N Engl J Med 2022 386 1303 - Protocol

Protocol
Protocol for: Yoshimura S, Sakai N, Yamagami H, et al. Endovascular therapy for acute stroke with a large
ischemic region. N Engl J Med 2022;386:1303-13. DOI: 10.1056/NEJMoa2118191
This trial protocol has been provided by the authors to give readers additional information about the work.
Trial Protocol and Statistical Analysis Plan
Endovascular therapy for acute stroke with a large ischemic core
Page (Upper right) Documents
1 Original protocol
41 Final protocol
81 Summary of changes
84 Original statistical analysis plan
98 Final statistical analysis plan
112 Summary of changes

1
Trial Protocol
Randomized clinical trial of endovascular therapy for acute large

vessel occlusion with a large ischemic core: Recovery by
Endovascular Salvage for Cerebral Ultra-acute Embolism-Japan
Large IscheMIc core Trial (RESCUE-Japan LIMIT)
Ver. 1.0, Date Prepared August 20, 2018
Clinical Trial Registration: ClinicalTrials.gov: NCT03702413

UMIN Clinical Trials Registry: UMIN 000034388
Confidentiality
Access of this protocol is limited to the persons concerned in this trial.
Disclosure to third parties without consent of the principal investigator is prohibited,
except for submission to the Institutional Review Board or disclosure to patients.
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Table of Contents
0. Scheme .................................................................................................................... 3
1. Purpose.................................................................................................................... 5
2. Rationale for the study ............................................................................................. 5
3. Overall design and plan of the study ........................................................................ 6
4. Eligibility criteria ....................................................................................................... 8
5. Enrollment and randomization ................................................................................. 9
6. Treatment ............................................................................................................... 11
7. Observation, tests, reporting items and schedule .................................................. 11
8. Definition of outcomes............................................................................................ 15
9. Definition, handling, and investigation related to adverse events........................... 17
10. Statistical considerations...................................................................................... 18
11. Case report........................................................................................................... 18
12. Submission of images .......................................................................................... 18
13. Ethical concerns ................................................................................................... 19
14. Study costs .......................................................................................................... 24
15. Revision of protocol.............................................................................................. 25
16. Monitoring and audit............................................................................................. 25
17. Termination and early discontinuation of trial ....................................................... 25
18. Handling of adverse events, serious adverse events, diseases, and other
serious events ............................................................................................................ 28
19. Storage of records................................................................................................ 29
20. Registration and publication related to the study.................................................. 30
21. Ownership of the study results ............................................................................. 30
22. Study organization ............................................................................................... 30
23. References ........................................................................................................... 34
24. Appendix .............................................................................................................. 35
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0. Summary
Scheme
Purpose The purpose of this study is to evaluate the efficacy of endovascular

therapy (EVT) for acute large vessel occlusion with moderate to severe
large ischemic core (ASPECTS of 3–5 on CT or DWI of MRI).
Eligibility criteria Patients who meet all the [Inclusion criteria] and do not meet any of the
[Exclusion criteria] are enrolled.
[Inclusion criteria]
1) Patients with acute ischemic stroke
2) Aged ≥ 18 years
3) NIHSS score ≥ 6 on admission
4) mRS 0–1 before the onset
5) occlusion site at ICA or M1 on CT angiography or MR angiography
6) ASPECTS of 3–5 on CT or DWI of MRI
7) Randomization can be finished within 4.5 hours from the time of last
known well.
8) EVT can be initiated within 60 minutes from randomization.
9) The patient or legally authorized representative has signed the
informed consent form.
[Exclusion criteria]
1) Significant mass effect with midline shift on CT or MRI
2) Known allergy (more severe than skin rash) to contrast agents
3) Evidence of acute intracranial hemorrhage on CT or MRI
4) Pregnant or potentially pregnant
5) Clinical evidence of chronic occlusion
6) High risk of hemorrhage (platelet < 40,000 /ul, APTT > 50 second
or PT-INR > 3.0)
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7) Participating in any other therapeutic investigational trial

8) Patients who, in the judgment of the investigator, are likely to be
non-compliant or uncooperative during the study
Target number 200 patients (number of patients who have completed patient
of patients enrollment)
100 patients (EVT group), 100 patients (no EVT group)
Study period Study period: 3 years, from the date of approval of the protocol to the
date of completion of the trial.
Study From after obtaining informed consent to 90 days from the onset.
participation
period
Study design Prospective, open-label, randomized controlled study
Outcomes [Primary outcomes]
Achievement of mRS 0–3 at 90 days
[Secondary outcomes]
1) Achievement of mRS 0–2 at 90 days
2) One scale shift of mRS (shift analysis)
3) NIHSS improvement of ≥ 8 points at 48 hours
[Safety outcomes]
1) Symptomatic intracranial hemorrhage within 48 hours
2) Any intracranial hemorrhage within 48 hours
3) Death (mRS 6) within 90 days
4) Recurrence of ischemic stroke within 90 days
5) Decompressive craniectomy within 7 days
mRS: modified Rankin Scale

NIHSS: National Institutes of Health Stroke Scale
ASPECTS: Alberta Stroke Program Early CT Score
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1. Purpose
The purpose of this study is to evaluate the efficacy of endovascular therapy (EVT)
for acute large vessel occlusion with moderate to severe large ischemic core defined by
Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of 3–5 on CT or
diffusion-weighted imaging (DWI) of magnetic resonance imaging (MRI).
2. Rationale for the study

For acute stroke caused by occlusion of proximal major artery in anterior
circulation, including internal carotid artery (ICA) and the horizontal segment of the middle
cerebral artery (M1), a series of comparative trial results were reported in 2015 showing
that addition of EVT mainly using stent retrievers in addition to medical therapy including
recombinant tissue plasminogen activator (rt-PA) had better patient outcomes compared to
medical therapy alone [1–5]. A meta-analysis for these randomized trials [6] was also
published, which established the evidence for EVT in large vessel occlusion in patients
with the following [7].
1) Functional independence (modified Rankin Scale (mRS) score 0–1) before the onset
2) Treated with rt-PA according to the guideline
3) Acute occlusion of ICA or proximal middle cerebral artery
4) Patient aged ≥ 18 years
5) Neurological symptoms (NIHSS ≥ 6)
6) Limited cerebral infarction area (ASPECTS ≥ 6)
7) EVT can be initiated within 6 hours from the time of onset.
In addition, in 2018, two randomized trials [8, 9] have demonstrated the efficacy of
EVT for strokes caused by large vessel occlusion after 6 hours from the onset. In the first
trial (DAWN trial), indication for patients with occlusion of ICA or M1 in 6–24 hours after
the time of last known well were selected according to age, neurological severity (NIHSS),
and ischemic core volume, and the group with standard therapy plus EVT resulted in
significantly better functional outcomes. In the DEFUSE 3 trial reported in the same year,
indication for patients with occlusion of ICA or M1 at 6–16 hours after he time of last
known well were selected by calculating a mismatch between the ischemic core volume
and volume of perfusion delay area. The functional outcomes were significantly better in
the group with EVT in addition to standard care. According to these results, the guidelines
of the American Heart Association and American Stroke Association recommend EVT with
a Class I recommendation and level of evidence A for patients who are in the period 6–16
hours from onset and meet the inclusion criteria for DAWN or DEFUSE 3 trials. Results of
these randomized trials demonstrate that EVT is effective for patients who have developed
collateral circulation to some extent, even if some time has passed from the onset.
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However, the calculation software used in DAWN and DEFUSE 3 trials for
ischemic core volume and volume of perfusion delay area is not approved in Japan, so it is
impossible to directly perform these trials in Japan.
On the other hand, efficacy of EVT for patients with ASPECTS score less than 6
has not been proven [6]. The results of RESCUE-Japan registry 2 [10] showed that EVT
was effective in a real-world population that included patients other than those
recommended by the guidelines. Furthermore, among patients with moderate to severe
large ischemic core with ASPECTS 3–5, the number of patients with mRS 0–3 at 90 days
from the onset, which is the primary outcome of this study, was 55 (37.7%) in 146 patients
who received EVT and 24 (12.5%) in 192 patients who did not receive EVT, respectively.
The adjusted odds ratio (OR) for mRS of 0–3 was 3.42, demonstrating the efficacy of EVT.
This suggests that EVT is effective even in patients with ASPECTS < 6.
Accordingly, based on the inclusion criteria unique to Japan, this trial is planned to
clarify the efficacy of EVT for acute large vessel occlusion with moderate to severe large
ischemic core.
3. Overall design and plan of the study

3.1 Design
3.1.1 Outline
Prospective, open-label, randomized clinical trial
<Rationale for setting the design>

The major purpose of this study is to evaluate the efficacy of EVT for patients with
acute large vessel occlusion with moderate to severe large ischemic core (ASPECTS of 3–
5 on CT or DWI of MRI), and the above study design is adopted. A schematic diagram of
the study flow is shown below.
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3.1.2 Target number of patients

200 patients (number of patients who have completed patient enrollment)
<Rationale for setting the target number of subjects>

From RESCUE-Japan Registry 2 data [10], among 338 patients with ASPECTS 3–
5, who are the target of this study, the number of patients with mRS 0–3 at 90 days from
the onset, which is the primary outcome of this study, was 55 (37.7%) in EVT group and
24 (12.5%) in no EVT group, respectively [11]. In addition, the adjusted OR was 3.42, but
since the study was an observational study and its effect could be larger than clinical trial,
we assume the relative risk at 2.7 times (3.42 × 0.8 = 2.7) with an allowance of 20% in
clinical trial. When type I error level is set at 0.05 two-sided and the power of the test at
0.90, 81 patients in each cohort are required. Estimating the clinical dropout rate of 15%,
required sample size is calculated to be 191 patients. Considering possible withdrawal of
consent, we set the target sample size to 100 patients in each cohort and a total of 200
patients.
3.1.3 Study period

3.1.3.1 Period per patient
Period from obtaining informed consent to 90 days after randomization.
3.1.3.2 Overall study period

Patient enrollment period: 3 years from the date of approval of the protocol.
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Overall study period: From the date of approval of this protocol to the date
specified in “17.3.2 Termination of this study”.
3.2 Study flow

The flow of this study is as shown below. For details of patient enrollment, study
treatment, investigation items and investigation schedule, see “5. Enrollment and
randomization”, “6. Treatment”, and “7. Observation, tests, reporting items and schedule”,
respectively.
4. Eligibility criteria
4.1 Eligibility criteria
Patients who meet all the “4.2.1 Inclusion criteria” and do not meet any of the
“4.2.2 Exclusion criteria” are enrolled.
4.2.1 Inclusion criteria

7) Randomization can be finished within 4.5 hours from the time of last known well.
9) The patient or legally authorized representative has signed the informed consent form.
4.2.2 Exclusion criteria

6) High risk of hemorrhage (platelet < 40,000 /ul, APTT > 50 second or PT-INR > 3.0)
8) Patients who, in the judgment of the investigator, are likely to be non-compliant or
uncooperative during the study
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5. Enrollment and randomization

5.1 Preparation
In this study, the Data Center handles patient enrollment and data collection using
the Electronic Data Capture (EDC) system via the Internet.
5.1.1 Hospital registration

The person in charge in the study office sends the list of hospital names and
principal investigator names to the Data Center.
5.1.2 EDC system user registration

The principal investigator at the hospital sends the list of names and emergency
contact information of the EDC system users, consisting of sub-investigators at each
hospital through the study office to the Data Center. If there is no problem or question, the
Data Center provides an ID and a password.
5.2. Patient enrollment

In enrolling patients to this study, the following procedures are taken for patient
enrollment.
1) Selection of patients
Principal investigator or sub-investigator selects patients for this study, taking “4.1
Eligibility criteria” into consideration.
2) Obtaining informed consent
Explanation of the details of this study to patients or their legal representatives and
obtaining informed consent from patients or their legal representatives in accordance
with “13.3 Obtaining Informed Consent”.
3) Surveillance to confirm eligibility for patient enrollment
Principal investigator or sub-investigator conducts surveillance to confirm eligibility
for patient enrollment in accordance with “7. Observation, tests, reporting items and
schedule” for patients whose written informed consent has been obtained from the
patient or the legal representative.
4) Entry and transmission of surveillance results
Principal investigator or sub-investigator confirms the surveillance results for
eligibility so that all items in “4.2.1 Inclusion criteria” are met and any items in “4.2.2
Exclusion criteria” are not met, access the website for patient enrollment, enter and
transmit the necessary information on the website.
EDC system receives the necessary information, confirms the details, and
indicates the eligibility or ineligibility on the website.
5) Confirmation of patient enrollment contact forms (completion of patient enrollment)
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Principal investigator or sub-investigator confirms the details, if eligibility message

is indicated, and enters the date of enrollment and study ID assigned by EDC system in
“Name list for subject enrollment”. The screen indicating the eligibility is printed and
kept with medical records. This completes the patient enrollment as a subject of this
study (Principal investigator or sub-investigator can start the study treatment only when
patient enrollment is completed).
5.3 Randomization
5.3.1 Randomization method
Dynamic randomization by minimization method is used for the randomization of
patients to EVT group or no EVT group. Randomization and enrollment of patients are
made using EDC system.
5.3.2 Enrollment and acquisition of randomization results

Principal investigator or sub-investigator selects patients who meet the eligibility
criteria, obtains informed consent from the patients, and then, based on the screening
results, confirms that the patient meets the inclusion criteria and do not conflict with the
exclusion criteria, and enrolls the patient using the EDC system. After enrollment, principal
investigator or sub-investigator obtains randomization results for study treatment from the
EDC system. The following items are entered in the EDC system at patient enrollment.
1) Enrolled hospital
2) Date of obtaining written informed consent
3) Age at enrollment
4) Time from onset or last known well to hospital arrival
5) NIHSS score at the time of obtaining informed consent
6) Whether the patient was treated with rt-PA after the onset
7) Eligibility information (confirmation of inclusion criteria and exclusion criteria)
5.3.3 Randomization factors

Randomization factors are as follows: enrolled hospital, age at the time of
obtaining informed consent (< 75 years or ≥ 75 years), time from onset or last known well
to hospital arrival (< 120 minutes or ≥ 120 minutes), NIHSS score at the time of obtaining
informed consent (< 21 or ≥ 21), and whether the patient was treated with rt-PA after the
onset.
5.3.4 Control and storage of randomization results

Randomization results are controlled and stored at the Data Center.
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5.4 Precautions
1) If the input data is insufficient, patient enrollment is not accepted until all data is
completed.
2) Except for refusal to use the data, once a patient has been enrolled, the patient will not
be unenrolled (deleted from the database). In a case of duplicate enrollment, the first
enrollment information (patient enrollment number) is adopted.
3) When a wrong enrollment or duplicate enrollment is found, contact the Data Center
immediately.
6. Treatment
6.1. Definition of treatment
Treatment shall be according to the randomization results. Regarding the details of
EVT, the most appropriate method of EVT should be selected for each case. The type of
device to be used for EVT is not important if regulatory approval has been obtained.
6.2. Treatment method

Local intraarterial fibrinolysis is not performed as endovascular recanalization
therapy. There is no provision for other types of treatment (e.g., internal medicine,
rehabilitation, etc.).
6.3. Discontinuation of treatment

This study does not have any criteria or restrictions in discontinuation of treatment.
6.4. Treatment options at recurrence

This study does not have any restriction in treatment options at recurrence.
7. Observation, tests, reporting items and schedule

7.0 Summary
Schedule At enrollment Observation period
Before After Very Early Early Discharge End
randomization randomization
Implementation Within 6 hours from the time of Within 12 Within 48 either 7 days 90 days (±
item/ last known well or within 6–24 hours after hours (± 12 (± 1 day) 30 days)
implementation hours from the time of last known randomi- hours) after after after
period well zation randomi- randomi- randomi-
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zation zation or at zation
discharge
which is
earlier
Informed ○
consent
Confirmation of ○
inclusion and
exclusion criteria
Basic data ○ ○
Only Details
randomization
factors
Demographics ○
and baseline
characteristics
data
Vital sign ○ ○ ○ ○ ○
Laboratory data ○ ○
Chest x-ray, ○
ECG test
mRS ○ (Before ○ ○
onset)
NIHSS ○ ○ ○ ○ ○
Only scores Details
Imaging ○ (*1) ○ ○
CT/CTA/CTP CT or MRI CT/CTA or
or MRI/MRA MRI/MRA
ASPECTS ○
Occclusion site ○
Type of cerebral ○ ○
infarction
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Details of EVT ○
and Only EVT
complications group
Recanalization ○
status Only EVT
(TICI grade) group
Recanalization △
status
(mMORI grade)
Serious adverse
events
Clinically
significant
adverse events
Decompressive
craniectomy
*1: Imaging (at enrollment)

Within 6 hours from last known well time: CT/CTA/CTP or MRI/MRA
Within 6–24 hours from last known well time: MRI/MRA
7.1 Primary outcomes and timing

1) Neurological assessment (NIHSS)
Neurological assessment is performed at enrollment, within 12 hours after
randomization, 48 hours (± 12 hours) after randomization, either 7 days (± 1 day) after
randomization or at discharge which is earlier, and 90 days (± 30 days).
2) mRS
mRS assessment is performed at enrollment (before the onset), either 7 days (± 1
day) after randomization or at discharge which is earlier, and 90 days (± 30 days) after
randomization. If a patient is unable to visit the hospital, surveillance by telephone is
also allowed.
3) Imaging
CT/CTA/CTP or MRI/MRA is performed at enrollment. CT or MRI is performed at
48 hours (± 12 hours) after randomization to assess the status of cerebral infarction
and intracranial hemorrhage. CT/CTA or MRI/MRA is performed either on 7 days (± 1
day) after randomization or at discharge whichever is earlier, to assess the status of
cerebral infarction or large vessel occlusion.
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4) Serious adverse events or clinically significant adverse events

All events occurred within 90 days after randomization are assessed.
7.2 At enrollment
7.2.1 Basic data
Hospital name, name of patient identification, age, sex, time of onset (time of
last known well), time of arrival at the hospital, allergy to contrast agent.
7.2.2 mRS before onset
7.2.3 rt-PA after onset
7.2.4 Imaging evaluation
Imaging start-time, type of head imaging, ASPECTS or DWI-ASPECTS (10
scores), and the occlusion site are assessed. DICOM images are submitted to the
office for central review.
7.2.5 Complications/Medical history
Atrial fibrillation/ cerebral infarction/ cerebral hemorrhage/ TIA/ subarachnoid
hemorrhage/ ischemic heart disease/ peripheral arterial disease
Hypertension / diabetes / dyslipidemia / smoking / drinking
7.2.6 Medication before onset
Antiplatelet drugs (aspirin, clopidogrel, cilostazol, prasugrel, ticagrelor,
ticlopidine, others)
Anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban, edoxaban,
heparin, argatroban, others)
Statins (atorvastatin, pitavastatin, rosuvastatin, pravastatin, simvastatin,
fluvastatin, others)
7.2.7 Type of cerebral infarction
Initial diagnosis: cardiogenic embolism, atherothrombosis, other type of
cerebral infarction, unknown causes
7.2.8 Blood test
WBC, Hb, Plt, BUN, Cre, Glu, CRP, PT-INR, APTT, LDL, HDL, t. chol, HbA1C
7.2.9 Chest x-ray, 12-lead ECG
7.2.10 Blood pressure, pulse, body temperature
7.3 Observation Period_Very-Early: within 12 hours after randomization

7.3.1 Details of treatment
Time for start of treatment (puncture), time of recanalization, time for completion of
procedures
Devices and drugs used
Recanalization status (modified TICI grade)
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Treatment complications and the details

