defined as duration of a focal or global neurological deficit <24 hours, any variable neuroimaging
does not demonstrate a new hemorrhage or infarction.
Composite vascular events within 1 year included any stroke, myocardial infarction, and unplanned
revascularization within 1 year.
Periprocedural outcomes are: (1) successful recanalization rate, (2) periprocedural complications: in-stent
thrombosis, distal embolization, symptomatic intracranial hemorrhage, parenchymal hematoma type 2
(defined by the Heidelberg classification34), arterial dissection, arterial perforation, (3) residual stenosis, (4)
NIHSS score at 24-72 hours, (5) death within 7 days.
Restenosis is defined as >50% stenosis within or immediately adjacent (within 5 mm) of the treated segment
and >20% absolute luminal loss, reocclusion is defined as total occlusion of the target artery segment.
3.10 Data Collection and Management
3.10.1 Baseline clinical data collection and evaluation

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When the patient is enrollled, clinical and neurological assessments will be completed per institutional
standard of care. linical data were comprehensively collected by independent neurologists. Data to be
collected and then captured on Case Report Form (CRF) include:

Medical history, concomitant medication, demographic data collection

Ischemic stroke history record

Relevant concomitant medications administered

Vital signs: Blood pressure, heart rate, respiration, body temperature

Laboratory tests: blood routine, urine routine, blood biochemistry, coagulation function examination
Blood biochemistry: Renal function: creatinine, urea (or urea nitrogen), glucose, uric acid, total
bilirubin, direct bilirubin, indirect bilirubin, lactate dehydrogenase, creatine kinase isoenzyme;
liver function: alkaline phosphatase, glutamyl transpeptidase, aspartate aminotransferase, alanine
aminotransferase; blood lipids: total cholesterol, low-density lipoprotein, high-density lipoprotein,
triglyceride;
Coagulation function: prothrombin time (PT), activated partial thromboplastin time (APTT),
thrombin time (TT), Fibrinogen (FIB), international normalized ratio (INR).

Significant findings from clinical assessment and physical exam

All significant neurological findings, pre-stroke mRS, mRS and NIHSS at enrollment assessed by
qualified personnel at time of admission
3.10.2 Perioperative and 7-day postoperative follow-up data collection
These data include:

Anesthesia Types: general anesthesia or local anesthesia

Procedure times (groin puncture time, time of first microcatheter placement across the occlusion, time
of initial flow restoration, time of guide catheter removal)

Site-assessed mTICI score at post procedure

Perioperative medication collection

Perioperative complications

Significant findings from clinical assessment and physical exam (e.g. all new, worsening or improved
conditions)

Patient compliance survey
3.10.3 30±7 days after enrollment data collection

Relevant concomitant medications collection (including anti-platelet, lipid-lowering, and other
medications)

Blood pressure, blood routine, urine routine, blood biochemistry

Fasting blood glucose, HbA1c (optional)

Patient smoking cessation, weight, and exercise data are collected

mRS

The disease treatment-related cost information collection

Outcome events observation

Patient compliance survey
3.10.4 90±7 days after enrollment data collection

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
Relevant concomitant medications collection (including anti-platelet, lipid-lowering, and other
medications)

Blood pressure, blood routine, urine routine, blood biochemistry

Fasting blood glucose, HbA1c (optional)

CT/MRI (optional)

CTP/perfusion weighted imaging (PWI) (optional)

CTA/DSA (optional)

Patient smoking cessation, weight, and exercise data are collected

mRS

The disease treatment-related cost information collection

Outcome events observation

Patient compliance survey
3.10.5 1 year±30 days after enrollment data collection

Relevant concomitant medications collection (including anti-platelet, lipid-lowering, and other
medications)

Blood pressure, blood routine, urine routine, blood biochemistry

Fasting blood glucose, HbA1c (optional)

CT/MRI (optional)

CTP/PWI (optional)

CTA/DSA (optional)

