Effect of Endovascular Treatment Alone Vs Intravenous

Research

JAMA | Original Investigation Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus Endovascular Treatment on Functional Independence in Patients With Acute Ischemic Stroke The DEVT Randomized Clinical Trial

Wenjie Zi, MD; Zhongming Qiu, MD; Fengli Li, MD; Hongfei Sang, MD; Deping Wu, MD; Weidong Luo, MD; Shuai Liu, MD; Junjie Yuan, MD; Jiaxing Song, MD; Zhonghua Shi, MD; Wenguo Huang, MD; Min Zhang, MS; Wenhua Liu, MD; Zhangbao Guo, MS; Tao Qiu, MD; Qiang Shi, MS; Peiyang Zhou, MD; Li Wang, MD; Xinmin Fu, MD; Shudong Liu, MD; Shiquan Yang, MD; Shuai Zhang, MD; Zhiming Zhou, MD; Xianjun Huang, MD; Yan Wang, MD; Jun Luo, MS; Yongjie Bai, MD; Min Zhang, MS; Youlin Wu, MS; Guoyong Zeng, MD; Yue Wan, MD; Changming Wen, MD; Hongbin Wen, MD; Wentong Ling, MS; Zhuo Chen, MS; Miao Peng, MS; Zhibing Ai, MD; Fuqiang Guo, MD; Huagang Li, MD; Jing Guo, MS; Haitao Guan, MD; Zhiyi Wang, MS; Yong Liu, MS; Jie Pu, MD; Zhen Wang, MD; Hansheng Liu, MD; Luming Chen, MD; Jiacheng Huang, MD; Guoqiang Yang, MD; Zili Gong, MD; Jie Shuai, MD; Raul G. Nogueira, MD; Qingwu Yang, MD, PhD; for the DEVT Trial Investigators

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IMPORTANCE For patients with large vessel occlusion strokes, it is unknown whether Editorial page 229 endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment (standard treatment) can achieve similar functional outcomes. Related article page 244 Supplemental content OBJECTIVE To investigate whether endovascular thrombectomy alone is noninferior to intravenous alteplase followed by endovascular thrombectomy for achieving functional CME Quiz at independence at 90 days among patients with large vessel occlusion stroke. jamacmelookup.com

DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, noninferiority trial conducted at 33 stroke centers in China. Patients (n = 234) were 18 years or older with proximal anterior circulation intracranial occlusion strokes within 4.5 hours from symptoms onset and eligible for intravenous thrombolysis. Enrollment took place from May 20, 2018, to May 2, 2020. Patients were enrolled and followed up for 90 days (final follow-up was July 22, 2020).

INTERVENTIONS A total of 116 patients were randomized to the endovascular thrombectomy alone group and 118 patients to combined intravenous thrombolysis and endovascular thrombectomy group.

MAIN OUTCOMES AND MEASURES The primary end point was the proportion of patients achieving functional independence at 90 days (defined as score 0-2 on the modified Rankin Scale; range, 0 [no symptoms] to 6 [death]). The noninferiority margin was −10%. Safety outcomes included the incidence of symptomatic intracerebral hemorrhage within 48 hours and 90-day mortality.

RESULTS The trial was stopped early because of efficacy when 234 of a planned 970 patients had undergone randomization. All 234 patients who were randomized (mean age, 68 years; 102 women [43.6%]) completed the trial. At the 90-day follow-up, 63 patients (54.3%) in the endovascular thrombectomy alone group vs 55 (46.6%) in the combined treatment group Author Affiliations: Author affiliations are listed at the end of this achieved functional independence at the 90-day follow-up (difference, 7.7%, 1-sided 97.5% article. CI, −5.1% to ϱ)P for noninferiority = .003). No significant between-group differences were Group Information: The DEVT Trial detected in symptomatic intracerebral hemorrhage (6.1% vs 6.8%; difference, −0.8%; 95% Investigators appear in Supplement 1. CI, −7.1% to 5.6%) and 90-day mortality (17.2% vs 17.8%; difference, −0.5%; 95% CI, −10.3% Corresponding Authors: Qingwu to 9.2%). Yang, MD, PhD, Department of Neurology, Xinqiao Hospital and The CONCLUSIONS AND RELEVANCE Among patients with ischemic stroke due to proximal anterior Second Affiliated Hospital, Army circulation occlusion within 4.5 hours from onset, endovascular treatment alone, compared Medical University (Third Military with intravenous alteplase plus endovascular treatment, met the prespecified statistical Medical University), No. 183 Xinqiao Main St, Shapingba District, threshold for noninferiority for the outcome of 90-day functional independence. These Chongqing 400037, China findings should be interpreted in the context of the clinical acceptability of the selected ([email protected]); Raul G. noninferiority threshold. Nogueira, MD, Department of Neurology, Marcus Stroke & TRIAL REGISTRATION Chinese Clinical Trial Registry: ChiCTR-IOR-17013568 Neuroscience Center, Grady Memorial Hospital, Emory University School of Medicine, 80 Jesse Hill Jr Dr SE, Room 8D108A, Atlanta, GA JAMA. 2021;325(3):234-243. doi:10.1001/jama.2020.23523 30303 ([email protected]).