7.3.2 Neurological assessment (NIHSS)
7.4 Observation Period_Early: 48 hours (± 12 hours) after randomization

7.4.2 Imaging
CT or MRI is performed to assess the status of cerebral infarction or intracranial
hemorrhage.
7.4.3 Blood test (WBC, Hb, Plt, BUN, Cre, Glu, CRP, PT-INR, APTT)
7.5 Observation Period_Discharge: Either 7 days (± 1 day) after randomization or at

discharge, which is earlier
7.5.1 mRS
7.5.3 Imaging
CT/CTA or MRI/MRA is performed to assess the status of cerebral infarction or
large vessel occlusion.
7.5.4 Blood test (WBC, Hb, Plt, BUN, Cre, Glu, CRP, PT-INR, APTT)
Final diagnosis: cardiogenic embolism, atherothrombosis, other type of cerebral
infarction, unknown causes
7.5.7 Therapeutic drugs (anticoagulants, antiplatelet drugs, antihypertensive agents,
statins)
7.6 Observation Period_End: 90 days (± 30 days) after randomization (Surveillance by

telephone or observation by a doctor from another hospital is also allowed.)
7.6.1 mRS
*mRS and NIHSS are assessed by a doctor or a physical therapist who does not know the
randomization.
8. Definition of outcomes
8.1 Primary outcomes
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8.2 Secondary outcomes

8.3 Safety outcomes

8.4 Cerebral ischemic events

Cerebral ischemic events include all the following events.
8.4.1 Cerebral infarction

Cases with neurological symptoms persisting for 24 hours or more and with
obvious responsible lesion on CT or MRI head image. Of these cases, cases with
remission of neurologic dysfunction within 7 days or cases with sustained worsening of
NIHSS score of less than 4 points are evaluated as mild stroke, and cases with sustained
neurologic dysfunction for more than 7 days or cases with sustained worsening of NIHSS
score of 4 points or more are evaluated as severe stroke.
8.4.2 Transient ischemic attack

Cases with transient neurologic deficit or transient retinal ischemia symptoms
associated with transient cerebral ischemia and with the duration of neurologic symptoms
of less than 24 hours, while there was no obvious abnormality that could explain the
symptoms by diagnostic imaging examination. Diagnosis of transient ischemic attack
should not be given based only on symptoms such as impaired consciousness (without
neurologic symptoms), convulsion, scintillating scotoma or unrelated dizziness, diplopia or
dysarthria.
8.5 Intracranial hemorrhage events

8.5.1 All intracranial hemorrhages
Cases with intracranial hemorrhage on CT or MRI head images. These cases
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include hemorrhagic infarction, bleeding from the brain parenchyma, subarachnoid

hemorrhage, and subdural hematoma.
8.5.2 Symptomatic intracranial hemorrhage

Symptomatic intracranial hemorrhage is defined as cases caused by intracranial
hemorrhage and with worse NIHSS score of 4 points or more compared to the time of
enrollment.
9. Definition, handling, and investigation related to adverse events

9.1 Definition of adverse events
An adverse event is any undesirable or unintended sign (including abnormal
laboratory value), symptom, or disease that occurs in the patient from the time of
enrollment to 90 days after randomization, regardless of the causal relationship with the
study treatment. In this study, only the adverse events listed in 9.2.1 and 9.2.2 are
reported.
9.2 Classification of adverse events

9.2.1 Serious adverse events
Serious adverse events are defined as follows.
1) Death
2) Life-threatening
3) Admission to the hospital or prolongation of hospitalization
4) Permanent damage
5) Risk of damage
6) Other serious medical events equivalent to 1)–5)
9.2.2 Clinically significant adverse events

The following adverse events are defined as clinically significant adverse events.
1) Symptomatic intracranial hemorrhage

2) All intracranial hemorrhages
3) Recurrent cerebral infarction
4) Cardiovascular events
Cardiovascular events are defined as clinically diagnosed acute coronary
syndrome (acute myocardial infarction, unstable angina), aortic disease (aortic dissection,
aortic aneurysm), and sudden cardiac death.
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10. Statistical considerations

10.1 Analysis set
The analysis set includes all subjects who were enrolled in this study. However,
subjects who withdrew the written consent after enrollment and refused to use the data are
excluded from the analysis set.
10.2 Analysis method

Major analysis is as follows. Additional explanatory analyses may be included as
needed.
10.2.1 Information related to baseline characteristics and treatment

Appropriate statistics are used to summarize.
10.2.2 Analysis of outcomes

1) Primary outcomes
Percentage of achieving mRS 0–3 at 90 days after randomization is compared
between two groups.
2) Secondary outcomes
Percentage of each secondary outcome is compared between the two groups.
Adverse events are summarized using descriptive statistics.
3) Safety outcomes
Percentage of each safety outcome is compared between two groups. Adverse
events are summarized using descriptive statistics.
11. Case report

In this study, medical records of participating hospitals and results of various
imaging and tests are used as the raw data. Necessary records on patients are stated in
medical records. A record of input and output into EDC system is used as a case report. A
record of input of the login ID and the password are regarded as a signature.
12. Submission of images

DICOM images are submitted to the study office for central review. Submitted
images are analyzed by the image determination committee members.
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13. Ethical concerns

13.1 Principles, laws and regulations, guidelines, etc. to be followed
This study is conducted in compliance with “World Medical Association Declaration
of Helsinki – Ethical Principles for Medical Research Involving Human Subjects”, and other
laws regulating this study, including “Ethical Guidelines for Medical and Health Research
Involving Human Subjects (established on December 22, 2014 [Ministry of Education,
Culture, Sports, Science and Technology, and Ministry of Health, Labour and Welfare,
Notification No. 3 of 2014], partially revised on February 28, 2017 [Ministry of Education,
Notification No. 1 of 2017]).
Since this study is neither a clinical study using research funds provided by
pharmaceutical companies nor a clinical study using unapproved or off-label use of drugs
or medical devices, this study does not fall under the specified clinical study subjected to
the Clinical Trials Act.
13.2 Obtaining permission at a participating hospital

Study representatives and principal Investigator submit the clinical trial protocol to
the chief executive of the participating hospital to ask for permission to implement this
study. The chief executive of the participating hospital asks for opinions to the ethical
review board on the details of the clinical trial protocol, etc. and appropriateness of this
study as necessary, respect the opinion, and decide whether or not to permit
implementation of this study and other necessary measures regarding this study.
13.3 Obtaining Informed Consent

13.3.1 Selection of patients
In selection of patients, principal investigator or sub-investigator carefully
considers requesting participation of patients in this study, taking into account their health
status, symptoms, age, sex, capacity to consent, dependency on principal investigator or
sub-investigator, and participation in other trials, according to the protection of human
rights, inclusion criteria and exclusion criteria.
13.3.2 Explanation to patients or their legal representatives

Principal investigator or sub-investigator explains the following contents orally to
each patient or his/her legal representative based on the explanatory documents and
informed consent form approved at the study institution.
The informed consent form approved at the participating hospital should be signed
by the principal investigator or sub-investigator who gave the explanation, and the date of
explanation should be stated. If a study collaborator provided supplementary explanation,
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the informed consent form should also be signed by the study collaborator, and the date of
explanation should be stated.
1) Approval by the chief executive of the participating hospital regarding the name of the
study and implementation of the study.
2) Names of participating hospital and study representatives.
3) Purpose and significance of the study.
4) Study method (including the purpose of use of samples and information collected from
patients) and duration.
5) Reason to be included as a study patient (if the patient is in "underage" or is an "adult
who does not have a capacity to give consent", the reason why it was necessary to
include a person "underage" or an "adult who does not have a capacity to give
consent" as a study patient for explanation to the legal representative, is included).
6) Subject burdens and expected risks (including blood transfusion and use of specified
biological products) and benefits.
7) A statement if the patient has consented to the conduct or continuation of the study,
he/she may withdraw consent at any time (when it is difficult to take measures
according to the contents of withdrawal from the patients, etc., the fact and the
reason).
8) A statement that the patients are not treated inappropriately if they disagree with the
conduct or continuation of the study or by withdrawing their consent.
9) Method of information disclosure regarding the study.
10) A statement that the protocol and materials related to the study methods can be
obtained or accessed at the request of patients, etc., to the extent that such access
does not interfere with protection of personal information of other patients, etc., or with
securing of originality of the study, and the method of obtaining or accessing such
materials.
11) Handling of personal information, etc. (including the method of anonymization when
including such cases, and the fact that anonymously processed information or
anonymized personal information is created when including such cases).
12) Method of storage and disposal of samples and information.
13) The situation related to conflicts of interest related to the study of representatives, such
as conflicts of interest related to the study at the participating hospital and personal
remuneration, including the source of funding.
14) Handling of consultations, etc., from patients, etc., and related parties.
15) In cases of any economic burden or reward for subjects, etc., a statement to the effect
and the details.
16) In cases of study involving medical treatment beyond normal medical care, matters
related to other treatment methods.
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17) In cases of study involving medical treatment beyond normal treatment, matters
related to provision of medical care to patients after the study.
18) Handling of study results (including incidental findings) pertaining to patients, if the
conduct of study may lead to important findings concerning the health of patients,
genetic characteristics which could be passed on to descendants, etc.
19) Compensation for health damage caused by the study and the details.
20) If samples and information obtained from patients may be used for future study that is
not specified at the time consent is obtained from patients or provided to other
research hospitals, a statement to that effect and the expected contents at the time
consent is obtained.
21) A statement to the effect that persons engaged in monitoring and auditing may access
to samples and information concerning the study patients to the necessary extent,
provided that the confidentiality of patients is maintained.
A legal representative refers to a person who is recognized as appropriate to give
consent with or on behalf of the patient when the patient lacks sufficient capacity to give
consent. A legal representative shall be a person who has custody of the patient, a
spouse, a guardian, or other equivalent person, and, in a view of actual living conditions of
both and the psychological relationship, who can serve the best interests of the patient.
13.3.3 Obtaining consent

The principal investigator or sub-investigator shall explain the study to the patient
or the legal representative, and then provide opportunity to ask questions about the study
and sufficient time to decide whether to participate in the study. After confirming that the
patient or the legal representative fully understands the details of the study, the principal
investigator or sub-investigator shall ask for participation in the study. When the patient
freely and voluntarily gave consent to participate in this study, the patient's signature or
name/seal and the date of consent shall be obtained on the consent form which were
approved by the participating hospital. The same applies in cases where a legal
representative has consented to participate in the study. Patients cannot be included in
this study before written consent has been obtained.
The principal investigator or sub-investigator shall confirm that the consent form is
complete and make one copy of the form. The principal investigator or sub-investigator
shall keep the original copy in the medical record or in a location designated by the
participating hospital. The copy is handed to the patient or his/her legal representative.
13.3.4 Provision of information to patients or their legal representatives

If the principal investigator or sub-investigator obtains information that may affect
the patient's free will or the decision by the legal representative to continue participation in
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this study, the principal investigator or sub-investigator shall provide such information to
the patient or the legal representative to confirm whether the patient continues
participation in this study. The process and results of this confirmation are recorded in a
document. In addition, the principal investigator or sub-investigator shall revise the
explanatory document and consent form and obtain approval at the participating hospital,
and then the revised explanatory and consent form are used to obtain written consent
again for continuous participation in this study from the patient’s legal representative by
the free will of the patient.
13.3.5 Withdrawal of consent, etc.

If a patient or the legal representative withdraws consent or refuses consent in any
of the following cases, the principal investigator or sub-investigator shall, without delay,
take measures in accordance with the content of withdrawal or refusal and explain the
effect to the patient. However, in cases where it is difficult to take such measures, the
principal investigator or sub-investigator shall explain the effect that such measures are
not taken and the reasons, to make efforts to be understood. At the same time, the
principal investigator or sub-investigator shall confirm whether the data already entered
into the EDC can be used or not.
1) When the patient has withdrawn all or part of his/her consent to participate in this study
2) Although the legal representative has given consent to participate in this study, the
patient has refused all or part of the consent
13.3.6 Response to inquiries, consultations, etc. after consent

The principal investigator or sub-investigator shall respond to inquiries,
consultations, etc., regarding this study from patients or their family members after patient
enrollment. If it is difficult to determine the best way to respond, the principal investigator
or sub-investigator shall consult with the study representatives, study office, etc.,
according to the details of consultation.
13.4 Personal information, etc. and anonymously processed information

13.4.1 Basic responsibilities regarding personal information, etc.
13.4.1.1 Protection of personal information, etc.
1) The principal investigator and other parties involved in the conduct of study
(hereinafter, “investigators”) and the chief executive of the participating hospital shall
comply with the following laws and regulations regarding the handling of personal
information, anonymously processed information or anonymized personal information:
Act on the Protection of Personal Information (Act No. 57 of May 30, 2003, as last
amended by Act No. 49 of June 5, 2009), Act on the Protection of Personal Information
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Held by Administrative Organs (Act No. 58 of May 30, 2003, as last amended by Act
No. 51 of May 27, 2016), Act on the Protection of Personal Information Held by
Incorporated Administrative Agencies, etc. (Act No. 59 of May 30, 2003, as last
amended by Act No. 59 of July 17, 2015), and ordinances enacted by local
governments.
2) Investigators shall appropriately handle information that can identify specific individuals
regarding deceased persons in accordance with the provisions of “13.4.1.2
Appropriate acquisition, etc.” and “13.4.2 Safety control” and take necessary and
appropriate measures.
13.4.1.2 Appropriate acquisition, etc.

1) In the conduct of study, investigators do not obtain personal information (personal
information plus information about individuals, including information that can be used
to identify specific individuals regarding deceased persons) by falsification or other
wrongful means.
2) Investigators, in principle, do not handle personal information, etc. obtained in the
study beyond the scope of consent obtained from subjects, etc. in advance.
13.4.2 Safety control

13.4.2.1 Proper handling
1) Investigators shall appropriately handle personal information, etc. obtained in the
conduct of study that is owned by the participating hospital to which the principal
investigator, etc. belongs (including cases where the information is stored on
consignment. Hereinafter, “owned personal information, etc.”), for prevention of
leakage, loss, or damage, and other safety control purposes.
2) Investigators shall give necessary guidance and control to other investigators who
handle the information in cooperation with the chief executive of the participating
hospital, to ensure that the owned personal information, etc., is handled appropriately.
13.4.2.2 System and supervision, etc. for safety control

1) The chief executive of participating hospital shall take necessary and appropriate
measures to prevent leakage, loss or damage of personal information and other safety
control.
2) When the principal investigator involved in the study at the study institution is going to
handle the owned personal information, etc., the chief executive of the participating
hospital shall arrange the system and regulations necessary for safety control. In
addition, the chief executive of the participating hospital shall provide necessary and
appropriate supervision to investigators to ensure safe control of the owned personal
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information, etc.
13.4.3 Other precautions

1) When samples and information obtained from patients in this study are submitted to
external organizations, research IDs are used. Information such as names and medical
record numbers that can identify each patient is not included.
2) When publishing the study results, information such as names and medical record
numbers that can identify each patient is not included.
3) When samples and information obtained from patients in this study are used for
secondary purposes, information such as names and medical record numbers that can
identify each patient is not included.
4) Any person who has access to confidential information of patients associated with the
study shall maintain the information.
13.5 Response to subjects after study implementation

The principal investigator or sub-investigator makes every effort to ensure that
patients receive the best possible prevention, diagnosis, and treatment based on the
results of this study even after the end of this study.
13.6 Handling of study results pertaining to patients

If any important findings are obtained concerning patients' health, genetic
characteristics that could be passed on to descendants, etc. associated with this study
(including incidental findings, such as suspicion of diseases other than the target disease
which require further examination), the principal investigator or sub-investigator notifies the
patient or the legal representative within 7 days if the patient requests notification.
14. Study costs

14.1 Source of funding and financial relationship
This study was funded by research grants from the Department of Neurosurgery,
Hyogo College of Medicine. There is no apparent “possible conflict of interest” in planning,
implementation, statistical analysis, and reporting of this study that could affect the results
of the study or the interpretation at the time this protocol is prepared. Any “possible
conflicts of interest” that may arise during the study are appropriately controlled at the
institution where the investigators belong. In addition, implementation of the study does not
impair the rights and benefits of patients.
14.2 Costs for study treatment
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All treatments related to this study are covered by health insurance, and
regardless of randomization results, all study treatments are routine medical treatments
that are usually provided. Therefore, all medical expenses in this study are covered by
patients' health insurance.
14.3 Compensation for health damage

In case of any health damage to patients, appropriate treatment and care are
provided to the patients. In case of death or sequelae caused by this study, treatment is
provided within the scope of normal insurance care. Costs for the treatment of health
damage are covered by the patient's health insurance, and the patient is partially
responsible for the costs. No medical expense or medical benefit is provided.
Any adverse reactions or malfunctions caused by this study is covered by liability
insurance for clinical study.
15. Revision of protocol

If any changes in the study protocol is necessary during the study, the study
representatives shall revise the protocol. The study representatives report to the chief
executive of the participating hospital on the revision of the protocol with the details and
reasons. The chief executive of the participating hospital conducts the study in accordance
with the procedures of the participating hospital.
16. Monitoring and audit

16.1 Monitoring
Central monitoring is conducted by the Data Center in this study. Off-site
monitoring or on-site monitoring is combined as necessary. Monitoring shall be in
accordance with the monitoring procedures of the Data Center.
16.2 Audit
This study is not a specified clinical study, and does not require an audit. However,
if any question regarding the implementation of the study is raised, an audit will be
implemented. In auditing, an external institution capable of auditing is selected and
commissioned.
17. Termination and early discontinuation of trial

17.1 Discontinuation for individual patients
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17.1.1 Discontinuation criteria

In any of the following cases, the principal investigator or sub-investigator
discontinues the study on a patient.
1) When a patient or the legal representatives withdraws consent to participate in the
study.
2) When the principal investigator or sub-investigator judges that it is difficult to continue
the study on a patient.
3) When the principal investigator or sub-investigator judges that it is difficult for the
patient to continue the study due to reasons of the patient, such as the patient not
visiting the hospital and not being able to make contact.
4) When the principal investigator or sub-investigator judges that the study should be
discontinued due to a serious deviation from the protocol.
5) Any other cases when the principal investigator or sub-investigator judges that the
study should be discontinued.
17.1.2 Precaution for discontinuation

1) The principal investigator or sub-investigator conducts investigation at discontinuation
specified in the protocol as soon as possible. If the investigation at the time of
discontinuation is not available due to any reason of the patient, the reason for
discontinuation and health status of the patient (adverse events, course of symptoms,
etc.) shall be confirmed by telephone, etc., as much as possible.
2) Date of discontinuation, details of the reason for discontinuation (adverse events,
worsening of a patient's disease, etc.), and the investigation results at the time of
discontinuation shall be entered into the EDC as soon as possible.
3) When the reason for discontinuation is adverse events, necessary investigations,
procedures, or treatment should be taken place until the adverse event recovers.
4) When the reason for discontinuation is worsening of the patient disease, necessary
investigations, procedures, or treatment should be followed.
5) The date of discontinuation is the date of withdrawal of consent in cases that
discontinuation is according to 1) of “17.1.1 Discontinuation criteria”, and the date of
discontinuation determined by the principal investigator or sub-investigator in other
cases.
17.2 Discontinuation or interruption of overall study

17.2.1 Consideration to continue the study
The study representatives consider whether to continue the study in any of the
following cases.
1) When a fact or information that damages ethical validity or scientific rationality of the
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study is obtained
a) A fact that damages “ethical validity of the study” refers to any fact that should be
appropriately addressed in the conduct of study from a viewpoint of protection of
human rights and consideration for welfare of patients, including inadequate
procedures for obtaining informed consent or inappropriate handling of personal
information in the conduct of study.
b) “A fact that damages scientific rationality” refers to a fact that may change the
overall assessment of the burdens and expected risks and benefits to patients that
are stated in the study plan by the principal investigator before the start of study,
due to new scientific findings, contents, safety measure information implemented
by domestic or foreign regulatory authorities, etc., that are revealed after the start
of the study.
2) When a fact or information that damages appropriateness of the conduct of study or
reliability of the study results, is obtained.
a) A fact or information that damages “appropriateness of the conduct of study” refers
to a fact or information such as deviations from the study patient inclusion policy or
study methods based on the study plan in the conduct of study.
b) A fact or information that “damages reliability of the study results” refers to a fact
or information such as falsification or fabrication of study data.
3) When it is judged that the expected risks of conducting the study are higher than the
expected benefits of the study.
4) When it is judged that sufficient results have been obtained or that sufficient results will
not be obtained from the study.
Relevant information in 1)–4) is reported to the Independent Monitoring Committee
for deliberation.
17.2.2 Precaution for discontinuation or interruption