Patient smoking cessation, weight, and exercise data are collected

mRS, EQ-5D

The disease treatment-related cost information collection

Outcome events observation

Patient compliance survey
3.11 Safety and Adverse Events
3.11.1 Adverse events (AE)
An adverse event (AE) is defined as any unfavorable and unintended sign, symptom, or disease that occurs
to a study subject during the use of a medical treatment or intervention, regardless of whether it is deemed
related to the treatment. A preexisting condition should not be reported as an adverse event unless the
condition worsens or episodes increase in frequency during the adverse event reporting period.
3.11.2 Serious adverse events (SAE)
A serious adverse event (SAE) is defined as any adverse event that results in death, is life-threatening,
requires hospitalization or prolongation of existing hospitalization, results in persistent or significant
disability or incapacity, causes a congenital anomaly or birth defect, or requires medical intervention to
prevent one of the above-mentioned outcomes.
3.11.3 Anticipated Adverse Events
Anticipated AEs are events whose nature is consistent with the safety information contained in the device
documentation, specifically in the Instructions for Use (IFU) of the medical device utilized for the

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study-specific procedures. The term “anticipated” does not imply that these events are expected to occur as a
consequence of the underlying disease.
The assessment of whether an event is anticipated or not will be carried out by the investigator and the
second assessor.
The following list of adverse events and complications (derived from the Instructions for Use, IFUs) must be
considered during the assessment of “anticipatedness”. Only the events listed below are regarded as
anticipated：

Hematoma and hemorrhage at puncture site

Perforation or dissection of the vessel

Vasoconstriction (Vasospasm)

Change in mental status

Persistent neurological deficits

Neurologic deterioration including stroke progression and stroke in new vascular territory

Brain edema

Ischemia

Infection

Allergic reactions

Air embolism

Intracerebral/intracranial hemorrhage

Vascular occlusion

Pseudo aneurysm formation

Aneurysm perforation

Post procedure bleeding

Distal embolization including to a previous uninvolved territory

Adverse reaction/anaphylaxis to antiplatelet/anticoagulation agents

Adverse reaction (anaphylaxis, kidney damage) to contrast media

Device(s) deformation, collapse, fracture or malfunction

Thrombosis (acute and subacute)

Inability to completely remove thrombus

Arteriovenous fistula

Seizure

Pain/headache
3.11.4 Documentation of Adverse Events
All SAEs will be recorded in the case report form (CRF) table. The details of the SAEs, including start time,
end time, duration, treatment, outcome, and relationship to the intervention, will also be documented. The
frequency of SAEs will be summarized according to the study assignments. All recorded AEs and SAEs will
be reported to the investigator. In this study, SAEs primarily refer to disabling strokes, symptomatic
intracranial hemorrhages or death within 1 year after enrollment.
3.12 Outcome Events and Adverse Events Assessment

