RAPID Local Ischemic Postconditioning in Acute Ischemic Stroke pAtients receiVEd Successful Thrombectomy Reperfusion
Phase: NA
Conditions: Acute Ischemic Stroke, Mechanical Thrombectomy, Ischemic Postconditioning, Brain Edema, Neuroprotection
Sponsor: Shanghai Jiao Tong University Affiliated Sixth People's Hospital

 
 
RAPID local ischemic postconditioning in acute ischemic Stroke pAtients 
receiVEd successful thrombectomy reperfusion (RAPID-SAVE) 
STUDY PROTOCOL 
 
 
Principal Investigator 
Yueqi Zhu, MD 
Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School 
of Medicine 
 
 
 
Clinical Trial：NCT06526429 
 
Protocol Version 2.0 
Dec 23, 2024 
 
 

 
 
PROTOCOL SIGNATURE PAGE 
I have read this trial protocol and agree to adhere to the requirements. 
 
 
 
I will provide copies of this protocol and all pertinent information to the study 
personnel under my supervision. I will discuss this material with them and ensure they 
are fully informed regarding the investigational plan and the conduct of the study 
according to the Good Clinical Practices Guidelines and Institutional Review Board 
(IRB) requirements. 
 
 
 
 
 
 
 
 
 
 
Clinical Site:_______________________________________________________ 
 
Site Principal Investigator Printed Name:___________________ 
 
Site Principal Investigator Signature: _____________Date:_______

 
 
TABLE OF CONTENTS 
1 
RAPID-SAVE TRIAL PROTOCOL SYNOPSIS ............................................................ 1 
2 
1. FLOWCHARTS ................................................................................................................... 4 
3 
1.1 Graphical Study Design ......................................................................................................................... 4 
4 
1.2 Study Flowchart ..................................................................................................................................... 4 
5 
2 BACKGROUND AND SIGNIFICANCE ....................................................................... 6 
6 
3 STUDY OBJECTIVES ........................................................................................................ 7 
7 
4 STUDY DESIGN AND MANAGEMENT OVERVIEW ........................................... 7 
8 
4.1 Study design overview ........................................................................................................................... 7 
9 
4.2 Blinding .................................................................................................................................................... 8 
10 
4.3 Study milestones ..................................................................................................................................... 8 
11 
4.4 Site recruitment ...................................................................................................................................... 8 
12 
4.5 Site training, certification, and updates .............................................................................................. 8 
13 
4.6 Outcomes ................................................................................................................................................. 9 
14 
5 PARTICIPANT SELECTION ......................................................................................... 10 
15 
5.1 Inclusion and exclusion criteria ........................................................................................................ 10 
16 
5.2 Criteria for removal ............................................................................................................................ 12 
17 
5.3 Criteria for drop out ........................................................................................................................... 12 
18 
5.4 Criteria for discontinuation of clinical studies ................................................................................ 12 
19 

 
 
6 TREATMENTS .................................................................................................................... 12 
20 
7 SAFETY ................................................................................................................................. 13 
21 
7.1 Adverse events and management of SAEs ....................................................................................... 13 
22 
7.2 Definitions of adverse events and severe adverse events ............................................................... 13 
23 
7.3 Relationship to study treatment ........................................................................................................ 14 
24 
7.4 AE Reporting ........................................................................................................................................ 14 
25 
8 STATISTICAL CONSIDERATIONS ............................................................................ 15 
26 
8.1 Sample size estimates .......................................................................................................................... 15 
27 
8.2 Statistical analysis plans ..................................................................................................................... 15 
28 
8.3 Data safety monitoring plan .............................................................................................................. 15 
29 
9 ETHICAL AND REGULATORY STANDARDS ....................................................... 15 
30 
9.1 Ethical considerations ......................................................................................................................... 15 
31 
9.2 Informed consent ................................................................................................................................. 16 
32 
10 STUDY MONITORING ................................................................................................. 16 
33 
10.1 Site monitoring .................................................................................................................................. 16 
34 
10.2 Data collection .................................................................................................................................... 17 
35 
10.3 Data management and quality control ........................................................................................... 17 
36 
11 PUBLICATIONS POLICY ............................................................................................ 18 
37 
12 REFERENCES .................................................................................................................. 20 
38 
 