1) If the overall study is discontinued, the study representatives shall promptly report it
and the reason to the chief executive of the participating hospital in a written
document. In the case of interruption, the study plan shall be reviewed and, if
necessary, the protocol shall be revised. Any revisions shall be promptly reported to
the chief executive of the participating hospital. The chief executive of the participating
hospital shall restart the study in accordance with the procedures of the participating
hospital.
2) The principal investigator or sub-investigator notifies the patients participating in the
study for the discontinuation or interruption for any reason and performs necessary
investigations, procedures, or treatment.
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17.3 Termination of trial

17.3.1 Termination of trial in individual patients
Termination of trial on individual patients is defined as completion of final
investigation specified in the protocol for individual patients. The principal investigator shall
promptly enter the end date, etc. into the EDC after the termination of the study in
individual patients.
17.3.2 Termination of the overall trial

Termination of the overall trial is defined as the time when the final analysis report
is submitted to the study representatives and the Independent Monitoring Committee by
the statistical analysis manager. After the receipt of the final analysis report, the study
representatives shall promptly prepare a summary report and report the termination of the
study and a summary of the results to the chief executive of the participating hospital
without delay.
18. Handling of adverse events, serious adverse events, diseases, and other serious
events
18.1 Handling of adverse events
18.1.1 Handling of patients
When the principal investigator or sub-investigator identifies an adverse event, the
principal investigator or sub-investigator should immediately take appropriate measures,
including providing explanations to the relevant patients, etc.
18.1.2 Reporting to the study office

principal investigator or sub-investigator reports according to “9.2 Classification of adverse
events” in addition to the record to EDC.
18.2 Handling of serious adverse events

When the principal investigator or sub-investigator identifies a serious adverse
event, the principal investigator or sub-investigator should immediately take appropriate
measures, including providing explanations to patients, etc.

event, the principal investigator or sub-investigator should make reports to the EDC and to
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the study office through the principal investigator in addition to the report to medical
records.
18.3 Reporting to the chief executive of the participating hospital

When the principal investigator identifies a serious adverse event or a malfunction,
the principal investigator should report once a year to the chief executive of the hospital to
which the principal investigator belongs.
19. Storage of records

The principal investigator and other related parties involved in the study
(hereinafter, "study personnel") shall ensure the accuracy of the samples and information
used in the study and materials pertaining to the information (including records related to
provision of samples and information used in the study. Hereinafter, "information, etc.",
which includes the raw materials or raw data specified in "11. Case report") (This includes
confirming the accuracy of information not prepared by the study personnel (e.g., records
prepared by patients)). When revising or changing information, etc., a record is kept with
the date, name, and reason. In addition, personal information pertaining to the study
should be kept in updating form within the necessary extent to achieve the purpose of use.
Responsibilities for those involved in a storage of information, etc. are as follows.
19.1 Principal Investigator

1) The principal investigator instructs and controls the investigators to ensure the
accuracy of information, in accordance with the procedures for storage of samples and
information obtained from patients established in advance by the chief executive of the
participating hospital. Samples and information obtained from patients are stored in a
locked storage in an appropriate location in the participating hospital with the names
and details of consent obtained from the patients, to prevent leakage, confusion, theft,
loss, etc. In addition, the same applies to storage of all materials related to this study,
including protocol (including revisions), informed consent forms (including revisions),
explanatory documents (including revisions), procedures related to the implementation
of this study, contracts, and documents related to results of deliberations received from
Independent Monitoring Committee.
2) The principal investigator reports to the chief executive of the participating hospital on
the status of storage described in the previous section, in accordance with the
procedures for storage of samples and information obtained from patients established
by the chief executive of the participating hospital.
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20. Registration and publication related to the study

20.1 Registration of study summary and results
The study representatives register a study summary in University Hospital Medical
Information Network Clinical Trials Registry (UMIN-CTR) (http: //www.umin.ac.jp/ctr/index-
j.htm), ClinicalTrials.gov (https: //clinicaltrials.gov) before the start of the study and update
the summary as appropriate according to changes in the protocol or progress of the study.
When the study is completed, the study representatives register a study result without
delay.
20.2 Publication of study results

When the study is completed, the study representatives publish the results of the
study without delay, after taking necessary measures (e.g., to prevent identification of
specific study patients) to protect the human rights of patients and related parties or the
rights and benefits of patients and related parties. Author(s) of the paper are determined
by the study representatives according to Uniform Requirements for Manuscripts
Submitted to Biomedical Journals (http: //www.icmje.org/) by the International Committee
of Medical Journal Editors (ICMJE). All authors should review and agree to the details of
the paper prior to submission. The same goes for authors of conference presentations.
21. Ownership of the study results

The results, data, intellectual property rights, etc. obtained in this study belong to
the study representatives and not to the patients. Whether the intellectual property rights of
the study representatives belong to the individual or to the study institution is determined
by the agreement of the participating hospital.
22. Study organization

22.1 Study representatives
The study representatives are responsible for operation of this study and decide
on the policy for conducting the study.
Shinichi Yoshimura (Department of Neurosurgery, Hyogo College of Medicine)
Nobuyuki Sakai (Department of Neurosurgery, Kobe City Medical Center General
Hospital)
Hiroshi Yamagami (Department of Cerebrovascular Medicine, National Cerebral
and Cardiovascular Center)
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22.1.2 Study office

The study office organizes this study.
Department of Neurosurgery, Hyogo College of Medicine
Address: 11 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan
TEL: 0798-45-6458, FAX: 0798-45-6457
E-mail: rescue-j@hyo-med.ac.jp
Person in charge: Kazutaka Uchida (Department of Neurosurgery, Hyogo College
of Medicine)
Toshinori Takagi (Department of Neurosurgery, Hyogo College
of Medicine)
22.3 Study Steering Committee

The Study Steering Committee discusses practical matters related to study
implementation, including the study protocol, investigation items, various documents
including informed consent form, and handling of enrolled cases.
Hospital)
Hiroshi Yamagami (Department of Cerebrovascular Medicine, National Cerebral
Takeshi Morimoto (Department of Clinical Epidemiology, Hyogo College of
Medicine)
Kazunori Toyoda (Department of Cerebrovascular Medicine, National Cerebral
Yuji Matsumaru (Division of Stroke Prevention and Treatment, Department of
Neurosurgery, University of Tsukuba)
Yasushi Matsumoto (Department of Endovascular Neurosurgery, Kohnan Hospital)
22.4 Independent Monitoring Committee

To ensure safety of subjects in this study and to assure ethical and scientific
validity of this study as far as possible, Independent Monitoring Committee evaluates the
undergoing data of this study from third-party and neutral viewpoints. The Independent
Monitoring Committee makes appropriate recommendations and give advice to the study
representatives based on the results. Members of Independent Monitoring Committee are
not the authors of the academic paper but are listed in acknowledgments in a view of
dependence.
Kuniaki Ogasawara (Department of Neurosurgery, Iwate Medical University)
Naoya Kuwayama (Department of Endovascular Medicine, Toyama University
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Hospital)
Teruyuki Hirano (Department of Stroke Medicine, Kyorin University)
22.5 Imaging Evaluation Committee members

Reiichi Ishikura (Department of Radiology, Hyogo College of Medicine)
Manabu Inoue (Department of Cerebrovascular Medicine, National Cerebral and
Cardiovascular Center)
22.6 Data Center

Data Center builds the EDC system, controls the database, and performs central
monitoring.
Nexis Co., Ltd. Development Section 3
Address: Nichidai Building 3F, 226-8 Minoshima, Hakata-ku, Fukuoka-shi, Fukuoka
812-0017, Japan
TEL: 092-483-6033 FAX: 092-483-6035
E-mail: aspects@midinfo.co.jp
Person in charge: Akito Uchio
22.7 Chief study statististician

Chief study statististician supervises and conducts the design and statistical
analysis of this study.
Medicine)
22.8 Study Institution and Principal Investigator

Hyogo College of Medicine
Address: 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan
Chief executive of study institution: Koichi Noguchi
Principal Investigator: Shinichi Yoshimura
Sub-investigator: Kazutaka Uchida
Toshinori Takagi
Manabu Shirakawa
Hiroto Kakita
22.9 Participating institutions

Hyogo Prefectural Amagasaki General Medical Center; Masaomi Koyanagi
Iwate Prefectural Central Hospital; Naoto Kimura
Osaka University Hospital; Hajime Nakamura
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Okayama City Hospital; Koji Tokunaga

Kano General Hospital; Kazutomo Nakazawa
Kansai Rosai Hospital; Shingo Toyota
Gifu University Hospital; Yukiko Enomoto
National Hospital Organization Kyusyu Medical Center; Tomoyuki Tsumoto
Kyoto Okamoto Memorial Hospital; Naoki Tokuda
Kindai University Hospital; Norihito Fukawa
Japanese Red Cross Kumamoto Hospital; Seigo Shindo
Kochi Red Cross Hospital; Nobuhisa Matsushita
Kobe City Medical Center General Hospital; Hirotoshi Imamura
National Center for Global Health and Medicine; Masato Inoue
National Cerebral and Cardiovascular Center Hospital; Hiroshi Yamagami
Saiseikai Shigaken Hospital; Hidesato Takezawa
Saga University Hospital; Atsushi Ogata
Sapporo Medical University; Nobuhiro Mikuni
Shimizu Hospital; Fuminori Shimizu
Showa University Hospital; Hirotaka Okumura
Shinko Hospital; Yasushi ueno
Seisho Hospital; Masataka Takeuchi
University of Tsukuba; Yuji Matsumaru
Tsuchiura Kyodo General Hospital; Masataka Yoshimura
Tokyo Medical University Hachioji Medical Center; Junya Tsurukiri
Jikei University Hospital; Toshihiro Ishibashi
Tokushima University Hospital; Nobuaki Yamamoto
Toranomon Hospital; Wataro Tsuruta
Nagasaki University Hospital; Nobutaka Horie
National Hospital Organization Nagasaki Medical Center; Takeshi Hiu
Nakamura Memorial Hospital; Tatsuya Ogino
Nagareyama Central Hospital; Ryuzaburo Kanazawa
National Hospital Organization Nagoya Medical Center; Takumi Asai
Niigata City General Hospital; Kenichi Morita
Nishinomiya Kyoritsu Neurosurgical Hospital; Yoshitaka Yamada
Hakodate Shintoshi Hospital; Koichi Haraguchi
Hanwa Memorial Hospital; Akio Nishino
Hyogo College of Medicine; Shinichi Yoshimura
Hirosaki University Graduate School of Medicine; Norihito Shimamura
Mie University Hospital; Naoki Toma
Yamaguchi University Hospital; Hideyuki Ishihara
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Yokohama Shintoshi Neurosurgical Hospital; Masafumi Morimoto
23. References
1) Olvert A. Berkhemer, et al. A Randomized Trial of Intraarterial Treatment for Acute
Ischemic Stroke (MR CLEAN). N Engl J Med 2015; 372: 11-20. PMID: 25517348
2) Goyal M, et al. Randomized Assessment of Rapid Endovascular Treatment of
Ischemic Stroke (ESCAPE). N Engl J Med 2015; 372: 1019-30. PMID: 25671798
3) B.C.V. Campbell et al. Endovascular Therapy for Ischemic Stroke with Perfusion-
Imaging Selection (EXTEND-IA). N Engl J Med 2015; 372: 1009-18. PMID: 25671797
4) Saver JL, et al. Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in
Stroke (SWIFT PRIME). N Engl J Med 2015; 372: 2285-95. PMID: 25882376
5) Jovin TG et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke
(REVASCAT). N Engl J Med. 2015; 372: 2296-306. PMID: 25882510
6) Goyal M, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a
meta-analysis of individual patient data from five randomised trials (HERMES). Lancet.
2016 Apr 23;387(10029): 1723-31. PMID: 26898852
7) Powers WJ, et al. 2018 Guidelines for the Early Management of Patients with Acute
Ischemic Stroke: A Guideline for Healthcare Professionals from the American Heart
Association/American Stroke Association, Stroke. 2018 Mar;49(3): e46-e110, PMID:
29367334
8) Albers GW, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by
Perfusion Imaging (DEFUSE 3 trial). N Engl J Med. 2018 Feb 22;378(8): 708-718.
PMID: 29364767
9) Nogueira RG, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch
between Deficit and Infarct (DAWN trial). N Engl J Med. 2018 Jan 4;378(1): 11-21
PMID: 29129157
10) Yoshimura S, et al. Endovascular Therapy in Ischemic Stroke with Acute Large-Vessel
Occlusion: Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism
Japan Registry 2. J Am Heart Assoc. 2018 Apr 25;7(9). PMID: 29695384
11) Barber PA, Demchuk AM, Zhang J, et al. Validity and reliability of a quantitative
computed tomography score in predicting outcome of hyperacute stroke before
thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT
Score. Lancet. 355: 1670-4, 2000.
12) Nezu T, Koga M, Nakagawara J, et al. Early ischemic change on CT versus diffusion-
weighted imaging for patients with stroke receiving intravenous recombinant tissue-
type plasminogen activator therapy: stroke acute management with urgent risk-factor
assessment and improvement (SAMURAI) rt-PA registry. Stroke. 42: 2196-200, 2011.
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13) Zaidat OO, Yoo AJ, Khatri P, 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 44: 2650-2663, 2013.
14) Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with alteplase for acute
ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring
Study (SITS-MOST): an observational study. Lancet.369: 275-82, 2007.
15) van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement for the
assessment of handicap in stroke patients. Stroke 19: 604-607, 1988.
16) Schulman S; Subcommittee on Control of Anticoagulation of the Scientific and
Standardization Committee of the International Society on Thrombosis and
Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic
medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-
17) Rüdiger von Kummer et al. The Heidelberg Bleeding Classification Classification of
Bleeding Events After Ischemic Stroke and Reperfusion Therapy Stroke.2015; 46:
2981-2986
24. Appendix
National Institute of Health Stroke Scale (NIHSS)
Old version NIH Stoke Scale (NIHSS) (1994)
Name Score Item
Level of 0 = Alert 2 = Not alert, obtunded
1A
consciousness 1 = Alert with simple stimulation 3 = Unresponsive
Level of 0 = Answers both correctly 2 = Answers
consciousness neither correctly 1B
Questions 1 = Answers one correctly
Level of
0 = Performs both tasks correctly 2 = Performs neither task
consciousness 1C
1 = Performs one task correctly
Commands
0 = Normal 2 = Total gaze palsy
Gaze 2
1 = Partial gaze palsy
0 = No visual loss 2 = Complete hemlanopsia
Visual fields 3
1 = Partial hemlanopsia 3 = Bilateral hemlanopsia
Facial palsy 0 = Normal 2 = Partial paralysis 4
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1 = Minor paralysis 3 = Complete

paralysis
0 = No drift 3 = No effort against gravity
Motor arm Left 1 = Drift before 10 seconds 4 = No movement 5a
2 = Falls before 10 seconds
Motor arm Right 1 = Drift before 10 seconds 4 = No movement 5b
1 = Drift before 5 seconds 4 = No
Motor leg Left 6a
movement
Motor leg Right 6b
movement
0 = Absent 2 = Two limbs
Ataxia 7
1 = One limb
0 = Normal 2 = Severe loss
Sensory 8
1 = Mild loss
0 = Normal 2 = Severe aphasia
Language 1 = Mild aphasia 3 = Mute or global 9
aphasia
0 = Normal 2 = Severe
Dysarthria 10
1 = Mild
Extinction/Inatte 0 = Normal 2 = Severe
11
ntion 1 = Mild
Lyden P, Brott T, Tilley B, Welch KM, Mascha EJ, Levine S, et al. Improved reliability of the
NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke 1994; 25:
2220-2226.
・Alberta Stroke Program Early CT Score (ASPECTS), DWI-ASPECTS (10 points)
36
37
See ASIST Japan website: http: //asist.umin.jp/training/index.html

Barber PA, Demchuk AM, Zhang J, et al. Validity and reliability of a quantitative computed
tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy.
ASPECTS Study Group. Alberta Stroke Program Early CT Score. Lancet. 2000; 355:
1670-.
Nezu T, Koga M, Nakagawara J, et al. Early ischemic change on CT versus diffusion-
weighted imaging for patients with stroke receiving intravenous recombinant tissue-type
plasminogen activator therapy: stroke acute management with urgent risk-factor
assessment and improvement (SAMURAI) rt-PA registry. Stroke. 2011; 42: 2196-200.
Teruyuki Hirano, Evaluation of early ischemic change using ASPECTS and intravenous rt-
PA therapy. Jpn J Stroke 2015; 37: 347–351.
modified Rankin Scale (mRS)

modified Rankin Scale Notes
No subjective symptoms and objective
0 No symptoms at all
signs
Despite subjective symptoms or objective
No significant disability despite
signs, there has been no change in the
1 symptoms: able to carry out all
person’s ability to work and activities of
usual duties and activities
daily living compared to before the stroke
37
38
Despite some limitations in the person’s

Slight disability: unable to carry out all
ability to carry out his/her usual duties and
2 previous activities but able to look
activities compared to before the stroke,
after own affairs without assistance
he/she can lead an independent life
Assistance* is essential for using public
Moderate disability: requiring some
transport to get around, but is not essential
3 help, but able to walk without
for walking†, eating, maintaining routine
assistance
daily hygiene, using the toilet, etc.
Moderately severe disability: unable Assistance* is essential for walking†,
to walk without assistance, and eating, maintaining routine daily hygiene,
4
unable to attend to own bodily needs using the toilet, etc., but constant care is
without assistance not required
Severe disability: bedridden, Assistance* is necessary at all times
5 incontinent, and requiring constant
nursing care and attention
6 Death
* Assistance includes physical assistance, verbal instruction, or supervision by another
person.
† Ability to walk on a flat surface is mainly checked. In addition, assistance does not include
the use of any aid (3.g. stick/cane, or walking frame/walker).

van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver
agreement for the assessment of handicap in stroke patients. Stroke 1988;19: 604-607
Shinohara Y, Minematsu K, Amano T, Ohashi Y. Reliability of modified Rankin Scale -
Introduction of a guidance scheme and a questionnaire written in Japanese -. Jpn J Stroke
2007;29: 6-13
Shinohara Y, Minematsu K, Amano T, Ohashi Y. Modified Rankin Scale with expanded
guidance scheme and interview questionnaire: Interrater agreement and reproducibility of
assessment. Cerevrovasc Dis 2006;21: 271-278
・Standards of the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-

MOST)
HI 1 Small petechiae along the margins of the infarct
More confluent petechiae within the infarct area but
HI 2
without space-occupying effect
Blood clot(s) not exceeding 30% of the infarct area with
PH 1
some mild space-occupying effect
Blood clots exceeding 30% of the infarct area with
PH 2
substantial space-occupying effect
38
39
Small or medium sized blood clots located remote from

PHr 1 the actual infarct; a mild space-occupying effect could
be present
Large confluent dense blood clots in an area remote
PHr 2 from the actual infarct; substantial space-occupying
effect might be present
HI: hemorrhagic infarction, PH: parenchymal hematoma, PHr: remote parenchymal
hematoma
Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with alteplase for acute ischaemic
stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-
MOST): an observational study. Lancet.369: 275-82, 2007.
・modified TICI (mTICI) Grades

0 No perfusion
Antegrade reperfusion past the initial occlusion, but
1 limited distal branch filling with little or slow distal
reperfusion
Antegrade reperfusion of less than half of the occluded
2a target artery previously ischemic territory
Antegrade reperfusion of more than half of the
2b previously occluded target artery ischemic territory
Complete antegrade reperfusion of the previously
occluded target artery ischemic territory, with absence
3 of visualized occlusion in all distal branches
Zaidat OO, Yoo AJ, Khatri P, et al; Cerebral Angiographic Revascularization Grading
Stroke 44: 2650-2663, 2013.
・ Modified Mori Grade