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Endpoint events determination will be conducted through a meticulous review process by an independent
Outcome Event Arbitration Committee (OEAC), guaranteeing unbiased and systematic assessment.The
OEAC is constituted by three independent clinical experts, strategically selected to ensure comprehensive
and objective evaluation of critical research endpoints.First two independent experts will simultaneously
conduct parallel, back-to-back arbitration assessments.In cases of assessment inconsistency,a third expert
will be activated to render a conclusive judgment.
Meanwhile, members of the OEAC will systematically review and independently adjudicate all reported
complications in strict accordance with the predefined adverse events in the clinical events committee
manual of operations.When a potential endpoint may occur, the committee board will immediately convene
a meeting to evaluate whether such an event can be categorized as the primary outcome.
3.13 Blinding
All those involved in the subsequent clinical and imaging assessment of outcomes will be blinded to
treatment regime.
3.14 Imaging Core Laboratory
A centralized imaging core laboratory will be utilized to provide uniform and objective assessment of
radiological
images.The
imaging
core laboratory
evaluated
the
findings
including
the
ASPECT
(pc-ASPECTS for posterior circulation), baseline vessel imaging (CTA or DSA) for the location of the
occlusion, baseline collateral circulation status evaluated by DSA (American Society of Therapeutic and
Interventional Neuroradiology/Society of Interventional Radiology grade, ASTIN/SIR grade) , technical
efficacy outcomes regarding recanalization and residual stenosis of the qualifying artery assessed via DSA,
CTA or MRA at 24-72 hours for vessel recanalization status, and the CT at 24-72 hours for the occurrence
of intracerebral hemorrhage, restenosis or reocclusion during follow-up subsequent evaluation via CTA or
MRA and so on. All imaging studies will undergo blinded review by experienced neuroradiological experts
(over 10 years in advanced neuroimaging evaluation experience). Two neuroradiologists perform
independent, masked assessments of neuroimaging studies, ensuring complete blinding to treatment
allocation, clinical data, and outcomes. In cases of interpretative disagreement, a third experienced
neuroradiologist will be consulted to adjudicate and provide a definitive assessment.
3.15 Quality Control
Training of appropriate clinical site personnel will be the responsibility of the Sponsor or designee. To
ensure uniform data collection and protocol compliance, personnel from the Sponsor or designee will review
the techniques for the identification of eligible subjects, instructions on in-hospital data collection, methods
for soliciting data from alternative sources, and schedules for follow-up with the study center.To ensure that
the collected data is concordant with the protocol, each sub-center of this study will be regularly scrutinized.
3.16 Statistical Analyses
3.16.1 General statistical analyses
Categorical variables will be presented as numbers and percentages. Continuous variables or ordinal
variables will be summarized as mean (standard deviation, SD) or median (interquartile range, IQR).
Categorical variables will be compared between treatment groups using χ² or Fisher's exact test. Continuous

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variables
or
ordinal
variables
will
be
compared
between
treatment
groups
using
t-test
or
Wilcoxon-Mann-Whitney test.
3.16.2 Primary and secondary outcomes
The difference in primary outcome between groups was assessed using Kaplan-Meier analysis and
compared via log-rank test. The hazard ratio (HR) and adjusted hazard ratio (aHR) between groups, along
with their 95% CIs, will be determined using univariate and multivariate Cox proportional hazards
regression models. Time-to-event secondary outcomes will be evaluated using Kaplan-Meier survival
analysis and Cox regression model. The 1-year mRS score will be analyzed using ordinal logistic regression
to estimate the common odds ratio (OR). The 1-year EQ-5D scores will be compared between groups using
general linear regression analysis.
3.16.3 Subgroup analyses
Subgroup analyses on the primary outcome will be performed in the following subgroups:

Age, <65 years old vs. ≥65 years old;

Sex, men vs. Women;

Hypertension, yes vs. no;

Diabetes, yes vs. no;

Current smoking, yes vs. no;

Body mass index (BMI), <25 Kg/m2 vs. ≥25 Kg/m2;

Latest qualifying event, ischemic stroke vs. TIA;

Time from latest ischemic event to enrollment, ≤2 weeks vs. >2 weeks, ≤6 weeks vs. >6 weeks;

Occurrence of the qualifying event, first-onset vs. recurrent;

Symptomatic qualifying artery, anterior circulation vs. posterior circulation;

ASPECTS or pc-ASPECTS, 10 vs. 6-9.
3.16.4 Propensity score matching analysis
Propensity score matching (PSM)35 will be performed to reduce the possible influence of selection bias and
confounders on the outcomes. A PSM cohort will be established in a 1:1 ratio based on the nearest-neighbor
matching algorithm with a caliper width of 0.2 of the propensity score with main variables associated with
the primary outcome as covariates.Statistical analysis methods for baseline characteristics and outcome will
remain consistent before and after PSM.
3.16.5 Statistical Significance and Software
All statistical tests are performed by 2-sided tests. A 2-sided P value less than 0.05 is considered to
demonstrate a statistically significant difference. All analyses will be performed with SAS software version
9.4 (SAS Institute).
3.17 Publications
Based on the analysis pre-specified in this study protocol, the results of the study will be published in
open-access peer-reviewed scientific journals and presented to academic and policy stakeholders. By signing
the clinical trial protocol, the investigator agrees that the results of the clinical trial may be used for
publication. The investigator also agrees that he is not permitted to publish any data related to the trial
independent of the Sponsor.