39 

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RAPID-SAVE Trial Protocol Synopsis 
40 
Title 
RAPID local ischemic postconditioning in acute ischemic 
Stroke pAtients receiVEd successful thrombectomy 
reperfusion 
Objective 
To determine the safety and optimal dosage of RL-IPostC in 
AIS patients who have received successful thrombectomy 
reperfusion. 
Study design 
Bayesian Optimal Interval Phase I/II (BOIN12) trial design 
Patient population 
Patients with AIS and anterior circulation large vessel 
occlusion (LVO) who have undergone successful 
endovascular thrombectomy 
Inclusion/Exclusion 
criteria 
Inclusion Criteria: 
① Age ≥ 18 years 
② Presenting with symptoms consistent with acute anterior 
circulation ischemic stroke 
③ Pre-stroke modified Rankin Score 0-1 
④ Baseline National Institute of Health Stroke Scale 
(NIHSS) score≥6 
⑤ Endovascular treatment can be initiated (femoral 
puncture) within 24 hours from stroke onset (stroke 
onset time is defined as last known well time) 
⑥ Occlusion of the intracranial internal carotid artery, or 
the middle cerebral artery (MCA) (M1 or M2) and is the 
culprit artery 
⑦ Ischemic core volume is < 70 ml, mismatch ratio >1.8 
and mismatch volume is >15 ml as determined by CT 
perfusion imaging 

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⑧ Embolism verified as the etiology of occluded artery 
 
⑨ Modified Thrombolysis in Cerebral Infarction Score 
(mTICI) of 2b or 3 achieved after mechanical 
thrombectomy. 
⑩ Time from CT perfusion to reperfusion < 2 hours 
⑪ Informed consent signed 
Exclusion Criteria: 
① Stenosis (≥50%) of the proximal MCA, internal carotid 
artery (ICA), or common carotid artery (CCA) of the 
culprit artery 
② Presence of an ICA lesion that prevent the use of a 
balloon guide catheter 
③ Multiple vascular embolisms on different pathways (e.g., 
bilateral MCA occlusions, or an MCA and a basilar 
artery occlusion) 
④ Previous ischemic stroke within the past 3 months 
⑤ Expected survival time of less than 6 months, precluding 
follow-up at 90 days (e.g., patient with malignant tumor) 
⑥ Currently pregnant, mental disease, advanced hepatic or 
renal insufficiency, severe heart failure 
⑦ Participation in other clinical trials that may confound 
the outcome assessment of this trial 
⑧ Any other circumstances deemed inappropriate by the 
investigator for inclusion in this trial 
Endpoints 
Safety outcomes included the occurrence of malignant 
infarction, procedure-related serious adverse events, or other 
adverse events attributable to the procedure within 7 days. 

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Efficacy was defined as the absence of clinically significant 
infarction lesion growth (>10 mL) from baseline to 72 hours. 
Numbers of centers 
Six investigational sites of national comprehensive stroke 
centers in China. 
Sample size 
A sum of 60 patients, organized into 12 cohorts, each 
consisting of 5 patients. The maximum sample size of each 
dosage level is capped at 20 patients. 
Treatment 
RL-IPostC procedure is administered immediately (within 5 
minutes) following successful revascularization. A balloon 
guiding catheter placed properly at the ipsilateral C1 segment 
of ICA, inflated and deflated alternately to temporarily 
interrupt blood flow.  
 
 
41 

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1. FLOWCHARTS  
42 
1.1 Graphical Study Design 
43 
 
44 
LVO-AIS: large vessel occluded acute ischemic stroke. EVT: endovascular 
45 
thrombectomy.  RL-IPostC, Rapid local ischemic postconditioning. NIHSS: National 
46 
Institutes of Health Stroke Scale. mRS: modified Rankin Scale. EQ-5D-5L: European 
47 
Quality Five Dimension Five Level scale. SAE: serious adverse events. 
48 
1.2 Study Flowchart  
49 
Time points 
Screen 
Treat
ment 
Follow up 
-24 
~ 
0h 
0h 
24 ± 12h 72 ± 24h 7d ± 24h 90 ± 7d 
Demographic 
characteristics1 
X 
 
 
 
 
 
Medical history2 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
 
 
Key time3 
X 
X 
 
 
 
 
Vital signs4 
 
X 
X 
X 
 
 
Laboratory tests5 
X 
 
 
 
 
 
Thromblysis6 
X 
 
 
 
 
 
Multi-mode imaging7
X 
 
 
 
 
 

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（NCCT+CTP+CTA） 
Postoperative imaging8 
(NCCT+MRI+MRA/CTA
） 
 
 
X 
X 
X 
 
Eligibility screen  
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Endovascular 
thrombectomy9 
 
X 
 
 
 
 
sICH 
 
 
X 
X 
 
 
mRS 10 
X 
 
 
 