Grade 0 No reperfusion
Movement of thrombus not associated with any
Grade 1 flow improvement
Partial (branch) recanalization in <50% of the
Grade 2 branches in the occluded arterial territory
39
40
Nearly complete recanalization with reperfusion in

≥50% of the branches in the occluded-arterial
Grade 3 territory
Mori E, Minematsu K, Nakagawara J, et al; Japan Alteplase Clinical Trial II Group. Effects
of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in middle cerebral
artery occlusion: Japan Alteplase Clinical Trial II (J-ACT II). Stroke 41: 461-465, 2010.
40
41
Trial Protocol
Randomized clinical trial of endovascular therapy for acute large

vessel occlusion with a large ischemic core: Recovery by
Endovascular Salvage for Cerebral Ultra-acute Embolism-Japan
Large IscheMIc core Trial (RESCUE-Japan LIMIT)
Ver. 2.6, Date Prepared July 30, 2021
Clinical Trial Registration: ClinicalTrials.gov: NCT03702413

UMIN Clinical Trials Registry: UMIN 000034388
Confidentiality
Access of this protocol is limited to the persons concerned in this trial.
Disclosure to third parties without consent of the principal investigator is prohibited,
except for submission to the Institutional Review Board or disclosure to patients.
1
42
Table of Contents
0．Scheme ................................................................................................................... 3
1. Purpose.................................................................................................................... 5
2. Rationale for the study ............................................................................................. 5
3. Overall design and plan of the study ........................................................................ 6
4. Eligibility criteria ....................................................................................................... 8
5. Enrollment and randomization ................................................................................. 9
6. Treatment ............................................................................................................... 11
7. Observation, tests, reporting items and schedule .................................................. 11
8. Definition of outcomes............................................................................................ 15
9. Definition, handling, and investigation related to adverse events........................... 17
10. Statistical considerations...................................................................................... 17
11. Case report........................................................................................................... 19
12. Submission of images .......................................................................................... 19
13. Ethical concerns ................................................................................................... 19
14. Study costs .......................................................................................................... 25
15. Revision of protocol.............................................................................................. 26
16. Monitoring and audit............................................................................................. 26
17. Termination and early discontinuation of trial ....................................................... 26
18. Handling of adverse events, serious adverse events, diseases, and other
serious events ............................................................................................................ 29
19. Storage of records................................................................................................ 30
20. Registration and publication related to the study.................................................. 31
21. Ownership of the study results ............................................................................. 31
22. Use of collected information ................................................................................. 31
23. Study organization ............................................................................................... 32
24. References ........................................................................................................... 34
25. Appendix .............................................................................................................. 36
2
43
0. Summary
Scheme
Purpose The purpose of this study is to evaluate the efficacy of endovascular

therapy (EVT) for acute large vessel occlusion with moderate to severe
large ischemic core (ASPECTS of 3–5 on CT or DWI of MRI).
Eligibility Patients who meet all the [Inclusion criteria] and do not meet any of the
criteria [Exclusion criteria] are enrolled.
[Inclusion criteria]
7) Randomization can be finished within 6 hours from the time of last known
well, or 6 to 24 hours from the time of last known well without positive
lesion on MRI-FLAIR image.
9) The patient or legally authorized representative has signed the informed
consent form.
[Exclusion criteria]
3
44
6) High risk of hemorrhage (platelet < 40,000 /ul, APTT > 50 second or
PT-INR > 3.0)
8) Patients who, in the judgment of the investigator, are likely to be non-
compliant or uncooperative during the study
Target 200 patients (number of patients who have completed patient enrollment)
number of 100 patients (EVT group), 100 patients (no EVT group)
subjects
Study Study period: 4 years, from the date of approval of the protocol to the date
period of completion of the trial.
Study From after obtaining informed consent to 90 days from the onset.
participatio
n period
Study Prospective, open-label, randomized controlled study
design
Outcomes [Primary outcomes]
[Safety outcomes]
mRS: modified Rankin Scale

NIHSS: National Institute of Health Stroke Scale
ASPECTS: Alberta Stroke Program Early CT Score
4
45
1. Purpose
The purpose of this study is to evaluate the efficacy of endovascular therapy (EVT)
for acute large vessel occlusion with moderate to severe large ischemic core defined by
Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of 3–5 on CT or
diffusion-weighted imaging (DWI) of magnetic resonance imaging (MRI).
2. Rationale for the study

For acute stroke caused by occlusion of proximal major artery in anterior
circulation, including internal carotid artery (ICA) and the horizontal segment of the middle
cerebral artery (M1), a series of comparative trial results were reported in 2015 showing
that addition of EVT mainly using stent retrievers in addition to medical therapy including
recombinant tissue plasminogen activator (rt-PA) had better patient outcomes compared to
medical therapy alone [1–5]. A meta-analysis for these randomized trials [6] was also
published, which established the evidence for EVT in large vessel occlusion in patients
with the following [7].
1) Functional independence (modified Rankin Scale (mRS) score 0–1) before the onset
2) Treated with rt-PA according to the guideline
3) Acute occlusion of ICA or proximal middle cerebral artery
4) Patient aged ≥ 18 years
5) Neurological symptoms (NIHSS ≥ 6)
6) Limited cerebral infarction area (ASPECTS ≥ 6)
7) EVT can be initiated within 6 hours from the time of last known well.
In addition, in 2018, two randomized trials [8, 9] have demonstrated the efficacy of
EVT for strokes caused by large vessel occlusion after 6 hours from the onset. In the first
trial (DAWN trial), indication for patients with occlusion of ICA or M1 in 6–24 hours after
the time of last known well were selected according to age, neurological severity (NIHSS),
and ischemic core volume, and the group with standard therapy plus EVT resulted in
significantly better functional outcomes. In the DEFUSE 3 trial reported in the same year,
indication for patients with occlusion of ICA or M1 at 6–16 hours after he time of last
known well were selected by calculating a mismatch between the ischemic core volume
and volume of perfusion delay area. The functional outcomes were significantly better in
the group with EVT in addition to standard care. According to these results, the guidelines
of the American Heart Association and American Stroke Association recommend EVT with
a Class I recommendation and level of evidence A for patients who are in the period 6–16
hours from onset and meet the inclusion criteria for DAWN or DEFUSE 3 trials. Results of
these randomized trials demonstrate that EVT is effective for patients who have developed
collateral circulation to some extent, even if some time has passed from the onset.
5
46
However, the calculation software used in DAWN and DEFUSE 3 trials for
ischemic core volume and volume of perfusion delay area is not approved in Japan, so it is
impossible to directly perform these trials in Japan.
On the other hand, efficacy of EVT for patients with ASPECTS score less than 6
has not been proven [6]. The results of RESCUE-Japan registry 2 [10] showed that EVT
was effective in a real-world population that included patients other than those
recommended by the guidelines. Furthermore, among patients with moderate to severe
large ischemic core with ASPECTS 3–5, the number of patients with mRS 0–3 at 90 days
from the onset, which is the primary outcome of this study, was 55 (37.7%) in 146 patients
who received EVT and 24 (12.5%) in 192 patients who did not receive EVT, respectively.
The adjusted odds ratio (OR) for mRS of 0–3 was 3.42, demonstrating the efficacy of EVT.
This suggests that EVT is effective even in patients with ASPECTS < 6.
Accordingly, based on the inclusion criteria unique to Japan, this trial is planned to
clarify the efficacy of EVT for acute large vessel occlusion with moderate to severe large
ischemic core.
It has been suggested that a large signal on DWI of MRI but no large signal on
fluid-attenuated inversion recovery (FLAIR) images (DWI-FLAIR mismatch) indicates that it
is approximately 4.5 hours after the onset. The WAKE-UP study has demonstrated that rt-
PA improved the functional outcomes in patients with DWI-FLAIR mismatch with an
unknown time of onset [12]. With reference to the WAKE-UP study, patients with DWI-
FLAIR mismatch are included in this study even if it is 6–24 hours from the time of last
known well, because the time of onset is considered about 4.5 hours.
3. Overall design and plan of the study

3.1 Design
3.1.1 Outline
<Rationale for setting the design>

The major purpose of this study is to evaluate the efficacy of endovascular therapy
for patients with acute large vessel occlusion with moderate to severe large ischemic core
(CT-ASPECT score 3-5 or DWI-ASPECT score 3-5), and the above study design is
adopted. A schematic diagram of the study flow is shown below.
6
47
3.1.2 Target number of patients

200 patients (number of patients who have completed patient enrollment)
<Rationale for setting the target number of subjects>

From RESCUE-Japan Registry 2 data [10], among 338 patients with ASPECTS 3–
5, who are the target of this study, the number of patients with mRS 0–3 at 90 days from
the onset, which is the primary outcome of this study, was 55 (37.7%) in EVT group and
24 (12.5%) in no EVT group, respectively [11]. In addition, the adjusted OR was 3.42, but
since the study was an observational study and its effect could be larger than clinical trial,
we assume the relative risk at 2.7 times (3.42 × 0.8 = 2.7) with an allowance of 20% in
clinical trial. When type I error level is set at 0.05 two-sided and the power of the test at
0.90, 81 patients in each cohort are required. Estimating the clinical dropout rate of 15%,
required sample size is calculated to be 191 patients. Considering possible withdrawal of
consent, we set the target sample size to 100 patients in each cohort and a total of 200
patients.
3.1.3 Study period

3.1.3.1 Period per patient
Period from obtaining informed consent to 90 days after randomization.
3.1.3.2 Overall study period

Patient enrollment period: 3 years from the date of approval of the protocol.
7
48
Overall study period: From the date of approval of this protocol to the date
specified in “17.3.2 Termination of this study”.
3.2 Study flow

The flow of this study is as shown below. For details of patient enrollment, study
treatment, investigation items and investigation schedule, see “5. Enrollment and
randomization”, “6. Treatment”, and “7. Observation, tests, reporting items and schedule”,
respectively.
4. Eligibility criteria
4.1 Eligibility criteria

7) Randomization can be finished within 6 hours from the time of last known well, or 6 to 24
hours from the time of last known well without positive lesion on MRI-FLAIR image.
9) The patient or legally authorized representative has signed the informed consent form.

6) High risk of hemorrhage (platelet < 40,000 /ul, APTT > 50 second or PT-INR > 3.0)
8) Patients who, in the judgment of the investigator, are likely to be non-compliant or
uncooperative during the study
8
49
5. Enrollment and randomization

5.1 Preparation
In this study, the Data Center handles patient enrollment and data collection using
the Electronic Data Capture (EDC) system via the Internet.
5.1.1 Hospital registration

The person in charge in the study office sends the list of hospital names and
principal investigator names to the Data Center.
5.1.2 EDC system user registration

The principal investigator at the hospital sends the list of names and emergency
contact information of the EDC system users, consisting of sub-investigators at each
hospital through the study office to the Data Center. If there is no problem or question, the
Data Center provides an ID and a password.
5.2. Patient enrollment

In enrolling patients to this study, the following procedures are taken for patient
enrollment.
1) Selection of patients
Principal investigator or sub-investigator selects patients for this study, taking “4.1
Eligibility criteria” into consideration.
2) Obtaining informed consent
Explanation of the details of this study to patients or their legal representatives and
obtaining informed consent from patients or their legal representatives in accordance
with “13.3 Obtaining Informed Consent”.
3) Surveillance to confirm eligibility for patient enrollment
Principal investigator or sub-investigator conducts surveillance to confirm eligibility
for patient enrollment in accordance with “7. Observation, tests, reporting items and
schedule” for patients whose written informed consent has been obtained from the
patient or the legal representative.
4) Entry and transmission of surveillance results
Principal investigator or sub-investigator confirms the surveillance results for
eligibility so that all items in “4.2.1 Inclusion criteria” are met and any items in “4.2.2
Exclusion criteria” are not met, access the website for patient enrollment, enter and
transmit the necessary information on the website.
EDC system receives the necessary information, confirms the details, and
indicates the eligibility or ineligibility on the website.
9
50
5) Confirmation of patient enrollment contact forms (completion of patient enrollment)

Principal investigator or sub-investigator confirms the details, if eligibility message
is indicated, and enters the date of enrollment and study ID assigned by EDC system in
“Name list for subject enrollment”. The screen indicating the eligibility is printed and
kept with medical records. This completes the patient enrollment as a subject of this
study (Principal investigator or sub-investigator can start the study treatment only when
patient enrollment is completed).
5.3 Randomization
Dynamic randomization by minimization method is used for the randomization of
patients to EVT group or no EVT group. Randomization and enrollment of patients are
made using EDC system.
5.3.2 Enrollment and acquisition of randomization results

Principal investigator or sub-investigator selects patients who meet the eligibility
criteria, obtains informed consent from the patients, and then, based on the screening
results, confirms that the patient meets the inclusion criteria and do not conflict with the
exclusion criteria, and enrolls the patient using the EDC system. After enrollment, principal
investigator or sub-investigator obtains randomization results for study treatment from the
EDC system. The following items are entered in the EDC system at patient enrollment.
1) Enrolled hospital
2) Date of obtaining written informed consent
3) Age at enrollment
4) Time from onset or last known well to hospital arrival
5) NIHSS score at the time of obtaining informed consent
6) Whether the patient was treated with rt-PA after the onset
7) Eligibility information (confirmation of inclusion criteria and exclusion criteria)

obtaining informed consent (< 75 years or ≥ 75 years), time from onset or last known well
to hospital arrival (< 120 minutes or ≥ 120 minutes), NIHSS score at the time of obtaining
informed consent (< 21 or ≥ 21), and whether the patient was treated with rt-PA after the
onset.
5.3.4 Control and storage of randomization results

Randomization results are controlled and stored at the Data Center.
10
51
5.4 Precautions
1) If the input data is insufficient, patient enrollment is not accepted until all data is
completed.
2) Except for refusal to use the data, once a patient has been enrolled, the patient will not
be unenrolled (deleted from the database). In a case of duplicate enrollment, the first
enrollment information (patient enrollment number) is adopted.
3) When a wrong enrollment or duplicate enrollment is found, contact the Data Center
immediately.
6. Treatment
6.1. Definition of treatment
Treatment shall be according to the randomization results. Regarding the details of
EVT, the most appropriate method of EVT should be selected for each case. The type of
device to be used for EVT is not important if regulatory approval has been obtained.
However, devices that correspond to contraindications should not be used.
No EVT group receives standard treatment according to guidelines.
6.2. Treatment method

Local intraarterial fibrinolysis is not performed as endovascular recanalization
therapy. There is no provision for other types of treatment (e.g., internal medicine,
rehabilitation, etc.).
6.3. Discontinuation of treatment

This study does not have any criteria or restrictions in discontinuation of treatment.
6.4. Treatment options at recurrence

This study does not have any restriction in treatment options at recurrence.
7. Observation, tests, reporting items and schedule

7.0 Summary
Schedule At enrollment Observation period
Before After Very Early Early Discharge End
randomization randomization
11
52
Implementation Within 6 hours from the time of Within 12 Within 48 either 7 days 90 days (±
item/ last known well or within 6–24 hours after hours (± 24 (± 2 day) 30 days)
implementation hours from the time of last known randomi- hours) after after after
period well zation randomi- randomi- randomi-
zation zation or at zation
discharge
which is
earlier
Informed ○
consent
Confirmation of ○
inclusion and
exclusion criteria
Basic data ○ ○
Only Details
randomization
factors
Demographics ○
and baseline
characteristics
data
Vital sign ○ ○ ○ ○ ○
Laboratory data ○ ○
Chest x-ray, ○
ECG test
mRS ○ (Before ○ ○
onset)
NIHSS ○ ○ ○ ○ ○
Only scores Details
Imaging ○ (*1) ○ ○
CT/CTA/CTP CT or MRI CT/CTA or
or MRI/MRA MRI/MRA
ASPECTS ○
Occclusion site ○
12
53
Type of cerebral ○ ○
infarction
Details of EVT ○
and Only EVT
complications group
Recanalization ○
status Only EVT
(TICI grade) group
Recanalization △
status
(mMORI grade)
Serious adverse
events
Clinically
significant
adverse events
Decompressive
craniectomy
*1: Imaging (at enrollment)

Within 6 hours from last known well time: CT/CTA/CTP or MRI/MRA
Within 6–24 hours from last known well time: MRI/MRA
7.1 Primary outcomes and timing

randomization, 48 hours (± 24 hours) after randomization, and either 7 days (± 2 days)
after randomization or at discharge which is earlier.
2) mRS
mRS assessment is performed at enrollment (before the onset), either 7 days (± 2
days) after randomization or at discharge which is earlier, and 90 days (± 30 days)
after randomization. If a patient is unable to visit the hospital, surveillance by telephone
is also allowed.
3) Imaging
CT/CTA/CTP or MRI/MRA is performed at enrollment. CT or MRI is performed at
48 hours (± 24 hours) after randomization to assess the status of cerebral infarction
and intracranial hemorrhage. CT/CTA or MRI/MRA is performed either on 7 days (± 2
13
54
days) after randomization or at discharge whichever is earlier, to assess the status of

All events occurred within 90 days after randomization are assessed.
7.2 At enrollment
7.2.1 Basic data
Hospital name, name of patient identification, age, sex, time of onset (time of
last known well), time of arrival at the hospital, allergy to contrast agent.
7.2.2 mRS before onset
7.2.3 rt-PA after onset
7.2.4 Imaging evaluation
scores), and the occlusion site are assessed. DICOM images are submitted to the
office for central review.
7.2.5 Complications/Medical history
Atrial fibrillation/ cerebral infarction/ cerebral hemorrhage/ TIA/ subarachnoid
hemorrhage/ ischemic heart disease/ peripheral arterial disease
7.2.6 Medication before onset
Antiplatelet drugs (aspirin, clopidogrel, cilostazol, prasugrel, ticlopidine, others)
Anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban, edoxaban, others)
Statins (atorvastatin, pitavastatin, rosuvastatin, others)
Initial diagnosis: cardiogenic embolism, atherothrombosis, other type of
cerebral infarction, unknown causes
7.2.8 Blood test
WBC, Hb, Plt, BUN, Cre, Glu, CRP, PT-INR, LDL, HDL, t. chol, HbA1C
7.2.9 Chest x-ray, 12-lead ECG
7.3 Observation Period_Very-Early: within 12 hours after randomization

7.3.1 Details of treatment
Time for start of treatment (puncture), time of recanalization, time for
completion of procedures
14
55

7.4 Observation Period_Early: 48 hours (± 24 hours) after randomization

7.4.2 Imaging
CT or MRI is performed to assess the status of cerebral infarction or intracranial
hemorrhage.
7.4.3 Blood test (WBC, Hb, Plt, BUN, Cre, Glu, CRP, PT-INR)
7.5 Observation Period_Discharge: Either 7 days (± 2 days) after randomization or at

discharge, which is earlier
7.5.1 mRS
7.5.3 Imaging
CT/CTA or MRI/MRA is performed to assess the status of cerebral infarction or
large vessel occlusion.
Final diagnosis: cardiogenic embolism, atherothrombosis, other type of cerebral
infarction, unknown causes
7.6 Observation Period_End: 90 days (± 30 days) after randomization (Surveillance by

telephone or observation by a doctor from another hospital is also allowed.)
7.6.1 mRS
*mRS and NIHSS are assessed by a doctor or a physical therapist who does not know the
randomization.
8. Definition of outcomes
8.1 Primary outcomes
8.2 Secondary outcomes