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21.
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Aghaebrahim A, Jovin T, Jadhav AP, Noorian A, et al. Endovascular recanalization of complete
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Xu Z, Ma N, Mo D, et al. Endovascular recanalization for chronic symptomatic intracranial vertebral
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Dashti SR, Park MS, Stiefel MF, et al. Endovascular recanalization of the subacute to chronically
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Zhao W, Zhang J, Song Y, et al. Endovascular Recanalization for Symptomatic Subacute to Chronic
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Murphy BD, Fox AJ, Lee DH, et al. Identification of penumbra and infarct in acute ischemic stroke
using computed tomography perfusion-derived blood flow and blood volume measurements. Stroke.
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effects. Biometrika. 1983;70(1):41-55. doi: 10.1002/sim.3532

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5. Appendix
Appendix 1. Modified Rankin Scale
The modified Rankin Scale (mRS)* is an ordinal scale ranging from 0 to 5, with higher scores indicating
more severe disability. A score of 6 indicates death.
Category
Short description
Long description
0
No symptoms
No symptoms
1
Symptoms, no disability
Minor symptoms that do not interfere with lifestyle
2
Slight disability
Slight disability, symptoms that lead to some restriction in
lifestyle, but do not interfere with the patient's capacity to
look after himself.
3
Moderate disability
Moderate disability, symptoms that significantly restrict
lifestyle and prevent totally independent existence
4
Moderately severe
disability
Moderately severe disability, symptoms that clearly prevent
independent existence though not needing constant attention
5
Severe disability
Severe disability, totally dependent patient requiring constant
attention day and night.
6
Death
Death
*van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the
assessment of handicap in stroke patients. Stroke. 1988 May;19(5):604-7. doi: 10.1161/01.str.19.5.604

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Appendix 2. Modified TICI Scale (mTICI Scale)
The modified Thrombolysis in Cerebral Infarction (mTICI)* score is a grading system used to assess the
degree of reperfusion in patients with acute ischemic stroke, which was modified from the original TICI
(Thrombolysis in Cerebral Infarction)¶ scale.
Grades
Short description
Long description
0
No Perfusion
No Perfusion
1
Minimal Perfusion
Antegrade reperfusion past the initial occlusion, but limited
distal branch filling with little or slow distal reperfusion
2
Partial Perfusion
2a
Antegrade reperfusion of less than half of the occluded
target artery previously ischemic territory (eg, in 1 major
division of the MCA and its territory)
2b
Antegrade reperfusion of more than half of the previously
occluded target artery ischemic territory (eg, in 2 major
divisions of the MCA and their territories)
3
Complete Perfusion
Complete antegrade reperfusion of the previously occluded
target artery ischemic territory, with absence of visualized
occlusion in all distal branches
*Zaidat OO, Yoo AJ, Khatri P, Tomsick TA, et al; Cerebral Angiographic Revascularization Grading
(CARG) Collaborators; STIR Revascularization working group; STIR Thrombolysis in Cerebral Infarction
(TICI) Task Force. Recommendations on angiographic revascularization grading standards for acute
ischemic stroke: a consensus statement. Stroke. 2013 Sep;44(9):2650-63. doi: 10.1161/STROKEAHA.113.
001972
¶Higashida RT, Furlan AJ, Roberts H, et al. Trial design and reporting standards for intra-arterial cerebral
thrombolysis for acute ischemic stroke. Stroke. 2003;34(8):e109-e137. doi: 10.1161/01.STR.0000082721.
62796.09