 
X 
NIHSS 
X 
 
X 
X 
X 
 
EQ-5D-5L 
 
 
 
 
 
X 
TOAST 
 
 
 
X 
 
 
AE/SAE 
 
X 
X 
X 
 
X 
1. Demographic characteristics: age, sex； 
2. Medical history: including previous stroke, carotid artery disease, heart-related diseases, 
peripheral arterial disease, hypertension, diabetes, hyperlipidemia and other medical history, as well 
as high-risk factors such as smoking and alcohol history； 
3. Key time: including "onset time", "arrival time", "CTP time", "femoral artery puncture time", 
"DSA first imaging time", "endovascular treatment vascular recanalization time", "BGC adaptation 
first filling time "； 
4. Vital signs: including blood pressure, heart rate, temperature, and breathing； 
5. Laboratory tests: 
Red blood cell (RBC) count, white blood cell (WBC) count, neutrophil count, lymphocyte count, 
monocyte count, platelet (PLT) count, hemoglobin (Hb), creatinine（Cr）、Blood urea or urea nitrogen
（BUN）、blood glucose（Glu）；prothrombin time (PT), activated partial thromboplastin time 
(APTT), international normalized ratio (INR)； 
6. Thrombolysis information: including drug name, infusion dosage and time, and occurrence of 
adverse events； 
7. Imaging: multimodal CT (including cranial NCCT, CTP, CTA), if CTP can be used for cranial 
CTA reconstruction, CTA examination can be omitted; 
8. Postoperative imaging: MRI must be done within 72± 24 hours. NCCT is completed 24 ± 12 hour, 
and other times as needed. MRA/CTA is completed within the follow-up time point and only needs 

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2 BACKGROUND AND SIGNIFICANCE  
50 
Despite the well-established benefit of endovascular thrombectomy (EVT) in acute 
51 
ischemic stroke (AIS) with large vessel occlusion (LVO), over half of patients remain 
52 
functionally dependent at 90-day follow-up1-4. Efforts are increasing focus on 
53 
understanding the reasons for poor outcome and factors limiting the efficacy of EVT5. 
54 
Paradoxically, restoration of blood flow and reoxygenation can exacerbate tissue injury, 
55 
known as ‘reperfusion injury’6,7. This type of injury occurs immediately after blood 
56 
flow restoration and is a major contribution to neurologic deterioration8-10. Recent 
57 
clinical studies have confirmed that up to 37% of thrombectomy patients experience 
58 
infarct lesion growth despite successful vascular recanalization, which is significantly 
59 
associated with poor prognosis11.  
60 
Ischemic postconditioning conventionally refers to a series of brief blood vessel 
61 
occlusions and reperfusions, which may induce an endogenous neuroprotective effect 
62 
and reduce cerebral ischemia/reperfusion injury12. It has demonstrated that remote 
63 
ischemic postconditioning can improve 3‐month functional outcomes in patients with 
64 
moderate AIS13,14, but this finding was not confirmed by other reports15,16. The delay 
65 
of remote ischemic postconditioning initation after thrombolysis can’t protect from the 
66 
reperfusion injury. Rapid local ischemic postconditioning (RL-IPostC) , referring to the 
67 
intervention promptly initiated after the onset of reperfusion that directly modulates the 
68 
rapid augmentation of blood flow during reperfusion, may theoretically attenuate 
69 
reperfusion injury. Previous reports have demonstrated neuroprotective effects in 
70 
animal models of cerebral ischemia17-20, yet remain unproven in clinical practice. With 
71 
the widespread application of EVT for revascularization in LVO-AIS, RL-IPostC can 
72 
to be done once. 
9. Information on thrombectomy treatment, including but not limited to: anesthesia method, 
thrombectomy product information, reperfusion results after the first thrombectomy and final 
angiography, and the number of final mechanical thrombectomy； 
10. The mRS score of the selected group refers to the score before the onset of the disease. 
11. EQ-5D-5L：European Quality of Life Five Dimension Five Level Scale Questionnaire. 