15
56

8.3 Safety outcomes

8.4 Cerebral ischemic events

Cerebral ischemic events include all the following events.
8.4.1 Cerebral infarction

remission of neurologic dysfunction within 7 days or cases with sustained worsening of
NIHSS score of less than 4 points are evaluated as mild stroke, and cases with sustained
neurologic dysfunction for more than 7 days or cases with sustained worsening of NIHSS
score of 4 points or more are evaluated as severe stroke.
8.4.2 Transient ischemic attack

associated with transient cerebral ischemia and with the duration of neurologic symptoms
of less than 24 hours, while there was no obvious abnormality that could explain the
symptoms by diagnostic imaging examination. Diagnosis of transient ischemic attack
should not be given based only on symptoms such as impaired consciousness (without
neurologic symptoms), convulsion, scintillating scotoma or unrelated dizziness, diplopia or
dysarthria.
8.5 Intracranial hemorrhage events

8.5.1 All intracranial hemorrhages
Cases with intracranial hemorrhage on CT or MRI head images.These cases
include hemorrhagic infarction, bleeding from the brain parenchyma, subarachnoid
hemorrhage, and subdural hematoma.
8.5.2 Symptomatic intracranial hemorrhage

16
57
hemorrhage and with worse NIHSS score of 4 points or more compared to the time of
enrollment.
9. Definition, handling, and investigation related to adverse events

9.1 Definition of adverse events
laboratory value), symptom, or disease that occurs in the patient from the time of
enrollment to 90 days after randomization, regardless of the causal relationship with the
study treatment. In this study, only the adverse events listed in 9.2.1 and 9.2.2 are
reported.
9.2 Classification of adverse events

9.2.1 Serious adverse events
1) Death
2) Life-threatening
4) Permanent damage
5) Risk of damage
6) Other serious medical events equivalent to 1)–5)
9.2.2 Clinically significant adverse events

syndrome (acute myocardial infarction, unstable angina), aortic disease (aortic dissection,
aortic aneurysm), and sudden cardiac death.
10. Statistical considerations

10.1 Analysis set
The analysis set includes all subjects who were enrolled in this study. However,
subjects who withdrew the written consent after enrollment and refused to use the data are
excluded from the analysis set.
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58
10.2 Analysis method

Major analysis is as follows. Details of the analysis method should be included in
the Statistical Analysis Plan. Additional explanatory analyses may be included as needed.
10.2.1 Information related to baseline characteristics and treatment

Appropriate statistics are used to summarize.
10.2.2 Analysis of outcomes

1) Primary outcomes
Percentage of achieving mRS 0–3 at 90 days after randomization is compared
between two groups.
Percentage of each secondary outcome is compared between the two groups.
Adverse events are summarized using descriptive statistics.
3) Safety outcomes
Percentage of each safety outcome is compared between two groups. Adverse
events are summarized using descriptive statistics.
10.2.3 Pre-defined sub-analyses

Pre-defined sub-analyses include the following:
1) Patients who received prior anticoagulation therapy versus those who did not.
2) Patients who received prior antiplatelet therapy versus those who did not.
3) Patients who received prior statin therapy versus those who did not.
4) Patients who received prior IV-tPA versus those who did not.
5) Sex differences.
6) Region-dependent efficacy of MT based on DWI-ASPECTS (W, IC).
7) Association of intraoperative heparinization with hemorrhagic complication
among the EVT group.
8) Association of onset-to-hospitalization time with clinical outcomes.
9) Efficacy of MT with and without ischemic core in eloquent area.
10) Patients who received MT within 6 h versus 6-24 h from the onset.
11) Efficacy of MT based on CT-based versus MRI-based randomization.
12) Association of ischemic core volume with clinical outcomes.
13) Predictors of symptomatic intracranial hemorrhage.
14) Association of blood pressure management with clinical outcomes.
15) Association of acute glycemic control with clinical outcomes.
16) Association of prior anticoagulant thearpy with clinical outcomes.
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17) Association of the affected side with clinical outcomes.

18) Association of the ICA or M1 occlusion with discrepant infarct patterns with
clinical outcomes.
19) Association of the multiple LVO with clinical outcomes.
20) Association of the differences in occluded vessels between initial images and
DSA with clinical outcomes.
21) Impact of the COVID-19 epidemic on clinical outcomes.
22) Association of procedure time with clinical outcomes among the EVT group.
23) Association of FLAIR relative signal intensity in the DWI positive area with
clinical outcomes.
10.2.4 Image analysis

Inclusion of this study is determined by each hospital. In terms of determination of
high-signal regions matching early ischemic changes in head MRI FLAIR images, which is
required 6–24 hours after the time of last known well, imaging analysis training is
conducted in advance to obtain approval as a participating hospital.
In addition, images obtained in this study are subjected to central review.
11. Case report

In this study, medical records of participating hospitals and results of various
imaging and tests are used as the raw data. Necessary records on patients are stated in
medical records. A record of input and output into EDC system is used as a case report. A
record of input of the login ID and the password are regarded as a signature.
12. Submission of images

DICOM images are submitted to the study office for central review. Submitted
images are analyzed by the image determination committee members concerning the
following items.
1) Analysis of ischemic core regions from CTP or head MRI DWI images at enrollment.
2) High-signal regions on head MRI FLAIR images at enrollment, in the case of 6–24
hours from the time of last known well.
3) Analysis of final cerebral infarction regions on head MRI FLAIR images either 7 days
after randomization or at discharge which is earlier.
13. Ethical concerns
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13.1 Principles, laws and regulations, guidelines, etc. to be followed

This study is conducted in compliance with “World Medical Association Declaration
of Helsinki – Ethical Principles for Medical Research Involving Human Subjects”, and other
laws regulating this study, including “Ethical Guidelines for Medical and Health Research
Involving Human Subjects (established on December 22, 2014 [Ministry of Education,
Notification No. 3 of 2014], partially revised on February 28, 2017 [Ministry of Education,
Notification No. 1 of 2017]).
Since this study is neither a clinical study using research funds provided by
pharmaceutical companies nor a clinical study using unapproved or off-label use of drugs
or medical devices, this study does not fall under the specified clinical study subjected to
the Clinical Trials Act.
13.2 Obtaining permission at a participating hospital

Study representatives and principal Investigator submit the clinical trial protocol to
the chief executive of the participating hospital to ask for permission to implement this
study. The chief executive of the participating hospital asks for opinions to the ethical
review board on the details of the clinical trial protocol, etc. and appropriateness of this
study as necessary, respect the opinion, and decide whether or not to permit
implementation of this study and other necessary measures regarding this study.
13.3 Obtaining Informed Consent

13.3.1 Selection of patients
In selection of patients, principal investigator or sub-investigator carefully
considers requesting participation of patients in this study, taking into account their health
status, symptoms, age, sex, capacity to consent, dependency on principal investigator or
sub-investigator, and participation in other trials, according to the protection of human
rights, inclusion criteria and exclusion criteria.
13.3.2 Explanation to patients or their legal representatives

Principal investigator or sub-investigator explains the following contents orally to
each patient or his/her legal representative based on the explanatory documents and
informed consent form approved at the study institution.
The informed consent form approved at the participating hospital should be signed
by the principal investigator or sub-investigator who gave the explanation, and the date of
explanation should be stated. If a study collaborator provided supplementary explanation,
the informed consent form should also be signed by the study collaborator, and the date of
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explanation should be stated.

1) Approval by the chief executive of the participating hospital regarding the name of the
study and implementation of the study.
2) Names of participating hospital and study representatives.
3) Purpose and significance of the study.
4) Study method (including the purpose of use of samples and information collected from
patients) and duration.
5) Reason to be included as a study patient (if the patient is in "underage" or is an "adult
who does not have a capacity to give consent", the reason why it was necessary to
include a person "underage" or an "adult who does not have a capacity to give
consent" as a study patient for explanation to the legal representative, is included).
6) Subject burdens and expected risks (including blood transfusion and use of specified
biological products) and benefits.
7) A statement if the patient has consented to the conduct or continuation of the study,
he/she may withdraw consent at any time (when it is difficult to take measures
according to the contents of withdrawal from the patients, etc., the fact and the
reason).
8) A statement that the patients are not treated inappropriately if they disagree with the
conduct or continuation of the study or by withdrawing their consent.
9) Method of information disclosure regarding the study.
10) A statement that the protocol and materials related to the study methods can be
obtained or accessed at the request of patients, etc., to the extent that such access
does not interfere with protection of personal information of other patients, etc., or with
securing of originality of the study, and the method of obtaining or accessing such
materials.
11) Handling of personal information, etc. (including the method of anonymization when
including such cases, and the fact that anonymously processed information or
anonymized personal information is created when including such cases).
12) Method of storage and disposal of samples and information.
13) The situation related to conflicts of interest related to the study of representatives, such
as conflicts of interest related to the study at the participating hospital and personal
remuneration, including the source of funding.
14) Handling of consultations, etc., from patients, etc., and related parties.
15) In cases of any economic burden or reward for subjects, etc., a statement to the effect
and the details.
16) In cases of study involving medical treatment beyond normal medical care, matters
related to other treatment methods.
17) In cases of study involving medical treatment beyond normal treatment, matters
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related to provision of medical care to patients after the study.

18) Handling of study results (including incidental findings) pertaining to patients, if the
conduct of study may lead to important findings concerning the health of patients,
genetic characteristics which could be passed on to descendants, etc.
19) Compensation for health damage caused by the study and the details.
20) If samples and information obtained from patients may be used for future study that is
not specified at the time consent is obtained from patients or provided to other
research hospitals, a statement to that effect and the expected contents at the time
consent is obtained.
21) A statement to the effect that persons engaged in monitoring and auditing may access
to samples and information concerning the study patients to the necessary extent,
provided that the confidentiality of patients is maintained.
A legal representative refers to a person who is recognized as appropriate to give
consent with or on behalf of the patient when the patient lacks sufficient capacity to give
consent. A legal representative shall be a person who has custody of the patient, a
spouse, a guardian, or other equivalent person, and, in a view of actual living conditions of
both and the psychological relationship, who can serve the best interests of the patient.
13.3.3 Obtaining consent

The principal investigator or sub-investigator shall explain the study to the patient
or the legal representative, and then provide opportunity to ask questions about the study
and sufficient time to decide whether to participate in the study. After confirming that the
patient or the legal representative fully understands the details of the study, the principal
investigator or sub-investigator shall ask for participation in the study. When the patient
freely and voluntarily gave consent to participate in this study, the patient's signature or
name/seal and the date of consent shall be obtained on the consent form which were
approved by the participating hospital. The same applies in cases where a legal
representative has consented to participate in the study. Patients cannot be included in
this study before written consent has been obtained.
The principal investigator or sub-investigator shall confirm that the consent form is
complete and make one copy of the form. The principal investigator or sub-investigator
shall keep the original copy in the medical record or in a location designated by the
participating hospital. The copy is handed to the patient or his/her legal representative.
13.3.4 Provision of information to patients or their legal representatives

If the principal investigator or sub-investigator obtains information that may affect
the patient's free will or the decision by the legal representative to continue participation in
this study, the principal investigator or sub-investigator shall provide such information to
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the patient or the legal representative to confirm whether the patient continues
participation in this study. The process and results of this confirmation are recorded in a
document. In addition, the principal investigator or sub-investigator shall revise the
explanatory document and consent form and obtain approval at the participating hospital,
and then the revised explanatory and consent form are used to obtain written consent
again for continuous participation in this study from the patient’s legal representative by
the free will of the patient.
13.3.5 Withdrawal of consent, etc.

If a patient or the legal representative withdraws consent or refuses consent in any
of the following cases, the principal investigator or sub-investigator shall, without delay,
take measures in accordance with the content of withdrawal or refusal and explain the
effect to the patient. However, in cases where it is difficult to take such measures, the
principal investigator or sub-investigator shall explain the effect that such measures are
not taken and the reasons, to make efforts to be understood. At the same time, the
principal investigator or sub-investigator shall confirm whether the data already entered
into the EDC can be used or not.
1) When the patient has withdrawn all or part of his/her consent to participate in this study
2) Although the legal representative has given consent to participate in this study, the
patient has refused all or part of the consent
13.3.6 Response to inquiries, consultations, etc. after consent

The principal investigator or sub-investigator shall respond to inquiries,
consultations, etc., regarding this study from patients or their family members after patient
enrollment. If it is difficult to determine the best way to respond, the principal investigator
or sub-investigator shall consult with the study representatives, study office, etc.,
according to the details of consultation.
13.4 Personal information, etc. and anonymously processed information

13.4.1 Basic responsibilities regarding personal information, etc.
13.4.1.1 Protection of personal information, etc.
1) The principal investigator and other parties involved in the conduct of study
(hereinafter, “investigators”) and the chief executive of the participating hospital shall
comply with the following laws and regulations regarding the handling of personal
information, anonymously processed information or anonymized personal information:
Act on the Protection of Personal Information (Act No. 57 of May 30, 2003, as last
amended by Act No. 49 of June 5, 2009), Act on the Protection of Personal Information
Held by Administrative Organs (Act No. 58 of May 30, 2003, as last amended by Act
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No. 51 of May 27, 2016), Act on the Protection of Personal Information Held by
Incorporated Administrative Agencies, etc. (Act No. 59 of May 30, 2003, as last
amended by Act No. 59 of July 17, 2015), and ordinances enacted by local
governments.
2) Investigators shall appropriately handle information that can identify specific individuals
regarding deceased persons in accordance with the provisions of “13.4.1.2
Appropriate acquisition, etc.” and “13.4.2 Safety control” and take necessary and
appropriate measures.
13.4.1.2 Appropriate acquisition, etc.

1) In the conduct of study, investigators do not obtain personal information (personal
information plus information about individuals, including information that can be used
to identify specific individuals regarding deceased persons) by falsification or other
wrongful means.
2) Investigators, in principle, do not handle personal information, etc. obtained in the
study beyond the scope of consent obtained from subjects, etc. in advance.
13.4.2 Safety control

13.4.2.1 Proper handling
1) Investigators shall appropriately handle personal information, etc. obtained in the
conduct of study that is owned by the participating hospital to which the principal
investigator, etc. belongs (including cases where the information is stored on
consignment. Hereinafter, “owned personal information, etc.”), for prevention of
leakage, loss, or damage, and other safety control purposes.
2) Investigators shall give necessary guidance and control to other investigators who
handle the information in cooperation with the chief executive of the participating
hospital, to ensure that the owned personal information, etc., is handled appropriately.
13.4.2.2 System and supervision, etc. for safety control

1) The chief executive of participating hospital shall take necessary and appropriate
measures to prevent leakage, loss or damage of personal information and other safety
control.
2) When the principal investigator involved in the study at the study institution is going to
handle the owned personal information, etc., the chief executive of the participating
hospital shall arrange the system and regulations necessary for safety control. In
addition, the chief executive of the participating hospital shall provide necessary and
appropriate supervision to investigators to ensure safe control of the owned personal
information, etc.
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13.4.3 Other precautions

1) When samples and information obtained from patients in this study are submitted to
external organizations, research IDs are used. Information such as names and medical
record numbers that can identify each patient is not included.
2) When publishing the study results, information such as names and medical record
numbers that can identify each patient is not included.
3) When samples and information obtained from patients in this study are used for
secondary purposes, information such as names and medical record numbers that can
identify each patient is not included.
4) Any person who has access to confidential information of patients associated with the
study shall maintain the information.
13.5 Response to subjects after study implementation

The principal investigator or sub-investigator makes every effort to ensure that
patients receive the best possible prevention, diagnosis, and treatment based on the
results of this study even after the end of this study.
13.6 Handling of study results pertaining to patients

If any important findings are obtained concerning patients' health, genetic
characteristics that could be passed on to descendants, etc. associated with this study
(including incidental findings, such as suspicion of diseases other than the target disease
which require further examination), the principal investigator or sub-investigator notifies the
patient or the legal representative within 7 days if the patient requests notification.
14. Study costs

14.1 Source of funding and financial relationship
This study was funded by research grants from the Department of Neurosurgery,
Hyogo College of Medicine. There is no apparent “possible conflict of interest” in planning,
implementation, statistical analysis, and reporting of this study that could affect the results
of the study or the interpretation at the time this protocol is prepared. Any “possible
conflicts of interest” that may arise during the study are appropriately controlled at the
institution where the investigators belong. In addition, implementation of the study does not
impair the rights and benefits of patients.
14.2 Costs for study treatment

All treatments related to this study are covered by health insurance, and
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regardless of randomization results, all study treatments are routine medical treatments
that are usually provided. Therefore, all medical expenses in this study are covered by
patients' health insurance.
14.3 Compensation for health damage

In case of any health damage to patients, appropriate treatment and care are
provided to the patients. In case of death or sequelae caused by this study, treatment is
provided within the scope of normal insurance care. Costs for the treatment of health
damage are covered by the patient's health insurance, and the patient is partially
responsible for the costs. No medical expense or medical benefit is provided.
Any adverse reactions or malfunctions caused by this study may be covered by
the Relief system for sufferers from adverse drug reactions by the Pharmaceuticals and
Medical Devices Agency. In addition, this study is covered by liability insurance for clinical
study.
15. Revision of protocol

If any changes in the study protocol is necessary during the study, the study
representatives shall revise the protocol. The study representatives report to the chief
executive of the participating hospital on the revision of the protocol with the details and
reasons. The chief executive of the participating hospital conducts the study in accordance
with the procedures of the participating hospital.
16. Monitoring and audit

16.1 Monitoring
Central monitoring is conducted by the Data Center in this study. Off-site
monitoring or on-site monitoring is combined as necessary. Monitoring shall be in
accordance with the monitoring procedures of the Data Center.
16.2 Audit
This study is not a specified clinical study, and does not require an audit. However,
if any question regarding the implementation of the study is raised, an audit will be
implemented. In auditing, an external institution capable of auditing is selected and
commissioned.
17. Termination and early discontinuation of trial
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17.1 Discontinuation for individual patients

17.1.1 Discontinuation criteria
In any of the following cases, the principal investigator or sub-investigator
discontinues the study on a patient.
1) When a patient or the legal representatives withdraws consent to participate in the
study.
2) When the principal investigator or sub-investigator judges that it is difficult to continue
the study on a patient.
3) When the principal investigator or sub-investigator judges that it is difficult for the
patient to continue the study due to reasons of the patient, such as the patient not
visiting the hospital and not being able to make contact.
4) When the principal investigator or sub-investigator judges that the study should be
discontinued due to a serious deviation from the protocol.
5) Any other cases when the principal investigator or sub-investigator judges that the
study should be discontinued.
17.1.2 Precaution for discontinuation

1) The principal investigator or sub-investigator conducts investigation at discontinuation
specified in the protocol as soon as possible. If the investigation at the time of
discontinuation is not available due to any reason of the patient, the reason for
discontinuation and health status of the patient (adverse events, course of symptoms,
etc.) shall be confirmed by telephone, etc., as much as possible.
2) Date of discontinuation, details of the reason for discontinuation (adverse events,
worsening of a patient's disease, etc.), and the investigation results at the time of
discontinuation shall be entered into the EDC as soon as possible.
3) When the reason for discontinuation is adverse events, necessary investigations,
procedures, or treatment should be taken place until the adverse event recovers.
4) When the reason for discontinuation is worsening of the patient disease, necessary
investigations, procedures, or treatment should be followed.
5) The date of discontinuation is the date of withdrawal of consent in cases that
discontinuation is according to 1) of “17.1.1 Discontinuation criteria”, and the date of
discontinuation determined by the principal investigator or sub-investigator in other
cases.
17.2 Discontinuation or interruption of overall study

17.2.1 Consideration to continue the study
The study representatives consider whether to continue the study in any of the
following cases.
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1) When a fact or information that damages ethical validity or scientific rationality of the
study is obtained
a) A fact that damages “ethical validity of the study” refers to any fact that should be
appropriately addressed in the conduct of study from a viewpoint of protection of
human rights and consideration for welfare of patients, including inadequate
procedures for obtaining informed consent or inappropriate handling of personal
information in the conduct of study.
b) “A fact that damages scientific rationality” refers to a fact that may change the
overall assessment of the burdens and expected risks and benefits to patients that
are stated in the study plan by the principal investigator before the start of study,
due to new scientific findings, contents, safety measure information implemented
by domestic or foreign regulatory authorities, etc., that are revealed after the start
of the study.
2) When a fact or information that damages appropriateness of the conduct of study or
reliability of the study results, is obtained.
a) A fact or information that damages “appropriateness of the conduct of study” refers
to a fact or information such as deviations from the study patient inclusion policy or
study methods based on the study plan in the conduct of study.
b) A fact or information that “damages reliability of the study results” refers to a fact
or information such as falsification or fabrication of study data.
3) When it is judged that the expected risks of conducting the study are higher than the
expected benefits of the study.
4) When it is judged that sufficient results have been obtained or that sufficient results will
not be obtained from the study.
Relevant information in 1)–4) is reported to the Independent Monitoring Committee
for deliberation.
17.2.2 Precaution for discontinuation or interruption

1) If the overall study is discontinued, the study representatives shall promptly report it
and the reason to the chief executive of the participating hospital in a written
document. In the case of interruption, the study plan shall be reviewed and, if
necessary, the protocol shall be revised. Any revisions shall be promptly reported to
the chief executive of the participating hospital. The chief executive of the participating
hospital shall restart the study in accordance with the procedures of the participating
hospital.
2) The principal investigator or sub-investigator notifies the patients participating in the
study for the discontinuation or interruption for any reason and performs necessary
investigations, procedures, or treatment.
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17.3 Termination of trial

17.3.1 Termination of trial in individual patients
Termination of trial on individual patients is defined as completion of final
investigation specified in the protocol for individual patients. The principal investigator shall
promptly enter the end date, etc. into the EDC after the termination of the study in
individual patients.
17.3.2 Termination of the overall trial

Termination of the overall trial is defined as the time when the final analysis report
is submitted to the study representatives and the Independent Monitoring Committee by
the statistical analysis manager. After the receipt of the final analysis report, the study
representatives shall promptly prepare a summary report and report the termination of the
study and a summary of the results to the chief executive of the participating hospital
without delay.
18. Handling of adverse events, serious adverse events, diseases, and other serious
events
18.1 Handling of adverse events
principal investigator or sub-investigator should immediately take appropriate measures,
including providing explanations to the relevant patients, etc.

principal investigator or sub-investigator reports according to “9.2 Classification of adverse
events” in addition to the record to EDC.
18.2 Handling of serious adverse events

event, the principal investigator or sub-investigator should immediately take appropriate
measures, including providing explanations to patients, etc.