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Appendix 3. National Institute of Health Stroke Scale (NIHSS)
The National Institute of Health Stroke Scale (NIHSS)* is an ordinal scale to evaluate the severity of stroke
by assessing a patient’s performance in the neurological exam. Scores range from 0 to 42, with higher scores
indicating a more severe deficit.
Instructions
Scale definition
1a. Level of consciousness. The investigator 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 = Not alert; but arousable by minor
stimulation
to
obey,
answer,
or
respond.
2
=
Not
alert;
required
repeated
stimulation to attend, or is obtunded
and requires strong or
painful stimulation to make movements
(not stereotyped).
3 = Responds only with reflex motor or
autonomic
effects
or
totally
unresponsive, flaccid and areflexic.
1b. LOC Questions: The patient is asked the month and his/her
age. The answer must be correct – there is not partial credit for
being
close.
Phasic
and
stuporous
patients
who
do
not
comprehend the questions will score 2. Patients unable to speak
because of endotracheal intubation, orotracheal trauma, severe
dysarthria from any cause, language barrier, or any other problem
not secondary to aphasia are given a 1. It is important that only
the initial answer be graded and that the examiners not “help” the
patient with verbal or non-verbal clues.
0 = Answers both questions correctly.
1 = Answers one question correctly.
2 = Answers neither question correctly
1c. LOC Commands: The patient is asked to open and close the
eyes and then to grip and release the non-paretic hand. Substitute
another one step command if the hand cannot be used. Credit is
given if an unequivocal attempt is made but not completed due to
weakness. If the patient does not respond to command, the task
should be demonstrated to him or her (pantomime), and the result
scored (i.e. follows none, one or two commands). Patients with
0 = Performs both tasks correctly.
1 = Performs one task correctly.
2 = Performs neither task correctly.

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trauma, amputation, or other physical impediments should be
given suitable one-step commands. Only the first attempt is
scored.
2. Best Gaze: Only horizontal eye movements will be tested.
Voluntary or reflexive (oculocephalic) eye movements will be
scored, but caloric testing is not done. If the patient has a
conjugate deviation of the eyes that can be overcome by voluntary
or reflexive activity, the score will be a 1. If a patient has an
isolated peripheral nerve paresis (CN III, IV or VI), score a 1.
Gaze is testable in all aphasic patients. Patients with ocular
trauma, bandages, preexisting blindness, or other disorder of
visual acuity or fields should be tested with reflexive movements,
and a choice made by the investigator. Establishing eye contact
and then moving about the patient from side to side will
occasionally clarify the presence of a partial gaze palsy.
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: Visual fields (upper and lower quadrants) are tested by
confrontation,
using
finger
counting
or
visual
threat,
as
appropriate. Patients may be encouraged, but if they look at the
side of the moving finger appropriately, this can be scored as
normal. If there is unilateral blindness or enucleation, visual fields
in the remaining eye are scored. Score 1 only if a clearcut
asymmetry, including quadrantanopia, is found. If patient is blind
from any cause, score 3.
Double simultaneous stimulation is performed in this case.
If there is extinction, the patient receives a 1, and the results are
used to respond to item 11.
0= No visual loss.
1= Partial hemianopia.
2= Complete hemianopia.
3=
Bilateral
hemianopia
(blind
including cortical blindness)
4. Facial palsy: Ask or use pantomime to encourage the patient to
show teeth or raise eyebrows and close eyes. Score symmetry of
grimace in response to noxious stimuli in the poorly response or
non-comprehending
patient.
If
facial
trauma/bandages,
orotracheal tube, tape or other physical barriers obscure the face,
these should be removed to the extent possible.
0 = Normal symmetrical movements.
1=
Minor
paralysis
(flattened
nasolabial fold, asymmetry on smiling)
2= Partial paralysis (total or near-total
paralysis of lower face)
3= Complete paralysis of one or both
sides
(absence of facial movement in the