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now be rapidly and conveniently implemented. Recent studies indicate that RL-IPostC 
73 
is feasible and well-tolerated in AIS patients undergoing EVT, suggesting it could be a 
74 
promising therapy to mitigate cerebral ischemia-reperfusion injury21-23. The most 
75 
effective ischemic postconditioning protocol, has yet to be identified.  
76 
3 STUDY OBJECTIVES  
77 
To determine the safety and efficacy of RL-IPostC on LVO-AIS of successful 
78 
thrombectomy, and the optimal dosage of RL-IPostC. 
79 
4 STUDY DESIGN AND MANAGEMENT OVERVIEW 
80 
4.1 Study design overview  
81 
The study is an investigator-initiated prospective, adaptive, multicenter clinical trial. It 
82 
employs the Bayesian Optimal Interval Phase I/II (BOIN12) trial design to assess the 
83 
safety and determine the optimal dosage of ischemic postconditioning intervention. The 
84 
BOIN12 design facilitates decisions regarding dosage escalation and de-escalation by 
85 
simultaneously taking account of toxicity and efficacy. It quantifies the desirability of 
86 
a dosage in terms of toxicity-efficacy trade-off. Within the BOIN12 framework, 
87 
patients are adaptively assigned to the most desirable dosage, balancing optimal toxicity 
88 
and efficacy. The rank-based desirability score (RDS) can be pre-tabulated before the 
89 
trial commences using the quasi-beta-binomial model24. In this trial, the following 
90 
toxicity-efficacy trade-off utilities are established for calculating the RDS: (No Toxicity, 
91 
Efficacy) = 100; (Toxicity, Efficacy) = 60; (No Toxicity, No Efficacy) = 40; (Toxicity, 
92 
No Efficacy) = 0. The RDS table will be detailed in statistical analysis plan. 
93 
Stopping criteria are implemented to prevent the allocation of patients to dosage that is 
94 
severely toxic or ineffective. BOIN12 utilizes two dosage-acceptability criteria to 
95 
determine which dosage may be administered. If the probability of a toxicity outcome 
96 
exceeding the upper limit of toxicity 0.15 is greater than 0.95, then dosage level and 
97 
higher are eliminated from the trial. Conversely, if the probability of an efficacy 
98 

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outcome falling below the lower limit of efficacy 0.60 is more than 0.90, then dosage 
99 
level is removed from consideration. The dosage that is both admissible and has the 
100 
highest estimated utility will be selected as the optimal dosage. 
101 
4.2 Blinding 
102 
Although the treatment medications are known to the patients and the treating 
103 
neurointerventionist, the study employs a blinded assessment. Investigators responsible 
104 
for follow-up neurological evaluations, as well as the independent Clinical Events 
105 
Committee (CEC), are kept unaware of treatment group assignment to maintain 
106 
objectivity. These assessors have no role in patient care.4.3 Study milestones 
107 
A 16-month budget and recruitment plan have been planned; the key study milestones 
108 
are shown in the table below. 
109 
STUDY MILESTONES 
 
Pre-enrollment study initiation  
2 months 
Recruitment and follow-up  
9 months 
Completion of follow-up  
3 months 
Data analysis and publication  
2 months 
Total duration 
16 months 
This schedule is preliminary and may be adjusted based on the progress of the study. 
110 
4.4 Site recruitment  
111 
Six National Comprehensive Stroke Centers will be designated as trial sites. Selection 
112 
will be based primarily on the following criteria: (1) prior experience in multicenter 
113 
clinical trials; (2) an annual volume of no fewer than 50 endovascular thrombectomy 
114 
procedures for AIS over the past three years; and (3) routine use of a balloon guide 
115 
catheter in these procedures. 
116 
4.5 Site training, certification, and updates.  
117 
All investigators are required to complete the following training modules and receive 
118 
certification: 
119 

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l 
Study procedures 
120 
l 
Primer on the diagnosis of ischemic stroke. 
121 
l 
Rapid-SAVE eligibility 
122 
l 
Modified Rankin Scale score 
123 
l 
NIHSS 
124 
Successful completion of the training program and approval from the local Institutional 
125 
Review Board (IRB) for human research will be required before a site can be certified 
126 
to enroll patients. Intermittent web-based meetings with the principal investigator and 
127 
key staff will be scheduled to address problems. A video of RL-IPostC conduction with 
128 
BGC is recorded for interventionist training, reviewed in detail in the training modules. 
129 
Case studies illustrating potential problems in adhering to the study protocol and 
130 
blinding will be discussed. This will serve as a guide for training clinical site personnel 
131 
and will be updated periodically throughout the study as needed. 
132 
An Executive Committee will be organized and periodically distribute a set of 
133 
frequently asked questions and answers to the participating centers. Any queries 
134 
regarding the study procedures during the study period will be addressed by the 
135 
executive committee through calls or messages through Wechat. 
136 
4.6 Outcomes   
137 
The safety outcomes within 7 days, which are categorized as dosage-limiting toxicities 
138 
(DLTs), including the following criteria: 1) Malignant MCA infarction, defined by a 
139 
midline shift of ≥5 mm at the level of septum pellucidum, anisocoria due to herniation, 
140 
or death resulting from herniation; 2) Complications associated with ischemic 
141 
postconditioning intervention that necessitate treatment, including distal vascular 
142 
embolism, local arterial dissection and vascular spasm at the intervention site of the 
143 
ICA; 3) Serious adverse events (SAEs) that are causally linked to the intervention.  
144 
The efficacy outcome is defined by the reduction in infarction growth, measured as an 
145 
infarction growth <10 mL from baseline to 72 hours post-intervention. Infarction 
146 
volume will be evaluated using automate software analysis, which assesses baseline 
147 