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event, the principal investigator or sub-investigator should make reports to the EDC and to
the study office through the principal investigator in addition to the report to medical
records.
18.3 Reporting to the chief executive of the participating hospital

When the principal investigator identifies a serious adverse event (*) or a
malfunction, the principal investigator should report once a year to the chief executive of
the hospital to which the principal investigator belongs.
(*) Subjects of this study are patients with a wide range of cerebral infarction, and almost
all patients are considered to have serious adverse events including having sequelae.
Therefore, only death cases and cases that are judged to be out of normal considerations
are reported immediately. Other adverse events are reported once a year.
19. Storage of records

The principal investigator and other related parties involved in the study
(hereinafter, "study personnel") shall ensure the accuracy of the samples and information
used in the study and materials pertaining to the information (including records related to
provision of samples and information used in the study. Hereinafter, "information, etc.",
which includes the raw materials or raw data specified in "11. Case report") (This includes
confirming the accuracy of information not prepared by the study personnel (e.g., records
prepared by patients)). When revising or changing information, etc., a record is kept with
the date, name, and reason. In addition, personal information pertaining to the study
should be kept in updating form within the necessary extent to achieve the purpose of use.
Responsibilities for those involved in a storage of information, etc. are as follows.
19.1 Principal Investigator

1) The principal investigator instructs and controls the investigators to ensure the
accuracy of information, in accordance with the procedures for storage of samples and
information obtained from patients established in advance by the chief executive of the
participating hospital. Samples and information obtained from patients are stored in a
locked storage in an appropriate location in the participating hospital with the names
and details of consent obtained from the patients, to prevent leakage, confusion, theft,
loss, etc. In addition, the same applies to storage of all materials related to this study,
including protocol (including revisions), informed consent forms (including revisions),
explanatory documents (including revisions), procedures related to the implementation
of this study, contracts, and documents related to results of deliberations received from
Independent Monitoring Committee.
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2) The principal investigator reports to the chief executive of the participating hospital on
the status of storage described in the previous section, in accordance with the
procedures for storage of samples and information obtained from patients established
by the chief executive of the participating hospital.
20. Registration and publication related to the study

20.1 Registration of study summary and results
The study representatives register a study summary in University Hospital Medical
Information Network Clinical Trials Registry (UMIN-CTR) (http: //www.umin.ac.jp/ctr/index-
j.htm), ClinicalTrials.gov (https: //clinicaltrials.gov) before the start of the study and update
the summary as appropriate according to changes in the protocol or progress of the study.
When the study is completed, the study representatives register a study result without
delay.
20.2 Publication of study results

When the study is completed, the study representatives publish the results of the
study without delay, after taking necessary measures (e.g., to prevent identification of
specific study patients) to protect the human rights of patients and related parties or the
rights and benefits of patients and related parties. Author(s) of the paper are determined
by the study representatives according to Uniform Requirements for Manuscripts
Submitted to Biomedical Journals (http: //www.icmje.org/) by the International Committee
of Medical Journal Editors (ICMJE). All authors should review and agree to the details of
the paper prior to submission. The same goes for authors of conference presentations.
21. Ownership of the study results

The results, data, intellectual property rights, etc. obtained in this study belong to
the study representatives and not to the patients. Whether the intellectual property rights of
the study representatives belong to the individual or to the study institution is determined
by the agreement of the participating hospital.
22. Use of collected information

Study Steering Committee determines whether to use the information obtained in
this study (hereinafter, “study data”) for study conducted by the Study representatives or
sub-investigators as a secondary analysis of this study.
If the analysis is judged to be beyond the scope of secondary analysis, or if the
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study data is used by a person except for the study representatives or sub-investigators of
this study, the Study Steering Committee prepares a separate protocol and conduct study
after undergoing ethical review in accordance with relevant laws and regulations and
ethical guidelines for medical research on human subjects.
23. Study organization

23.1 Study representatives
The study representatives are responsible for operation of this study and decide
on the policy for conducting the study.
Hospital)
Hiroshi Yamagami (Division of Stroke Medicine, National Hospital Organization
Osaka National Hospital)
23.1.2 Study office

The study office organizes this study.
Department of Neurosurgery, Hyogo College of Medicine
Address: 11 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan
TEL: 0798-45-6458, FAX: 0798-45-6457
E-mail: rescue-j@hyo-med.ac.jp
Person in charge: Kazutaka Uchida (Department of Neurosurgery, Hyogo College
of Medicine)
Mikiya Beppu (Department of Neurosurgery, Hyogo College of
Medicine)
23.3 Study Steering Committee

The Study Steering Committee discusses practical matters related to study
implementation, including the study protocol, investigation items, various documents
including informed consent form, and handling of enrolled cases.
Hospital)
Hiroshi Yamagami (Division of Stroke Medicine, National Hospital Organization
Osaka National Hospital)
Medicine)
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Kazunori Toyoda (Department of Cerebrovascular Medicine, National Cerebral

Yuji Matsumaru (Division of Stroke Prevention and Treatment, Department of
Neurosurgery, University of Tsukuba)
Yasushi Matsumoto (Department of Endovascular Neurosurgery, Kohnan Hospital)
Kazumi Kimura (Department of Neurology, Nippon Medical School)
23.4 Independent Monitoring Committee

To ensure safety of subjects in this study and to assure ethical and scientific
validity of this study as far as possible, Independent Monitoring Committee evaluates the
undergoing data of this study from third-party and neutral viewpoints. The Independent
Monitoring Committee makes appropriate recommendations and give advice to the study
representatives based on the results. Members of Independent Monitoring Committee are
not the authors of the academic paper but are listed in acknowledgments in a view of
dependence.
Kuniaki Ogasawara (Department of Neurosurgery, Iwate Medical University)
Naoya Kuwayama (Department of Endovascular Medicine, Toyama University
Hospital)
Teruyuki Hirano (Department of Stroke Medicine, Kyorin University)
23.5 Imaging Evaluation Committee members

Reiichi Ishikura (Department of Radiology, Hyogo College of Medicine)
Manabu Inoue (Department of Cerebrovascular Medicine, National Cerebral and
Cardiovascular Center)
23.6 Event Adjudication Committee

The Event Adjudication Committee adjudicates events in this study.
Chairperson: Fumihiro Sakakibara (Department of Neurosurgery, Social medical
corporation Aijinkai Chibune general hospital)
Members: Norito Kinjo (Department of Neurosurgery, Matsumoto hospital)
Takuya Saito (Department of Stroke Neurology, Kohnan Hospital)
23.7 Data Center

Data Center builds the EDC system, controls the database, and performs central
monitoring.
Nexis Co., Ltd. Development Section 3
Address: Nichidai Building 3F, 226-8 Minoshima, Hakata-ku, Fukuoka-shi, Fukuoka
812-0017, Japan
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TEL: 092-483-6033 FAX: 092-483-6035

E-mail: aspects@midinfo.co.jp
Person in charge: Akito Uchio
23.8 Chief study statististician

Chief study statististician supervises and conducts the design and statistical
analysis of this study.
Medicine)
23.9 Study Institution and Principal Investigator

Hyogo College of Medicine
Address: 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan
Chief executive of study institution: Koichi Noguchi
Principal Investigator: Shinichi Yoshimura
Sub-investigator: Kazutaka Uchida
Mikiya Beppu
23.10 Participating institutions

See Attachment “Participating institutions and Principal Investigator”
24. References
1) Olvert A. Berkhemer, et al. A Randomized Trial of Intraarterial Treatment for Acute
Ischemic Stroke (MR CLEAN). N Engl J Med 2015; 372: 11-20. PMID: 25517348
2) Goyal M, et al. Randomized Assessment of Rapid Endovascular Treatment of
Ischemic Stroke (ESCAPE). N Engl J Med 2015; 372: 1019-30. PMID: 25671798
3) B.C.V. Campbell et al. Endovascular Therapy for Ischemic Stroke with Perfusion-
Imaging Selection (EXTEND-IA). N Engl J Med 2015; 372: 1009-18. PMID: 25671797
4) Saver JL, et al. Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in
Stroke (SWIFT PRIME). N Engl J Med 2015; 372: 2285-95. PMID: 25882376
5) Jovin TG et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke
(REVASCAT). N Engl J Med. 2015; 372: 2296-306. PMID: 25882510
6) Goyal M, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a
meta-analysis of individual patient data from five randomised trials (HERMES). Lancet.
2016 Apr 23;387(10029): 1723-31. PMID: 26898852
7) Powers WJ, et al. 2018 Guidelines for the Early Management of Patients with Acute
Ischemic Stroke: A Guideline for Healthcare Professionals from the American Heart
Association/American Stroke Association, Stroke. 2018 Mar;49(3): e46-e110, PMID:
34
75
29367334
8) Albers GW, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by
Perfusion Imaging (DEFUSE 3 trial). N Engl J Med. 2018 Feb 22;378(8): 708-718.
PMID: 29364767
9) Nogueira RG, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch
between Deficit and Infarct (DAWN trial). N Engl J Med. 2018 Jan 4;378(1): 11-21
PMID: 29129157
10) Yoshimura S, et al. Endovascular Therapy in Ischemic Stroke with Acute Large-Vessel
Occlusion: Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism
Japan Registry 2. J Am Heart Assoc. 2018 Apr 25;7(9). PMID: 29695384
11) Kakita H, Yoshimura S, Uchida K, et al. The impact of endovascular therapy in patients
with large ischemic core; Sub-analysis of RESCUE-Japan Registry 2. Stroke. In press
12) Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-Guided Thrombolysis for Stroke with
Unknown Time of Onset. N Engl J Med. 2018 Aug 16;379(7): 611-622. PMID:
29766770
13) Barber PA, Demchuk AM, Zhang J, et al. Validity and reliability of a quantitative
computed tomography score in predicting outcome of hyperacute stroke before
thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT
Score. Lancet. 355: 1670-4, 2000.
14) Nezu T, Koga M, Nakagawara J, et al. Early ischemic change on CT versus diffusion-
weighted imaging for patients with stroke receiving intravenous recombinant tissue-
type plasminogen activator therapy: stroke acute management with urgent risk-factor
assessment and improvement (SAMURAI) rt-PA registry. Stroke. 42: 2196-200, 2011.
15) Zaidat OO, Yoo AJ, Khatri P, et al; Cerebral Angiographic Revascularization Grading
Stroke 44: 2650-2663, 2013.
16) Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with alteplase for acute
ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring
Study (SITS-MOST): an observational study. Lancet.369: 275-82, 2007.
17) van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement for the
assessment of handicap in stroke patients. Stroke 19: 604-607, 1988.
18) Schulman S; Subcommittee on Control of Anticoagulation of the Scientific and
Standardization Committee of the International Society on Thrombosis and
Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic
medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-
19) Rüdiger von Kummer et al. The Heidelberg Bleeding Classification Classification of
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Bleeding Events After Ischemic Stroke and Reperfusion Therapy Stroke.2015; 46:
2981-2986
25. Appendix
National Institute of Health Stroke Scale (NIHSS)
Old version NIH Stoke Scale (NIHSS) (1994)
Name Score Item
Level of 0 = Alert 2 = Not alert, obtunded
1A
consciousness 1 = Alert with simple stimulation 3 = Unresponsive
Level of 0 = Answers both correctly 2 = Answers
consciousness neither correctly 1B
Questions 1 = Answers one correctly
Level of
0 = Performs both tasks correctly 2 = Performs neither task
consciousness 1C
1 = Performs one task correctly
Commands
0 = Normal 2 = Total gaze palsy
Gaze 2
1 = Partial gaze palsy
0 = No visual loss 2 = Complete hemlanopsia
Visual fields 3
1 = Partial hemlanopsia 3 = Bilateral hemlanopsia
0 = Normal 2 = Partial paralysis
Facial palsy 1 = Minor paralysis 3 = Complete 4
paralysis
Motor arm Left 1 = Drift before 10 seconds 4 = No movement 5a
Motor arm Right 1 = Drift before 10 seconds 4 = No movement 5b
Motor leg Left 6a
movement
Motor leg Right 1 = Drift before 5 seconds 4 = No 6b
movement
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77

0 = Absent 2 = Two limbs
Ataxia 7
1 = One limb
0 = Normal 2 = Severe loss
Sensory 8
1 = Mild loss
0 = Normal 2 = Severe aphasia
Language 1 = Mild aphasia 3 = Mute or global 9
aphasia
0 = Normal 2 = Severe
Dysarthria 10
1 = Mild
Extinction/Inatte 0 = Normal 2 = Severe
11
ntion 1 = Mild
Lyden P, Brott T, Tilley B, Welch KM, Mascha EJ, Levine S, et al. Improved reliability of the
NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke 1994; 25:
2220-2226.
・Alberta Stroke Program Early CT Score (ASPECTS), DWI-ASPECTS (10 points)
See ASIST Japan website: http: //asist.umin.jp/training/index.html

Barber PA, Demchuk AM, Zhang J, et al. Validity and reliability of a quantitative computed
tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy.
37
78
ASPECTS Study Group. Alberta Stroke Program Early CT Score. Lancet. 2000; 355:
1670-.
Nezu T, Koga M, Nakagawara J, et al. Early ischemic change on CT versus diffusion-
weighted imaging for patients with stroke receiving intravenous recombinant tissue-type
plasminogen activator therapy: stroke acute management with urgent risk-factor
assessment and improvement (SAMURAI) rt-PA registry. Stroke. 2011; 42: 2196-200.
Teruyuki Hirano, Evaluation of early ischemic change using ASPECTS and intravenous rt-
PA therapy. Jpn J Stroke 2015; 37: 347–351.
modified Rankin Scale (mRS)

modified Rankin Scale Notes
No subjective symptoms and objective
0 No symptoms at all
signs
Despite subjective symptoms or objective
No significant disability despite
signs, there has been no change in the
1 symptoms: able to carry out all
person’s ability to work and activities of
usual duties and activities
daily living compared to before the stroke
Despite some limitations in the person’s
Slight disability: unable to carry out all
ability to carry out his/her usual duties and
2 previous activities but able to look
activities compared to before the stroke,
after own affairs without assistance
he/she can lead an independent life
Assistance* is essential for using public
Moderate disability: requiring some
transport to get around, but is not essential
3 help, but able to walk without
for walking†, eating, maintaining routine
assistance
daily hygiene, using the toilet, etc.
Moderately severe disability: unable Assistance* is essential for walking†,
to walk without assistance, and eating, maintaining routine daily hygiene,
4
unable to attend to own bodily needs using the toilet, etc., but constant care is
without assistance not required
Severe disability: bedridden, Assistance* is necessary at all times
5 incontinent, and requiring constant
nursing care and attention
6 Death
* Assistance includes physical assistance, verbal instruction, or supervision by another
person.
† Ability to walk on a flat surface is mainly checked. In addition, assistance does not include
the use of any aid (3.g. stick/cane, or walking frame/walker).
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79
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver
agreement for the assessment of handicap in stroke patients. Stroke 1988;19: 604-607
Shinohara Y, Minematsu K, Amano T, Ohashi Y. Reliability of modified Rankin Scale -
Introduction of a guidance scheme and a questionnaire written in Japanese -. Jpn J Stroke
2007;29: 6-13
Shinohara Y, Minematsu K, Amano T, Ohashi Y. Modified Rankin Scale with expanded
guidance scheme and interview questionnaire: Interrater agreement and reproducibility of
assessment. Cerevrovasc Dis 2006;21: 271-278
・Standards of the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-

MOST)
HI 1 Small petechiae along the margins of the infarct
More confluent petechiae within the infarct area but
HI 2
without space-occupying effect
Blood clot(s) not exceeding 30% of the infarct area with
PH 1
some mild space-occupying effect
Blood clots exceeding 30% of the infarct area with
PH 2
substantial space-occupying effect
Small or medium sized blood clots located remote from
PHr 1 the actual infarct; a mild space-occupying effect could
be present
Large confluent dense blood clots in an area remote
PHr 2 from the actual infarct; substantial space-occupying
effect might be present
HI: hemorrhagic infarction, PH: parenchymal hematoma, PHr: remote parenchymal
hematoma
Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with alteplase for acute ischaemic
stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-
MOST): an observational study. Lancet.369: 275-82, 2007.
・modified TICI (mTICI) Grades

0 No perfusion
Antegrade reperfusion past the initial occlusion, but
1 limited distal branch filling with little or slow distal
reperfusion
Antegrade reperfusion of less than half of the occluded
2a target artery previously ischemic territory
Antegrade reperfusion of more than half of the
2b previously occluded target artery ischemic territory
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80
Complete antegrade reperfusion of the previously

occluded target artery ischemic territory, with absence
3 of visualized occlusion in all distal branches
Zaidat OO, Yoo AJ, Khatri P, et al; Cerebral Angiographic Revascularization Grading
Stroke 44: 2650-2663, 2013.
・ Modified Mori Grade