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upper and lower face).
5. Motor arm: The limb is placed in the appropriate position:
extend the arms (palms down) 90 degrees (if sitting) or 45 degrees
(if supine). Drift is scored if the arm falls before 10 seconds. The
aphasic patient is encouraged using urgency in the voice and
pantomime, but not noxious stimulation. Each limb is tested in
turn, beginning with the non-paretic arm. Only in the case of
amputation or joint fusion at the shoulder,
the examiner should record the score as untestable (UN), and
clearly write the explanation for this choice.
0= No drift; limb holds 90 (or 45)
degrees for full 10 seconds.
1= Drift; limb holds 90 (or 45) degrees,
but drifts down before full 10 seconds;
does not
hit bed or other support.
2= Some effort against gravity; limb
cannot get to or maintain (if cued) 90
(or 45) degrees, drifts down to bed, but
has some effort against gravity.
3= No effort against gravity; limb falls.
4= No movement.
UN = Amputation or joint fusion:
explain:
5a = Left Arm.
5b = Right arm.
6. Motor leg: The limb is placed in the appropriate position: hold
the leg at 30 degrees (always tested supine). Drift is scored if the
leg falls before 5 seconds. The aphasic patient is encouraged
using urgency in the voice and pantomime, but not noxious
stimulation. Each limb is tested in turn, beginning with the
non-paretic leg. Only in the case of amputation or joint fusion at
the hip, the examiner should record the score as untestable (UN),
and clearly write the explanation for this choice.
0=
No
drift;
leg
holds
30-degree
position for full 5 seconds.
1= Drift; leg falls by the end of the
5-second period but does not hit bed.
2= Some effort against gravity; leg
falls to bed by 5 seconds, but has some
effort against gravity.
3= No effort against gravity; leg falls
to bed immediately.
4= No movement.
UN = Amputation or joint fusion:
explain:
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. In case of visual
defect, ensure testing is done in intact visual field. The
0= Absent.
1= Present in one limb.
2= Present in two limbs.

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finger-nose-finger and heel-shin tests are performed on both sides,
and ataxia is scored only if present out of proportion to weakness.
Ataxia is absent in the patient who cannot understand or is
paralyzed. Only in the case of amputation or joint fusion, the
examiner should record the score as untestable (UN), and clearly
write the explanation for this choice. In case of blindness, test by
having the patient touch nose from extended arm position.
UN = Amputation or joint fusion:
explain:
8. Sensory: Sensation or grimace to pinprick when tested, or
withdrawal from noxious stimulus in the obtunded or aphasic
patient. Only sensory loss attributed to stroke is scored as
abnormal and the examiner should test as many body areas (arms
[not hands], legs, trunk, face) as needed to accurately check for
hemisensory loss. A score of 2, 'severe or total sensory loss',
should only be given when a severe or total loss of sensation can
be clearly demonstrated. Stuporous and aphasic patients will,
therefore, probably score 1 or 0. The patient with brainstem stroke
who has bilateral loss of sensation is scored 2. If the patient does
not respond and is quadriplegic, score 2.
Patients in a coma (item 1a=3) are automatically given a 2 on this
item.
0= Normal; no sensory loss.
1=
Mild-to-moderate
sensory
loss;
patients
feels pinprick is less sharp or is dull on
the affected side; or there is a loss of
superficial
pain
with
pinprick,
but
patient is aware 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:
A
great
deal
of
information
about
comprehension will be obtained during the preceding sections of
the examination. For this scale item, the patient is asked to
describe what is happening in the attached picture, to name the
items on the attached naming sheet and to read from the attached
list of sentences. Comprehension is judged from responses here,
as well as to all of the commands in the preceding general
neurological exam. If visual loss interferes with the tests, ask the
patient to identify objects placed in the hand, repeat, and produce
speech. The intubated patient should be asked to write. The
patient in a coma (item 1a=3) will automatically score 3 on this
item. The examiner must choose a score for the patient with
stupor or limited cooperation, but a score of 3 should be used only
if the patient is mute and follows no one-step commands.
0= No aphasia; normal
1= Mild-to-moderate aphasia; some
obvious loss of fluency or facility of
comprehension,
without
significant
limitation on ideas expressed or form
of expression. Reduction of speech
and/or
comprehension,
however,
makes
conservation
about
provided
materials difficult or impossible. For
example,
in
conversation
about
provided
materials,
examiner
can
identify picture or naming card content
from patient's response.
2= Severe aphasia; all communication