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CTP defined by relative cerebral blood flow (rCBF)＜30% and 72-hour diffusion-
148 
weighted imaging (DWI) or CT hypodensity volume.  
149 
5 PARTICIPANT SELECTION  
150 
All subjects will undergo a neurological and clinical assessment, routine laboratory 
151 
blood test and baseline brain imaging. All these materials will be collected and 
152 
screened by site physician. This includes standard of care use of non-contrast CT/ CT 
153 
angiography/ CT perfusion. In order to track the potential for enrollment, screening 
154 
log is required. Potential embolic LVO-AIS within 24 h of symptom onset ready for 
155 
thrombectomy will be screened and signed informed consent if patients meet the 
156 
inclusion and exclusion criteria except the item 9 and 10 of inclusion criteria. Before 
157 
patient enrollment, all collaborating centers will obtain approval from the local IRBs 
158 
or ethics committees which have access to all trial documents. 
159 
5.1 Inclusion and exclusion criteria  
160 
Inclusion Criteria: 
161 
① Age ≥ 18 years 
162 
② Presenting with symptoms consistent with acute anterior circulation ischemic 
163 
stroke 
164 
③ Pre-stroke modified Rankin Score 0-1 
165 
④ Baseline National Institute of Health Stroke Scale (NIHSS) score≥6 
166 
⑤ Endovascular treatment can be initiated (femoral puncture) within 24 hours 
167 
from stroke onset (stroke onset time is defined as last known well time) 
168 
⑥ Occlusion of the intracranial internal carotid artery, or the middle cerebral 
169 
artery (MCA) (M1 or M2) and is the culprit artery 
170 

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⑦ Ischemic core volume is < 70 ml, mismatch ratio >1.8 and mismatch volume 
171 
is >15 ml as determined by CT perfusion imaging 
172 
⑧ Embolism verified as the etiology of occluded artery 
173 
⑨ Modified Thrombolysis in Cerebral Infarction Score (mTICI) of 2b or 3 
174 
achieved after endovascular thrombectomy. 
175 
⑩ Time from CT perfusion to successful reperfusion < 2 hours 
176 
⑪ Informed consent signed 
177 
Exclusion Criteria: 
178 
① Stenosis (≥50%) of the proximal MCA, internal carotid artery (ICA), or 
179 
common carotid artery (CCA) of the culprit artery 
180 
② Presence of an ICA lesion that prevent the use of a balloon guide catheter 
181 
③ Multiple vascular embolisms on different pathways (e.g., bilateral MCA 
182 
occlusions, or an MCA and a basilar artery occlusion) 
183 
④ Previous ischemic stroke within the past 3 months 
184 
⑤ Expected survival time of less than 6 months, precluding follow-up at 90 days 
185 
(e.g., patient with malignant tumor) 
186 
⑥ Currently pregnant, mental disease, advanced hepatic or renal insufficiency, 
187 
severe heart failure 
188 
⑦ Participation in other clinical trials that may confound the outcome 
189 
assessment of this trial 
190 
⑧ Any other circumstances deemed inappropriate by the investigator for 
191 
inclusion in this trial 
192 