Grade 0 No reperfusion
Movement of thrombus not associated with any
Grade 1 flow improvement
Partial (branch) recanalization in <50% of the
Grade 2 branches in the occluded arterial territory
Nearly complete recanalization with reperfusion in
≥50% of the branches in the occluded-arterial
Grade 3 territory
Mori E, Minematsu K, Nakagawara J, et al; Japan Alteplase Clinical Trial II Group. Effects
of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in middle cerebral
artery occlusion: Japan Alteplase Clinical Trial II (J-ACT II). Stroke 41: 461-465, 2010.
40
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Summary of changes
Version Date of Changes Reasons for change

revised
Ver. 1.1 2018/12/10 The registration number (NCT03702413) Because the registration
of the clinical trial gov. was added. was completed in Clinical
trial gov. and the trial
number was revealed.
Changed the allowances for evaluation To enable evaluation of
points. images and other data as
“48 hours (± 12 hours) after much as possible.
randomization”
→ “48 hours (± 24 hours) after
randomization” (7.0, 7.1, 7.4)
“7 days (± 1 day) after randomization”
→ “7 days (± 2 days) after
randomization” (7.0, 7.1, 7.5)
NIHSS assessment, removed at 90 Because it is difficult to
days. (7.0, 7.1, 7.6) evaluate after discharge
from the hospital.
Changed the description of With regard to insurance for
compensation for health damage. “this clinical research, this
study is not covered by liability insurance research is not for off-label
for clinical study.” (14.3) use, and the adverse drug
reaction relief system will be
applied in the event of
physical injury due to
malfunction of the
equipment used.
Ver. 1.2 2019/02/12 The section of “Use of collected Because it did not mention
information” was added. (22) any details about the use of
the information collected.
In the selection of devices during EVT, it Because there was no
was added that “However, devices that mention of the use of
correspond to contraindications should devices that fall under
not be used.” (6.1) contraindications.
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Ver. 2.0 2019/04/17 Changed the description in the rationale To accurately reflect the
for the study. descriptions in the
“time of onset” guidelines.
→ “time of last known well” (2)
The selection criterion was changed to To increase the number of
“Randomization can be finished within 6 registered cases.
hours from the time of last known well, or
6 to 24 hours from the time of last known
well without positive lesion on MRI-
FLAIR image”. (4.2.1)
For the no EVT group, it was added that For the no endovascular
“No EVT group receives standard treatment group, it was
treatment according to guidelines.” (6.1) added that standard
treatment in accordance
with the guidelines should
be performed. (6.1)
Added the image analysis. (10.2.4) To describe the image
analysis methods in detail.
Added the concerns about submission of Due to changes in the
images. (12) selection criteria, the need
for a central decision in
image analysis arose.
Ver. 2.1 2019/09/10 Created a new Image Analysis Plan Ver. To describe the image
1.1. analysis methods in detail.
Changed the description of reporting to This study will focus on
the chief executive of the participating patients with cerebral large
hospital. “only death cases and cases vessel occlusions who have
that are judged to be out of normal extensive early ischemic
considerations are reported immediately. changes, because almost
Other adverse events are reported once all of them will have
a year.” (18.3) sequelae, all of which will
be serious adverse events.
Changed the description of It was pointed out that the
compensation for health damage. “this previous description might
study may be covered by the Relief be inappropriate because it
system for sufferers from adverse drug gave the impression that
reactions by the Pharmaceuticals and the PMDA's relief system
Medical Devices Agency.” (14.3) would cover everything.
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83
Ver. 2.2 2019/11/12 Changed the description of Because the phrase

compensation for health damage. “indemnity insurance for
“In addition, this study is covered by clinical research” may be
liability insurance for clinical study.” misleading.
(14.3)
Ver. 2.3 2020/02/12 The Japanese notation of “Principal Because it is difficult to
Investigator” was changed. (18.3) understand the responsible
physician of each facility
and it causes
misunderstanding.
Ver. 2.4 2021/01/18 Extension of the implementation period. To allow days for the
“September 30, 2021.” completion of conference
→ “September 30, 2022.” presentations, papers, etc.
Ver. 2.5 2021/03/05 The section of “Event Adjudication To increase the credibility of
Committee” was added, and a new the research.
Event Adjudication Protocol Ver. 1.0 was
created. (23.6)
2021/07/13 Created a Statistical Analysis Plan Ver. To describe the statistical
1.0. analysis methods in detail.
Ver. 2.6 2021/09/10 Added sub-analyses. (10.2.3) To ensure the quality of the
Image analysis (10.2.3)→(10.2.4) results of clinically important
sub-analyses by specifying
them in the research
protocol prior to data
fixation.
Updated the Image Analysis Plan from To ensure the quality of the
Ver. 1.1 to 1.2. research by making more
rigorous image judgments.
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Statistical Analysis Plan
Randomized controlled trial of endovascular therapy for acute

large vessel occlusion with large ischemic core
(RESCUE-Japan LIMIT)
NCT03702413
Ver. 1.0, Date Prepared: June 18, 2021
Chief study statistician

Takeshi Morimoto, MD, PhD, MPH
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Table of Contents
1. Purpose ............................................................................................................ .......... 3

2. Outline of statistical analysis............................................................................. .......... 3
3. Definitions of terms and abbreviations.............................................................. .......... 3
3.1. Terms .................................................................................................................... 3
3.2. Abbreviations ........................................................................................................ 3
4. Outline of this study .......................................................................................... .......... 4
4.1. Eligibility criteria .................................................................................................... 4
4.2. Study design ......................................................................................................... 5
4.3. Outcomes .............................................................................................................. 5
4.4. Planned sample size ............................................................................................. 6
5. Patient handling (Definition of analysis set) ...................................................... .......... 6
6. Data handling ................................................................................................... .......... 7
6.1. Completion of missing values ............................................................................... 7
6.2. Handling period ..................................................................................................... 7
7. Confirmation of enrollment status ..................................................................... .......... 8
8. Description of statistical analysis ...................................................................... .......... 8
8.1. Test significance level and confidence coefficient for interval estimation .............. 8
8.2. Software used for statistical analysis .................................................................... 8
9. Interim analysis ................................................................................................. .......... 8
10. Target patients................................................................................................ .......... 8
10.1. Enrollment status ................................................................................................ 8
11. Efficacy and safety evaluation ........................................................................ .......... 8
11.1. Analyzed data sets .............................................................................................. 8
11.2. Demographic and other reference value characteristics ................................... 10
11.3. Statistical considerations ................................................................................... 12
11.4. Analysis method ................................................................................................ 12
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1. Purpose
The purpose of this plan “Statistical Analysis Plan for Randomized controlled
trial of endovascular therapy for acute large vessel occlusion with large ischemic
core” (hereinafter, “Analysis Plan”) is to detail the statistical analysis in
“Randomized controlled trial of endovascular therapy for acute large vessel
occlusion with large ischemic core” (hereinafter, this study).
2. Outline of statistical analysis

The purpose of this study is to clarify the efficacy of endovascular treatment for
acute large vessel occlusion with moderate to severe large ischemic core (CT-
ASPECT score 3-5 or DWI-ASPECT score 3-5).
3. Definitions of terms and abbreviations

Terms and abbreviations used in the Analysis Plan are defined as follows.
3.1. Terms
1) Descriptive statistics values
Descriptive statistics values refer to sample size, mean, standard
deviation, median, interquartile range, minimum, and maximum.
3.2. Abbreviations
1) RESCUE-Japan LIMIT ： Randomized controlled trial of endovascular
therapy for acute large vessel occlusion with large ischemic core
2) EVT: Endovascular therapy
3) TIA: transient ischemic attack
4) FAS: Full Analysis Set
5) PPS: Per Protocol Set
6) ASPECTS-DWI ： Alberta stroke program early CT score - diffusion
weighted image
7) ASPECTS： Alberta stroke program early CT score
8) NIHSS: National Institutes of Health stroke scale
9) rt-PA: recombinant tissue type plasminogen activator
10) LVO: Large vessel occlusion
11) mRS：modified Rankin Scale
12) ICH: intracranial hemorrhage
13) MRI: magnetic resonance image
14) NCCT: non-contrast computed tomography
15) CTA: computed tomography angiography
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16) DSA: digital subtraction angiography

17) SD: standard deviation
18) IQR: median and interquartile range
19) ORs: odds ratios
20) 95% Cis: 95% confidence intervals
21) PT: prothrombin time
22) PT-INR: prothrombin time-international normalized ratio
23) aPTT: activated partial thromboplastin time
4. Outline of this study

4.1. Eligibility criteria

1) Acute cerebral infarction patients
2) Patients aged ≥ 18
3) Patients with NIHSS ≥ 6
4) Prestroke Modified Rankin Score 0-1
5) ICA or M1 occlusion on CT angiography or MR angiography
6) ASPECTS 3-5 or DWI-ASPECTS 3-5
7) Randomization can be finished within 6 hours from the last known well time,
or 6 to 24 hours from the last known well time without positive lesion on MRI-
FLAIR image.
8) Endovascular treatment can be initiated within 60 minutes from
randomization.
consent form.

1) Significant mass effect with midline shift in CT (or MRI).
2) Known allergy (more severe than skin rash) to contrast agents.
3) Evidence of acute intracranial hemorrhage in CT (or MRI).
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6) High risk of hemorrhage (platelet < 40,000/ul, APTT > 50 second or PT-INR
> 3.0)
8) Subjects who, in the judgment of the investigator, are likely to be non-
4.2. Study design


Dynamic randomization by minimization method is used for the randomization
of subjects to the endovascular therapy group or the non-endovascular therapy
group. Randomization and enrollment of subjects are made using EDC system.

informed consent (<75 years or ≥ 75 years), time from onset of cerebral
infraction or last known well to hospital arrival (<120 minutes or ≥ 120 minutes),
NIHSS score at the time of obtaining informed consent (<21 or ≥ 21), and
whether the patient was treated with intravenous alteplase after the onset of
cerebral infraction.
After investigators confirm that the patient meets the inclusion criteria and do
not conflict with the exclusion criteria, as well as obtaining written informed
consent from the subject or a legal representative such as a family member, the
investigators access the web-based enrollment system and enroll the patient
who met the inclusion criteria as consecutive cases. Informed consent should
be obtained before the randomization of treatment. In addition, the investigators
prepare and securely control the “List of enrolled cases” that links the case
enrollment number issued automatically at the time of enrollment to the patient’s
name and the medical record number.
Observation period is 90 days from the date of onset of acute cerebral
infarction due to large vessel occlusion.
4.3. Outcomes
[Primary outcomes]
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Achievement of modified Rankin Scale 0-3 at 90 days
1) Achievement of modified Rankin Scale 0-2 at 90 days
3) Distribution of patients across the modified Rankin scale
4) NIHSS improvement of 8 points or more at 48 hours
[Safety outcomes]
2) Intracranial hemorrhage within 48 hours
4) Recurrence of cerebral infarction within 90 days
4.4. Planned sample size

200 subjects (Number of subjects who have completed patient enrollment)
100 subjects (endovascular therapy group), 100 subjects (non-endovascular
therapy group)
[Rationale]
From the data of RESCUE-Japan Registry 2, we analyzed 338 patients
with DWI-ASPECTS 3-5 at hospital visit that are the target of this study. 24
patients (12.5%) and 55 patients (37.67%) had an mRS of 0-3 at 90 days,
which is the primary outcome in this study, among 192 patients in the non-
endovascular group and 146 patients in the endovascular group, respectively
[1]. In addition, the odds ratio (OR) with the baseline adjusted was 3.42, but
since this was an observational study and its effect may be large, we set the
relative risk at 2.7 times (3.42×0.8=2.7) with an allowance of 20% in clinical
practice. When type I error level is set at 0.05 two-sided and the power of the
test at 0.90, 81 patients in each cohort are required. Estimating the clinical
dropout rate at 15%, required sample size is calculated to be 191 patients in
both groups. Considering possible withdrawal of consent, we set the target
sample size to 100 patients in each cohort and a total of 200 patients.
5. Patient handling (Definition of analysis set)

Analysis population is defined as follows.
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[Safety analysis set]

Safety analysis set (SAS)
All enrolled patient populations. It does not matter whether the treatment
is assigned or not.
[Efficacy analysis set]

Full Analysis Set (FAS)
The population of patients who were allocated and whose mRS was
measured after the allocated treatment.
[Per protocol set]

Per protocol set (PPS)
A population of patients who meet eligible criteria, receive protocol-
defined allocation of treatment, and have an observed primary endpoint.
Based on the treatment status of each patient, investigators determine the

method of handling the efficacy analysis set and the safety analysis set.
Investigators determine the final method of handling each patient before data
fixation.
In addition, investigators confirm the status of deviation from the protocol, and
the observation status (whether a patient was observed after 90 days, and
deviation in period), etc.
6. Data handling
6.1. Completion of missing values
Missing values are not complemented by taking over the previous values, but
in the cases like drug use, blank parts are replaced with "0".
6.2. Handling period

The period is calculated from the following formula.
Period = Relevant date - Start date + 1
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7. Confirmation of enrollment status

Patient enrollment status and demographics/baseline characteristics are
summarized as needed.
8. Description of statistical analysis

8.1. Test significance level and confidence coefficient for interval estimation
The significance level of the test is two-tailed 5%. In addition, the confidence
coefficient for interval estimation is two-tailed 95%.
8.2. Software used for statistical analysis

The software used for statistical analysis is SAS (SAS Institute Inc.) version
9.1.3 or newer or JMP (SAS Institute Inc.) version 14 or newer.
9. Interim analysis
No interim analysis is planned.
10. Target patients

10.1. Enrollment status
Enrolled patients are analyzed.
Number of enrolled patients are counted according to the period.
11. Efficacy and safety evaluation

11.1. 1 Analyzed data sets
The sample size for the following classification is shown in a flowchart.
[Classification]
Enrolled cases, SAS, cases excluded from SAS, FAS, cases excluded
from FAS, PPS, and cases excluded from PPS are classified, and each
frequency and the reason for exclusion of cases excluded from each sets
are described.
11.1.2 Definition of safety event outcomes

11.1.2.1 Cerebral ischemia events
Cerebral ischemia events include all of the following events.
Cerebral infarction
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remission of neurologic dysfunction within 7 days or cases with sustained

worsening of NIHSS score of less than 4 points are evaluated as mild stroke, and
cases with sustained neurologic dysfunction for more than 7 days or cases with
sustained worsening of NIHSS score of 4 points or more are evaluated as severe
stroke.
Transient ischemic attack
associated with transient cerebral ischemia and with the duration of neurologic
symptoms of less than 24 hours, while there was no obvious abnormality that
could explain the symptoms by diagnostic imaging examination. Diagnosis of
transient ischemic attack (TIA) should not be given based only on symptoms such
as impaired consciousness (without neurologic symptoms), convulsion,
scintillating scotoma or unrelated dizziness, diplopia or dysarthria.
11.1.2.2 Intracranial hemorrhage events

All intracranial hemorrhages
Cases with intracranial hemorrhage on CT or MRI head images.
These cases include hemorrhagic infarction, bleeding from the brain parenchyma,
subarachnoid hemorrhage, and subdural hematoma.
Symptomatic intracranial hemorrhage
hemorrhage and with worse NIHSS score of 4 points or more compared to the
time of enrollment.
11.1.3 Definition, handling, and investigation of adverse events

11.1.3.1 Definition of adverse events
laboratory value), symptom, or disease that occurs in a study subject from the
time of enrollment to 90 days after randomization, regardless of the causal
relationship with the study treatment. In this study, only the adverse events listed
in 11.1.3.2 and 11.1.3.3 are reported.
11.1.3.2 Serious adverse events

1) Death
2) Life-threatening
4) Permanent damage
5) Risk of damage
6) Other serious medical events equivalent to 1)-5)
11.1.3.3 Clinically significant adverse events

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syndrome (acute myocardial infarction, unstable angina), acute heart failure
requiring urgent treatment, aortic disease (aortic dissection, aortic aneurysm),
and sudden cardiac death.
11.2. Demographic and other reference value characteristics

FAS and PPS are analyzed.
Primary outcomes and period
randomization, 48 hours (±24 hours) after randomization, and either 7 days (±2
days) after randomization or at discharge which is earlier.
2) mRS
mRS assessment is performed at enrollment (before the onset), either 7
days (±2 days) after randomization or at discharge which is earlier, and 90 days
(±30 days) after randomization. If a subject is unable to visit the hospital,
surveillance by telephone is also allowed.
3) Head imaging examination
CT/CTA/CTP or MRI/MRA is performed at enrollment. CT or MRI is
performed at 48 hours (±24 hours) after randomization to assess the status of
cerebral infarction and intracranial hemorrhage. CT/CTA or MRI/MRA is
performed either on 7 days (±2 days) after randomization or at discharge which
is earlier, to assess the status of cerebral infarction or large vessel occlusion.
All events occurring within 90 days after randomization are assessed.
Significant adverse events occurring within 90 days of randomization are
evaluated only for the first time, and external decompression cases are
evaluated for up to 7 days.
At enrollment
Baseline data:
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94
Hospital name/ name of patient identification/ age/ sex/ time of onset (last
known well time)/ time of arrival at the hospital/ mRS before onset/ Intravenous
alteplase after onset
Imaging evaluation:
scores), and the occlusion site are assessed. DICOM images are submitted to
the office for central review.
Concomitant disease/Medical history:
Atrial fibrillation/ cerebral infarction/ cerebral hemorrhage/ TIA/
subarachnoid hemorrhage/ ischemic heart disease/ peripheral arterial
disease
Medication before onset:
Type of cerebral infarction (Initial diagnosis):
Cardiogenic embolism, atherothrombosis, other type of cerebral infarction,
unknown causes
Blood test:
WBC, Hb, Plt, BUN, Cre, Glu, CRP, PT-INR, APTT, LDL, HDL, t. chol,
HbA1C
Chest x-ray, 12-lead ECG
Blood pressure, pulse, body temperature
Observation Period_Very-Early: within 12 hours after randomization

Details of treatment:
Treatment start (puncture) time, time of recanalization, time for completion
of procedures
Neurological assessment (NIHSS)
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Observation Period_Early: 48 hours (±24 hours) after randomization

Head imaging: CT or MRI is performed to assess the status of cerebral
infarction or intracranial hemorrhage.
Blood test (WBC, Hb, Plt, BUN, Cre, Glu, CRP, PT-INR, APTT)
Observation Period_Discharge: Either 7 days (±2 days) after randomization

or at discharge, which is earlier
mRS
Head imaging: CT/CTA or MRI/MRA is performed to assess the status of
Type of cerebral infarction (Final diagnosis):
unknown causes
Therapeutic drugs (anticoagulants, antiplatelet drugs, antihypertensive agents,
statins)
Observation Period_End: 90 days (±30 days) after randomization

(Surveillance by telephone or observation by a doctor from another hospital is
also allowed.)
mRS
*mRS and NIHSS are assessed by a doctor or a physical therapist who does
not know the randomization.
11.3. Statistical considerations

FAS is the primary analysis population. PPS is the secondary analysis
population.
11.4. Analysis method

1) Analysis of demographics and baseline characteristics
12
96
The analysis set is divided into the endovascular therapy group and the non-
endovascular therapy group, and descriptive statistics are calculated on the
demographics and baseline characteristics.
2) Analysis of primary outcomes

The number of subjects, percentages, ORs, and 95% confidence intervals of
patients with a mRS score of 0-3 at 90 days after the start of hospitalization are
calculated for the endovascular and non-endovascular therapy group,
respectively. The results are subjected to test between the endovascular and
non-endovascular therapy groups.
The number of subjects, percentages, ORs, and 95% confidence intervals for
each secondary endpoint are calculated for the endovascular and non-
endovascular therapy groups, respectively. The results are subjected to test
between the endovascular and non-endovascular therapy groups. Common OR
with one level lower shift analysis is calculated for mRS.
4) Safety outcomes
each safety outcomes are calculated for the endovascular and non-
between the endovascular and non-endovascular therapy groups.
In addition, for endpoints with low incidence valuables, descriptive statistics
using n and % are used for adverse events, and no validations are performed.
For the safety outcomes, SAS is also analyzed.
5) Subgroup analysis for efficacy outcomes

ORs and 95% confidence intervals are calculated for mRS 0-3 at 90 days after
the start of hospitalization, which is the primary outcome. Interaction for each
sub-groups are examined.
Following subgroup factors

 Age at the time of informed consent (<75 years or ≥ 75 years)
 Time from onset of cerebral infraction or last known well to hospital arrival
(<120 minutes or ≥ 120 minutes)
13
97
 NIHSS score at the time of informed consent (<21 or ≥ 21)