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is
through fragmentary expression; great
need for inference, questioning, and
guessing by the listener. Range of
information that can be exchanged is
limited;
listener
carries
burden
of
communication.
Examiner
cannot
identify
materials
provided
from
patient response.
3 = Mute, global aphasia: no usable
speech or auditory comprehension.
10. Dysarthria: If patient is thought to be normal, an adequate
sample of speech must be obtained by asking patient to read or
repeat words from the attached list. If the patient has severe
aphasia, the clarity of articulation of spontaneous speech can be
rated. Only if patient is intubated or has other physical barriers to
producing speech, the examiner should record the score as
untestable (UN), and clearly write an explanation for this choice.
Do not tell the patient why he or she is being tested.
0= Normal.
1=
Mild-to-moderate
dysarthria;
patient slurs at least some words and, at
worst, can be understood by some
difficulty.
2= Severe dysarthria: patient's speech
is so slurred as to be unintelligible in
the absence of or out of proportion to
any dysphasia, or is mute/anarthric.
UN = Intubated or other physical
barrier.
11. Extinction and Inattention (formerly Neglect): Sufficient
information to identify neglect may be obtained during the prior
testing. If the patient has a severe visual loss preventing visual
double simultaneous stimulation, and the cutaneous stimuli are
normal, the score is normal. If the patient has aphasia but does
appear to attend to both sides, the score is normal. The presence
of visual spatial neglect or anosagnosia may also be taken as
evidence of abnormality. Since the abnormality is scored only if
present, the item is never untestable.
0= No abnormality.
1= Visual, tactile, auditory, spatial, or
personal inattention or extinction to
bilateral simultaneous stimulation in
one of the sensory modalities.
2=
Profound
hemi-inattention
or
extinction to more than one modality;
does not recognize own hand or orients
to only one side of space.
*Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination
scale. Stroke. 1989;20(7):864-870. doi: 10.1161/01.str.20.7.864

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Appendix 4. EuroQoL 5D-5L*
Under each heading, please tick the ONE box that best describes your health TODAY
Mobility
I have no problems in walking about

I have slight problems in walking about

I have moderate problems in walking about

I have severe problems in walking about

I am unable to walk about

Self-care
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

Usual activities (e.g. work, study, housework, family or leisure activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

Pain/discomfort
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort

Anxiety/depression
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed


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
We would like to know how good or bad your health is
TOADY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.

0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is
TODAY.

Now, please write the number you marked on the scale in
the box below.
YOUR HEALEH TOADY =
*Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version
of EQ-5D (EQ-5D-5L). Quality of Life Research. 2011;20(10):1727-17.doi: 10.1007/s11136-011-9903-x

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Appendix 5. Heidelberg bleeding classification*
Class Type Description of Intracranial Hemorrhages
1 Hemorrhagic transformation of infarcted brain tissue
1a
HI1
Scattered small petechiae, no mass effect
1b
HI2
Confluent petechiae, no mass effect
1c
PH1
Hematoma within infarcted tissue, occupying < 30%, no substantive mass effect
2 Intracerebral hemorrhage within and beyond infarcted brain tissue
PH2
Hematoma occupying 30% or more of the infarcted tissue, with obvious mass effect
3 Intracerebral hemorrhage outside the infarcted brain tissue or intracranial-extracerebral
hemorrhage
3a
Parenchymal hematoma remote from infarcted brain tissue
3b
Intraventricular hemorrhage
3c
Subarachnoid hemorrhage
3d
Subdural hemorrhage
*von Kummer R, Broderick JP, Campbell BC, Demchuk A, et al. The Heidelberg Bleeding Classification:
Classification of Bleeding Events After Ischemic Stroke and Reperfusion Therapy. Stroke. 2015
Oct;46(10):2981-6. doi: 10.1161/STROKEAHA.115. 010049