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5.2 Criteria for removal  
193 
Patients shall be withdrawn from the study after enrollment if either of the following 
194 
protocol deviations occurs: (1) the RL-IPostC procedure is not initiated within 5 
195 
minutes after recanalization, or (2) the procedure is not completed as per the required 
196 
dosage. However, termination of RL-IPostC due to patient intolerance will not 
197 
warrant withdrawal; such cases must be adjudicated by the Clinical Events Committee 
198 
(CEC) to determine if they constitute an RL-IPostC-related adverse event. All 
199 
withdrawal cases will be documented in the case report form (CRF) and preserved for 
200 
audit. Withdrawn patients will be excluded from the efficacy analysis. 
201 
5.3 Criteria for drop out  
202 
All patients enrolled in the trial will be retained until the completion of the follow-
203 
up. Subjects may request the withdrawal of informed consent and withdrawal from 
204 
this study at any time without any reason, and their medical rights will not be affected. 
205 
The investigator may also consider it medically necessary for the subject to 
206 
discontinue the study. For subjects who withdraw from the study, their reason for 
207 
withdrawal will be recorded, and the mRS score will be completed as far as possible 
208 
before withdrawal. 
209 
5.4 Criteria for discontinuation of clinical studies  
210 
This study will provide an optimal balance between safety and efficacy according to 
211 
pre-designed acceptable criteria, and the dosage will be abandoned or stopped once 
212 
unacceptable safety and efficacy criteria are met. 
213 
6 TREATMENTS  
214 
RL-IPostC procedure is administered immediately (within 5 minutes) following 
215 
revascularization. A balloon guiding catheter (BGC) is positioned at the ipsilateral C1 
216 
segment of ICA and is inflated and deflated to temporary stop antegrade blood flow. 
217 
This study examines six dosages levels, with the initial dosage set at Dosage 
218 
3(2min/2min, 4 cycles). The dosing schedule is as follows:  
219 

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① Dosage 1 (RL-IPostC 15/15, 5cycles): The intervention dosage consist of 15 
220 
seconds of occlusion followed by 15 seconds of reperfusion, repeated for 5 cycles.   
221 
② Dosage 2 (RL-IPostC 60/60, 4 cycles): The intervention dosage consist of 60 
222 
seconds of occlusion followed by 60 seconds of reperfusion, repeated for 4 cycles.   
223 
③ Dosage 3 (RL-IPostC 120/120, 4 cycles): The intervention dosage consist of 120 
224 
seconds of occlusion followed by 120 seconds of reperfusion, repeated for 4 cycles.   
225 
④ Dosage 4 (RL-IPostC 180/180, 4 cycles): The intervention dosage consist of 180 
226 
seconds of occlusion followed by 180 seconds of reperfusion, repeated for 4 cycles.   
227 
⑤ Dosage 5 (RL-IPostC 240/240, 4 cycles): The intervention dosage consist of 240 
228 
seconds of occlusion followed by 240 seconds of reperfusion, repeated for 4 cycles.   
229 
⑥ Dosage 6 (RL-IPostC 300/300, 4 cycles): The intervention dosage consisted of 300 
230 
seconds of occlusion followed by 300 seconds of reperfusion, repeated for 4 cycles. 
231 
7 SAFETY  
232 
7.1 Adverse events and management of SAEs  
233 
All adverse events occurring during the trial must be truthfully recorded in the adverse 
234 
event table. The investigator should give targeted treatment and follow-up for adverse 
235 
events until symptoms disappear or symptoms stabilize. In cases of serious adverse 
236 
events, the investigator should take necessary treatment measures immediately to 
237 
protect the safety of the subject when informed of the case.  
238 
7.2 Definitions of adverse events and severe adverse events 
239 
Adverse events: Any adverse medical occurrence from the time the subject signed the 
240 
informed consent form to the last follow-up visit, regardless of whether there is a causal 
241 
relationship with the trial treatment, is considered an adverse event. Adverse events that 
242 
may occur during mechanical thrombectomy procedures usually include, but are not 
243 
limited to: (1) Allergic reactions, (2) Puncture point bleeding, (3) Thromboembolic 
244 
events, (4) Cerebral vasospasm, (5) Acute occlusion Possible causes, (6) Thrombosis 
245 
and plaque shedding, (7) Blood vessel rupture, (8) Cerebral hyperperfusion syndrome. 
246 

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Serious adverse events: Events requiring hospitalization, prolonged hospitalization, 
247 
disability, affecting work capacity, endangering life or death, and causing congenital 
248 
malformations during clinical trials. The following hospitalizations are not considered 
249 
SAEs: Elective surgery already planned before signing the informed consent form; 
250 
routine physical examination; hospitalization due to medical procedures not planned by 
251 
the protocol; Elective admission to the hospital for stent implantation; Continued 
252 
hospitalization for the purpose of neurorehabilitation therapy only.  
253 
7.3 Relationship to study treatment  
254 
RL-IPostC operation related adverse events are judged by CEC, including but not 
255 
limited to distal vascular embolization within the territory, local arterial dissection, local 
256 
vasospasm of the internal carotid artery requiring treatment, and large infarction growth 
257 
due to delayed reperfusion. Treatment measures: Once the distal blood vessel embolism 
258 
is blocked, antiplatelet drugs should be used immediately, thrombectomy should be 
259 
performed if necessary, local arterial dissection should be observed in light cases, and 
260 
stent implantation should be performed in severe cases. 
261 
7.4 AE Reporting  
262 
Once an adverse event (including serious adverse events) occurs, the time of occurrence 
263 
of the adverse event, clinical manifestations, treatment process and duration, outcome 
264 
and relationship with the drug should be recorded in detail on the case report form. If 
265 
there are abnormal laboratory tests, the patient must be followed until the test results 
266 
return to normal. Serious adverse events should be completed and reported to the 
267 
investigator, the Ethics Committee (EC)within 24 hours after being notified. 
268 
The CEC consists of three experts, two neurointerventionists and a neurologist. The 
269 
committee will assess all complications that occur during the course of the study and 
270 
classify the severity and relevance according to the definitions in the Adverse Events 
271 
(AEs) section. The CEC may request any relevant images and information required for 
272 
the AE determination. 
273 