 Whether the patient was treated with intravenous alteplase after the onset of
cerebral infraction
Continuous variables are indicated by mean and standard deviation or median

and quartiles, depending on the type of distribution, and t-test or Wilcoxon rank
sum test is used. In addition, categorical variables are indicated by the sample
size or percentages, and chi-square test or Fisher’s exact test is used. Two-
tailed P<0.05 is regarded as significant difference.
References
[1] Hiroto Kakita, Shinichi Yoshimura, Kazutaka Uchida, Nobuyuki Sakai,
Hiroshi Yamagami, Takeshi Morimoto, RESCUE-Japan Registry 2 Investigators
Impact of Endovascular Therapy in Patients with Large Ischemic Core:
Subanalysis of Recovery by Endovascular Salvage for Cerebral Ultra-Acute
Embolism Japan Registry 2、Stroke. 2019 Apr;50(4):901-908.
14
98
Statistical Analysis Plan
Randomized controlled trial of endovascular therapy for acute

large vessel occlusion with large ischemic core
(RESCUE-Japan LIMIT)
NCT03702413
Ver. 1.0, Date Prepared: June 18, 2021
Chief study statistician

Takeshi Morimoto, MD, PhD, MPH
1
99
Table of Contents
1. Purpose ............................................................................................................ .......... 3

2. Outline of statistical analysis............................................................................. .......... 3
3. Definitions of terms and abbreviations.............................................................. .......... 3
3.1. Terms .................................................................................................................... 3
3.2. Abbreviations ........................................................................................................ 3
4. Outline of this study .......................................................................................... .......... 4
4.1. Eligibility criteria .................................................................................................... 4
4.2. Study design ......................................................................................................... 5
4.3. Outcomes .............................................................................................................. 5
4.4. Planned sample size ............................................................................................. 6
5. Patient handling (Definition of analysis set) ...................................................... .......... 6
6. Data handling ................................................................................................... .......... 7
6.1. Completion of missing values ............................................................................... 7
6.2. Handling period ..................................................................................................... 7
7. Confirmation of enrollment status ..................................................................... .......... 8
8. Description of statistical analysis ...................................................................... .......... 8
8.1. Test significance level and confidence coefficient for interval estimation .............. 8
8.2. Software used for statistical analysis .................................................................... 8
9. Interim analysis ................................................................................................. .......... 8
10. Target patients................................................................................................ .......... 8
10.1. Enrollment status ................................................................................................ 8
11. Efficacy and safety evaluation ........................................................................ .......... 8
11.1. Analyzed data sets .............................................................................................. 8
11.2. Demographic and other reference value characteristics ................................... 10
11.3. Statistical considerations ................................................................................... 12
11.4. Analysis method ................................................................................................ 12
2
100
1. Purpose
The purpose of this plan “Statistical Analysis Plan for Randomized controlled
trial of endovascular therapy for acute large vessel occlusion with large ischemic
core” (hereinafter, “Analysis Plan”) is to detail the statistical analysis in
“Randomized controlled trial of endovascular therapy for acute large vessel
occlusion with large ischemic core” (hereinafter, this study).
2. Outline of statistical analysis

The purpose of this study is to clarify the efficacy of endovascular treatment for
acute large vessel occlusion with moderate to severe large ischemic core (CT-
ASPECT score 3-5 or DWI-ASPECT score 3-5).
3. Definitions of terms and abbreviations

Terms and abbreviations used in the Analysis Plan are defined as follows.
3.1. Terms
1) Descriptive statistics values
Descriptive statistics values refer to sample size, mean, standard
deviation, median, interquartile range, minimum, and maximum.
3.2. Abbreviations
1) RESCUE-Japan LIMIT ： Randomized controlled trial of endovascular
therapy for acute large vessel occlusion with large ischemic core
2) EVT: Endovascular therapy
3) TIA: transient ischemic attack
4) FAS: Full Analysis Set
5) PPS: Per Protocol Set
6) ASPECTS-DWI ： Alberta stroke program early CT score - diffusion
weighted image
7) ASPECTS： Alberta stroke program early CT score
8) NIHSS: National Institutes of Health stroke scale
9) rt-PA: recombinant tissue type plasminogen activator
10) LVO: Large vessel occlusion
11) mRS：modified Rankin Scale
12) ICH: intracranial hemorrhage
13) MRI: magnetic resonance image
14) NCCT: non-contrast computed tomography
15) CTA: computed tomography angiography
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101
16) DSA: digital subtraction angiography

17) SD: standard deviation
18) IQR: median and interquartile range
19) ORs: odds ratios
20) 95% Cis: 95% confidence intervals
21) PT: prothrombin time
22) PT-INR: prothrombin time-international normalized ratio
23) aPTT: activated partial thromboplastin time
4. Outline of this study

4.1. Eligibility criteria

1) Acute cerebral infarction patients
2) Patients aged ≥ 18
3) Patients with NIHSS ≥ 6
4) Prestroke Modified Rankin Score 0-1
5) ICA or M1 occlusion on CT angiography or MR angiography
6) ASPECTS 3-5 or DWI-ASPECTS 3-5
7) Randomization can be finished within 6 hours from the last known well time,
or 6 to 24 hours from the last known well time without positive lesion on MRI-
FLAIR image.
8) Endovascular treatment can be initiated within 60 minutes from
randomization.
consent form.

1) Significant mass effect with midline shift in CT (or MRI).
2) Known allergy (more severe than skin rash) to contrast agents.
3) Evidence of acute intracranial hemorrhage in CT (or MRI).
4
102
6) High risk of hemorrhage (platelet < 40,000/ul, APTT > 50 second or PT-INR
> 3.0)
8) Subjects who, in the judgment of the investigator, are likely to be non-
4.2. Study design


Dynamic randomization by minimization method is used for the randomization
of subjects to the endovascular therapy group or the non-endovascular therapy
group. Randomization and enrollment of subjects are made using EDC system.

informed consent (<75 years or ≥ 75 years), time from onset of cerebral
infraction or last known well to hospital arrival (<120 minutes or ≥ 120 minutes),
NIHSS score at the time of obtaining informed consent (<21 or ≥ 21), and
whether the patient was treated with intravenous alteplase after the onset of
cerebral infraction.
After investigators confirm that the patient meets the inclusion criteria and do
not conflict with the exclusion criteria, as well as obtaining written informed
consent from the subject or a legal representative such as a family member, the
investigators access the web-based enrollment system and enroll the patient
who met the inclusion criteria as consecutive cases. Informed consent should
be obtained before the randomization of treatment. In addition, the investigators
prepare and securely control the “List of enrolled cases” that links the case
enrollment number issued automatically at the time of enrollment to the patient’s
name and the medical record number.
Observation period is 90 days from the date of onset of acute cerebral
infarction due to large vessel occlusion.
4.3. Outcomes
[Primary outcomes]
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103
Achievement of modified Rankin Scale 0-3 at 90 days
3) Distribution of patients across the modified Rankin scale
4) NIHSS improvement of 8 points or more at 48 hours
[Safety outcomes]
2) Intracranial hemorrhage within 48 hours
4) Recurrence of cerebral infarction within 90 days
4.4. Planned sample size

200 subjects (Number of subjects who have completed patient enrollment)
100 subjects (endovascular therapy group), 100 subjects (non-endovascular
therapy group)
[Rationale]
From the data of RESCUE-Japan Registry 2, we analyzed 338 patients
with DWI-ASPECTS 3-5 at hospital visit that are the target of this study. 24
patients (12.5%) and 55 patients (37.67%) had an mRS of 0-3 at 90 days,
which is the primary outcome in this study, among 192 patients in the non-
endovascular group and 146 patients in the endovascular group, respectively
[1]. In addition, the odds ratio (OR) with the baseline adjusted was 3.42, but
since this was an observational study and its effect may be large, we set the
relative risk at 2.7 times (3.42×0.8=2.7) with an allowance of 20% in clinical
practice. When type I error level is set at 0.05 two-sided and the power of the
test at 0.90, 81 patients in each cohort are required. Estimating the clinical
dropout rate at 15%, required sample size is calculated to be 191 patients in
both groups. Considering possible withdrawal of consent, we set the target
sample size to 100 patients in each cohort and a total of 200 patients.
5. Patient handling (Definition of analysis set)

Analysis population is defined as follows.
6
104
[Safety analysis set]

Safety analysis set (SAS)
All enrolled patient populations. It does not matter whether the treatment
is assigned or not.
[Efficacy analysis set]

Full Analysis Set (FAS)
The population of patients who were allocated and whose mRS was
measured after the allocated treatment.
[Per protocol set]

Per protocol set (PPS)
A population of patients who meet eligible criteria, receive protocol-
defined allocation of treatment, and have an observed primary endpoint.
Based on the treatment status of each patient, investigators determine the

method of handling the efficacy analysis set and the safety analysis set.
Investigators determine the final method of handling each patient before data
fixation.
In addition, investigators confirm the status of deviation from the protocol, and
the observation status (whether a patient was observed after 90 days, and
deviation in period), etc.
6. Data handling
6.1. Completion of missing values
Missing values are not complemented by taking over the previous values, but
in the cases like drug use, blank parts are replaced with "0".
6.2. Handling period

The period is calculated from the following formula.
Period = Relevant date - Start date + 1
7
105
7. Confirmation of enrollment status

Patient enrollment status and demographics/baseline characteristics are
summarized as needed.
8. Description of statistical analysis

8.1. Test significance level and confidence coefficient for interval estimation
The significance level of the test is two-tailed 5%. In addition, the confidence
coefficient for interval estimation is two-tailed 95%.
8.2. Software used for statistical analysis

The software used for statistical analysis is SAS (SAS Institute Inc.) version
9.1.3 or newer or JMP (SAS Institute Inc.) version 14 or newer.
9. Interim analysis
No interim analysis is planned.
10. Target patients

10.1. Enrollment status
Number of enrolled patients are counted according to the period.
11. Efficacy and safety evaluation

11.1. 1 Analyzed data sets
The sample size for the following classification is shown in a flowchart.
[Classification]
Enrolled cases, SAS, cases excluded from SAS, FAS, cases excluded
from FAS, PPS, and cases excluded from PPS are classified, and each
frequency and the reason for exclusion of cases excluded from each sets
are described.
11.1.2 Definition of safety event outcomes

11.1.2.1 Cerebral ischemia events
Cerebral ischemia events include all of the following events.
Cerebral infarction
8
106
remission of neurologic dysfunction within 7 days or cases with sustained

worsening of NIHSS score of less than 4 points are evaluated as mild stroke, and
cases with sustained neurologic dysfunction for more than 7 days or cases with
sustained worsening of NIHSS score of 4 points or more are evaluated as severe
stroke.
Transient ischemic attack
associated with transient cerebral ischemia and with the duration of neurologic
symptoms of less than 24 hours, while there was no obvious abnormality that
could explain the symptoms by diagnostic imaging examination. Diagnosis of
transient ischemic attack (TIA) should not be given based only on symptoms such
as impaired consciousness (without neurologic symptoms), convulsion,
scintillating scotoma or unrelated dizziness, diplopia or dysarthria.
11.1.2.2 Intracranial hemorrhage events

All intracranial hemorrhages
Cases with intracranial hemorrhage on CT or MRI head images.
These cases include hemorrhagic infarction, bleeding from the brain parenchyma,
subarachnoid hemorrhage, and subdural hematoma.
Symptomatic intracranial hemorrhage
hemorrhage and with worse NIHSS score of 4 points or more compared to the
time of enrollment.
11.1.3 Definition, handling, and investigation of adverse events

11.1.3.1 Definition of adverse events
laboratory value), symptom, or disease that occurs in a study subject from the
time of enrollment to 90 days after randomization, regardless of the causal
relationship with the study treatment. In this study, only the adverse events listed
in 11.1.3.2 and 11.1.3.3 are reported.
11.1.3.2 Serious adverse events

1) Death
2) Life-threatening
4) Permanent damage
5) Risk of damage
6) Other serious medical events equivalent to 1)-5)
11.1.3.3 Clinically significant adverse events

9
107


syndrome (acute myocardial infarction, unstable angina), acute heart failure
requiring urgent treatment, aortic disease (aortic dissection, aortic aneurysm),
and sudden cardiac death.
11.2. Demographic and other reference value characteristics

FAS and PPS are analyzed.
Primary outcomes and period
randomization, 48 hours (±24 hours) after randomization, and either 7 days (±2
days) after randomization or at discharge which is earlier.
2) mRS
mRS assessment is performed at enrollment (before the onset), either 7
days (±2 days) after randomization or at discharge which is earlier, and 90 days
(±30 days) after randomization. If a subject is unable to visit the hospital,
surveillance by telephone is also allowed.
3) Head imaging examination
CT/CTA/CTP or MRI/MRA is performed at enrollment. CT or MRI is
performed at 48 hours (±24 hours) after randomization to assess the status of
cerebral infarction and intracranial hemorrhage. CT/CTA or MRI/MRA is
performed either on 7 days (±2 days) after randomization or at discharge which
is earlier, to assess the status of cerebral infarction or large vessel occlusion.
All events occurring within 90 days after randomization are assessed.
Significant adverse events occurring within 90 days of randomization are
evaluated only for the first time, and external decompression cases are
evaluated for up to 7 days.
At enrollment
Baseline data:
10
108
Hospital name/ name of patient identification/ age/ sex/ time of onset (last
known well time)/ time of arrival at the hospital/ mRS before onset/ Intravenous
alteplase after onset
Imaging evaluation:
scores), and the occlusion site are assessed. DICOM images are submitted to
the office for central review.
Concomitant disease/Medical history:
Atrial fibrillation/ cerebral infarction/ cerebral hemorrhage/ TIA/
subarachnoid hemorrhage/ ischemic heart disease/ peripheral arterial
disease
Medication before onset:
Type of cerebral infarction (Initial diagnosis):
unknown causes
Blood test:
WBC, Hb, Plt, BUN, Cre, Glu, CRP, PT-INR, APTT, LDL, HDL, t. chol,
HbA1C
Chest x-ray, 12-lead ECG
Observation Period_Very-Early: within 12 hours after randomization

Details of treatment:
Treatment start (puncture) time, time of recanalization, time for completion
of procedures
11
109
Observation Period_Early: 48 hours (±24 hours) after randomization

Head imaging: CT or MRI is performed to assess the status of cerebral
infarction or intracranial hemorrhage.
Blood test (WBC, Hb, Plt, BUN, Cre, Glu, CRP, PT-INR, APTT)
Observation Period_Discharge: Either 7 days (±2 days) after randomization

or at discharge, which is earlier
mRS
Head imaging: CT/CTA or MRI/MRA is performed to assess the status of
Type of cerebral infarction (Final diagnosis):
unknown causes
Therapeutic drugs (anticoagulants, antiplatelet drugs, antihypertensive agents,
statins)
Observation Period_End: 90 days (±30 days) after randomization

(Surveillance by telephone or observation by a doctor from another hospital is
also allowed.)
mRS
*mRS and NIHSS are assessed by a doctor or a physical therapist who does
not know the randomization.
11.3. Statistical considerations

FAS is the primary analysis population. PPS is the secondary analysis
population.
11.4. Analysis method

1) Analysis of demographics and baseline characteristics
12
110
The analysis set is divided into the endovascular therapy group and the non-
endovascular therapy group, and descriptive statistics are calculated on the
demographics and baseline characteristics.
2) Analysis of primary outcomes

The number of subjects, percentages, ORs, and 95% confidence intervals of
patients with a mRS score of 0-3 at 90 days after the start of hospitalization are
calculated for the endovascular and non-endovascular therapy group,
respectively. The results are subjected to test between the endovascular and
non-endovascular therapy groups.
each secondary endpoint are calculated for the endovascular and non-
between the endovascular and non-endovascular therapy groups. Common OR
with one level lower shift analysis is calculated for mRS.
4) Safety outcomes
each safety outcomes are calculated for the endovascular and non-
between the endovascular and non-endovascular therapy groups.
In addition, for endpoints with low incidence valuables, descriptive statistics
using n and % are used for adverse events, and no validations are performed.
For the safety outcomes, SAS is also analyzed.
5) Subgroup analysis for efficacy outcomes

ORs and 95% confidence intervals are calculated for mRS 0-3 at 90 days after
the start of hospitalization, which is the primary outcome. Interaction for each
sub-groups are examined.
Following subgroup factors

 Age at the time of informed consent (<75 years or ≥ 75 years)
 Time from onset of cerebral infraction or last known well to hospital arrival
(<120 minutes or ≥ 120 minutes)
13
111
 NIHSS score at the time of informed consent (<21 or ≥ 21)

 Whether the patient was treated with intravenous alteplase after the onset of
cerebral infraction
Continuous variables are indicated by mean and standard deviation or median

and quartiles, depending on the type of distribution, and t-test or Wilcoxon rank
sum test is used. In addition, categorical variables are indicated by the sample
size or percentages, and chi-square test or Fisher’s exact test is used. Two-
tailed P<0.05 is regarded as significant difference.
References
[1] Hiroto Kakita, Shinichi Yoshimura, Kazutaka Uchida, Nobuyuki Sakai,
Hiroshi Yamagami, Takeshi Morimoto, RESCUE-Japan Registry 2 Investigators
Impact of Endovascular Therapy in Patients with Large Ischemic Core:
Subanalysis of Recovery by Endovascular Salvage for Cerebral Ultra-Acute
Embolism Japan Registry 2、Stroke. 2019 Apr;50(4):901-908.
14
112
Summary of changes
Version Date of Changes Reasons for change

revised
Ver. 1.0 2021/06/18 Initial version was made. No change
thereafter.

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Protocol

Endovascular therapy for acute stroke with a large ischemic core

Page (Upper right) Documents

84 Original statistical analysis plan

98 Final statistical analysis plan

112 Summary of changes

Randomized clinical trial of endovascular therapy for acute large

Ver. 1.0, Date Prepared August 20, 2018

Clinical Trial Registration: ClinicalTrials.gov: NCT03702413

Purpose The purpose of this study is to evaluate the efficacy of endovascular

7) Participating in any other therapeutic investigational trial

mRS: modified Rankin Scale

2. Rationale for the study

3. Overall design and plan of the study

<Rationale for setting the design>

3.1.2 Target number of patients

<Rationale for setting the target number of subjects>

3.1.3 Study period

3.1.3.2 Overall study period

3.2 Study flow

4.2.1 Inclusion criteria

4.2.2 Exclusion criteria

5. Enrollment and randomization

5.1.1 Hospital registration

5.1.2 EDC system user registration

5.2. Patient enrollment

Principal investigator or sub-investigator confirms the details, if eligibility message

5.3.2 Enrollment and acquisition of randomization results

5.3.3 Randomization factors

5.3.4 Control and storage of randomization results

6.2. Treatment method

6.3. Discontinuation of treatment

6.4. Treatment options at recurrence

7. Observation, tests, reporting items and schedule

Schedule At enrollment Observation period

Before After Very Early Early Discharge End

period well zation randomi- randomi- randomi-

zation zation or at zation

Only scores Details

CT/CTA/CTP CT or MRI CT/CTA or

and Only EVT

status Only EVT

(TICI grade) group

*1: Imaging (at enrollment)

7.1 Primary outcomes and timing

4) Serious adverse events or clinically significant adverse events

7.3 Observation Period_Very-Early: within 12 hours after randomization

Treatment complications and the details

7.4 Observation Period_Early: 48 hours (± 12 hours) after randomization

7.5 Observation Period_Discharge: Either 7 days (± 1 day) after randomization or at

7.6 Observation Period_End: 90 days (± 30 days) after randomization (Surveillance by

Achievement of mRS 0–3 at 90 days

8.2 Secondary outcomes

8.3 Safety outcomes

8.4 Cerebral ischemic events

8.4.1 Cerebral infarction

8.4.2 Transient ischemic attack

8.5 Intracranial hemorrhage events

include hemorrhagic infarction, bleeding from the brain parenchyma, subarachnoid

8.5.2 Symptomatic intracranial hemorrhage

9. Definition, handling, and investigation related to adverse events

9.2 Classification of adverse events