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Appendix 6. Scoring System of Pons-Midbrain Index (PMI)*
A PMI of 0 indicates absence of any ischemic changes in the pons and midbrain, and a score of 8 indicates
greater than 50% hyperintensity bilaterally in these brainstem territories.
Lesion
Score (DWI as an example)
Left pons
0, no hyperintensity; 1, equal or less than 50% hyperintensity; or 2, greater than 50%
hyperintensity
Right pons
0, no hyperintensity; 1, equal or less than 50% hyperintensity; or 2, greater than 50%
hyperintensity
Left midbrain
0, no hyperintensity; 1, equal or less than 50% hyperintensity; or 2, greater than 50%
hyperintensity
Right midbrain
0, no hyperintensity; 1, equal or less than 50% hyperintensity; or 2, greater than 50%
hyperintensity
*Pallesen LP, Khomenko A, Dzialowski I, Barlinn J, et al. CT-angiography source images indicate less fatal
outcome despite coma of patients in the Basilar Artery International Cooperation Study. Int J Stroke. 2017
Feb;12(2):145-151. doi: 10.1177/1747493016669886

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Appendix 7.Alberta Stroke Program Early CT Score (ASPECTS)
The Alberta Stroke Program Early CT Score (ASPECTS)* is a semiquantitative method of estimation of
infarct size with non-contrast CT during the acute phase. The territory of the middle cerebral artery is
allotted 10 points. 1 point is subtracted for an area of early ischaemic change, such as focal swelling, or
parenchymal hypoattenuation, for each of the defined regions. A normal CT scan has an ASPECTS value of
10 points. A score of 0 indicates diffuse ischaemia throughout the territory of the middle cerebral artery.
A=anterior circulation; P=posterior circulation; C=caudate; L=lentiform; IC=internal capsule; I=insular
ribbon; MCA=middle cerebral artery; M1=anterior MCA cortex; M2=MCA cortex lateral to insular ribbon;
M3=posterior MCA cortex; M4, M5, and M6 are anterior, lateral, and posterior MCA territories
immediately superior to M1, M2, and M3, rostral to basal ganglia.
Subcortical structures are allotted 3 points (C, L, and IC).
MCA cortex is allotted 7 points (insular cortex, M1, M2, M3, M4, M5, and M6).
*Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed
tomography
score
in
predicting
outcome
of
hyperacute
stroke
before
thrombolytic
therapy. Lancet. 2000;355(9216):1670-1674. doi: 10.1016/s0140-6736(00)02237-6

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Appendix 8. posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS)*
pc-ASPECTS. From 10 points, 1 or 2 points each (as indicated) are subtracted for early ischemic changes
(NCCT) or hypoattenuation (CTASI) in: left or right thalamus, cerebellum or PCA-territory, respectively (1
point); any part of midbrain or pons (2 points). Pc-ASPECTS=10 indicates a normal scan, pc-ASPECTS=0
indicates early ischemic changes (NCCT) or hypoattenuation (CTASI) in all above territories
*Puetz V, Khomenko A, Hill MD, et al; Basilar Artery International Cooperation Study (BASICS) Group.
Extent of hypoattenuation on CT angiography source images in basilar artery occlusion: prognostic value in
the
Basilar
Artery
International
Cooperation
Study.
Stroke.
2011
Dec;42(12):3454-9.
doi:
10.1161/STROKEAHA.111.622175