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8 STATISTICAL CONSIDERATIONS  
274 
8.1 Sample size estimates  
275 
This maximum sample size of 60 and 12 cohorts, with a sample size of 5 for each cohort. 
276 
8.2 Statistical analysis plans  
277 
Details in supplementary material of statistical analysis plans (SAP). 
278 
8.3 Data safety monitoring plan  
279 
The independent Data and Safety Monitoring Board (DSMB) is composed of 
280 
experienced two neurologists and one biostatistician who are neither directly involved 
281 
in the study. The DSMB meets before the study initiation and during the study as 
282 
required to reviews structured open-ended reports provided by research statisticians. 
283 
The DSMB is responsible for making recommendations to the Executive Committee on 
284 
the dosage escalation and deescalation, cessation or continuation of the study. In 
285 
addition, the DSMB will review the occurrence of SAEs and make recommendations 
286 
on the safety of the trial to continue, stop, or modify the study protocol. 
287 
9 ETHICAL AND REGULATORY STANDARDS  
288 
9.1 Ethical considerations  
289 
This clinical study must be conducted in accordance with the requirements of the 
290 
Declaration of Helsinki and other relevant regulations. Before the study begins, the 
291 
study protocol and informed consent form (ICF) and other documents must be approved 
292 
by the Ethics Committee of the research center before the study can be conducted. 
293 
Before each subject is selected for this study, the investigator should first give him or 
294 
his legal representative a complete and comprehensive introduction to the purpose, 
295 
procedures and possible risks of this study, and should let them know that they have the 
296 
right to withdraw from this study at any time. The ICF shall then be signed by the 
297 
subject or his/her legal representative and the investigator, and the signed ICF shall be 
298 
kept as a clinical study document for future reference. Before the start of the clinical 
299 
study, the investigator is required to submit the clinical study protocol, ICF and other 
300 

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relevant documents to the Ethics Committee. Clinical studies can only be started after 
301 
approval by the ethics committee. Any modifications to the study protocol must be 
302 
approved by the Ethics Committee before implementation. SAEs that occur during the 
303 
course of the clinical study should be reported in writing to the Ethics Committee within 
304 
24 hours of being informed by the investigator. The ethics committee of other clinical 
305 
research centers participating in the study may review the feasibility of the study in the 
306 
clinical research center by means of meeting review or document review, including the 
307 
qualifications and experience of the investigator, equipment and conditions, etc., on the 
308 
premise of accepting the review opinions of the ethics committee of the lead unit. The 
309 
Ethics Committee will follow up and supervise the clinical research of the clinical 
310 
research center, and may request the suspension or termination of the clinical study at 
311 
any time in writing if it finds that the rights and interests of the subjects cannot be 
312 
protected. Suspended clinical studies may not be resumed without the consent of the 
313 
Ethics Committee. If SAE occurs in clinical research, the investigator should 
314 
immediately take appropriate treatment measures for the subject and report in writing 
315 
to the ethics committee of the clinical research center. 
316 
9.2 Informed consent  
317 
The investigator must provide the subject or his/her legal representative with an easy-
318 
to-understand informed consent form approved by the ethics committee and give the 
319 
subject or his/her legal representative sufficient time to consider this study, and the 
320 
subject shall not be enrolled until a signed written informed consent form is obtained 
321 
from the subject. Subjects will be provided with all updated versions of informed 
322 
consent along with written information during subject participation. Informed consent 
323 
should be kept as an important document for clinical trials. 
324 
10 STUDY MONITORING  
325 
10.1 Site monitoring  
326 
During this study, a contract research organization (CRO) will organize and manage the 
327 

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project, and a clinical monitor will be assigned to conduct regular on-site monitoring of 
328 
the site, and the monitor should be allowed to evaluate data quality and study integrity. 
329 
The ombudsman is responsible for cross-checking clinical study records with the 
330 
subject's original medical records and working with the investigator to address any 
331 
issues that arise during the trial. During the entire study period, the inspector was 
332 
responsible for regularly checking the case report form (CRF), verifying the 
333 
implementation and completion of the program, and ensuring the consistency and 
334 
accuracy of the data filled in the form. The inspector can obtain the required laboratory 
335 
test reports and medical records to verify the entry of pathology report forms. 
336 
10.2 Data collection  
337 
This study uses an electronic data capture (EDC) system to collect data, and the 
338 
investigator should record all the data of each subject in the trial. Data will be entered 
339 
into the electronic Case Report Form (eCRF) by the investigator or authorized clinical 
340 
research site staff. Investigators and authorized clinical site staff will be properly trained 
341 
and appropriate information security measures will be taken before clinical research 
342 
site initiation or data entry. The investigator is responsible for maintaining all original 
343 
documents and ensuring that they are monitored by a Clinical Research Associate (CRA) 
344 
at each visit. In addition, the investigator is required to submit a complete eCRF for 
345 
each participant enrolled in the study, regardless of the duration of the study. Study 
346 
numbers and subject numbers submitted with the eCRF should be carefully verified and 
347 
all personal privacy information (including subject names) should be deleted or made 
348 
illegible to protect subject privacy.  
349 
10.3 Data management and quality control  
350 
In order to ensure the truthfulness, accuracy and reliability of clinical trial data and 
351 
improve the quality of clinical data, the clinical monitor will review the completeness, 
352 
consistency and accuracy of the trial data in accordance with the standard operating 
353 
procedures during the trial project, and guide the personnel of the research institution 
354 
to supplement and correct the problem data as necessary. The data manager writes a 
355 

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program to check the data logically, including missing data, duplicate data, outliers, etc. 
356 
The Clinical Ombudsman or Data Controller will raise the challenge in the form of an 
357 
electronic challenge form, and the investigator or clinical research coordinator (CRC) 
358 
must respond to the question and make corrections or explanations to the problem data, 
359 
and if necessary, issue the challenge multiple times until the problem data is resolved.  
360 
After cleaning, review and confirmation of data accuracy, the data will be locked and 
361 
the locked data file will not be changed unless there are special circumstances. 
362 
11 PUBLICATIONS POLICY  
363 
The RAPID-SAVE study protocol and all related data and materials are confidential 
364 
and are provided only to the investigator for the purpose of completing this study, and 
365 
no content of this study protocol may be disclosed or disclosed to a third party without 
366 
the prior written consent of the principal investigator. The RAPID-SAVE may provide 
367 
data to other clinical investigators or government regulators as needed. All site 
368 
investigators are obliged to provide the Steering Committee (SC)with all complete data 
369 
collected during this study. At the end of the study, a writing committee will be 
370 
established to review and publish the research data. The committee will consist of 
371 
steering committee members and a subset of researchers. The writing committee will 
372 
write/review abstracts and full-text manuscripts and select appropriate journals or 
373 
conferences for publication. The RAPID-SAVE steering committee commits that data 
374 
from the study will be published regardless of the study results and that the trial will be 
375 
published on the clinical trial registry website. 
376 
 
377 
Appendix 1 - Modified Rankin Scale25 
378 
Grade 
Description 
0 
No symptoms at all 
1 
No significant disability despite symptoms: able to carry out all usual 
duties and activities 

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2 
Slight disability：unable to carry out all previous activities but able to 
look after own affairs without assistance 
3 
Moderate disability ：require some help, but able to walk without 
assistance 
4 
Moderate severe disability：unable to walk without assistance, and unable 
to attend to own bodily needs without assistance 
5 
Severe disability：bedridden, incontinent, and require constant nursing 
care and attention 
6 
Death 
 
379 
Appendix 2 -mTICI26 
380 
Grade 
Description 
0 
No perfusion 
1 
Antegrade reperfusion past the initial occlusion, but limited distal branch 
filling with little or slow distal reperfusion 
2a 
Antegrade reperfusion of less than half of the occluded target artery 
previously ischemic territory (eg, in 1 major division of the MCA and its 
territory) 
2b 
Antegrade reperfusion of more than half of the previously occluded target 
artery ischemic territory (eg, in 2 major divisions of the MCA and their 
territories) 
3 
Complete antegrade reperfusion of the previously occluded target artery 
ischemic territory, with absence of visualized occlusion in all distal 
branches 
 
381 

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382 
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