234 (Reprinted) jama.com

© 2021 American Medical Association. All rights reserved. Effect of Endovascular Treatment With vs Without IV Alteplase on Functional Independence After Acute Ischemic Stroke Original Investigation Research

even randomized clinical trials have consistently demonstrated that patients with a large vessel occlusion in Key Points the anterior circulation benefit from endovascular treat- S Question Among patients with ischemic stroke secondary to large 1-7 ment following intravenous thrombolysis (IVT). However, vessel occlusion and eligible for thrombolysis, is endovascular IVT prior to endovascular treatment has potential benefits and treatment alone noninferior to intravenous alteplase plus risks. Intravenous thrombolysis may sometimes contribute to endovascular treatment with regard to functional independence? reperfusion, averting the need for endovascular treatment.5 Findings In this randomized clinical trial that included 234 Intravenous thrombolysis may facilitate endovascular reper- patients with acute ischemic stroke, the proportion who achieved fusion and promote dissolution of downstream microemboli functional independence at 90 days was 54.3% in the improving distal perfusion.8,9 Conversely, IVT may increase the endovascular treatment alone group vs 46.6% in the intravenous risk of intracranial or systemic hemorrhage, lead to thrombus alteplase plus endovascular treatment group, a difference that met fragmentation and worsening distal perfusion, and delay the the prespecified noninferiority margin of 10%. start of the endovascular treatment.10,11 Furthermore, IVT lim- Meaning Among patients with acute ischemic stroke due to its the use of antithrombotic therapy within 24-hour, and in- large vessel occlusion and eligible for thrombolysis, endovascular creases health care costs.12 treatment alone, compared with intravenous alteplase plus The recently reported randomized clinical trial of Endo- endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional vascular Thrombectomy With or without Intravenous Alteplase independence, although the clinical acceptability of the threshold in Acute Stroke (DIRECT-MT) showed that endovascular throm- for noninferiority should be considered when interpreting 13 bectomy alone was noninferior to thrombectomy after IVT. the results. Similar effect directions were seen in the SKIP trial,14 although this study was underpowered and, as such, was unable to demonstrate significance for noninferiority. The aim of the Direct Endovascular Thrombectomy vs Combined IVT Study candidates were 18 years or older with acute ische- and Endovascular Thrombectomy for Patients With Acute Large mic stroke, eligible for IV alteplase treatment within 4.5 Vessel Occlusion in the Anterior Circulation (DEVT) trial was hours of onset, and had occlusion of the intracranial internal to test the hypothesis that endovascular thrombectomy alone carotid artery or the first segment of the middle cerebral was noninferior to combined IVT and endovascular throm- artery confirmed by computed tomographic (CT) angiogra- bectomy in patients with proximal anterior circulation occlu- phy or magnetic resonance (MR) angiography. Time of stroke sions treated within 4.5 hours of onset. onset was defined as when the patient was last known to be well. Randomization was performed no later than 4 hours 15 minutes from onset (Figure 1). The main exclusion criteria Methods were imaging evidence of intracranial hemorrhage and pre- morbidity with a modified Rankin Scale score of 2 or more Trial Design and Oversight (mRS; range, 0 [no symptoms] to 6 [death]). Additional This trial was a multicenter, randomized, open-label, clinical trial detailed study criteria are provided in eMethods 1 in Supple- with blinded central evaluation of outcomes in patients with ment 4. Central blinded readers assigned a collateral score stroke. The trial protocol was approved by medical ethics com- using the 5-point American Society of Interventional and mittee of the Second Affiliated Hospital of the Army Medical Uni- Therapeutic Neuroradiology/Society of Interventional Radi- versity and all participating centers. Written informed consent ology (ASITN/SIR) collateral flow grading scale (range, 0 [no was obtained from all enrolled patients or their legal represen- collaterals visible] to 4 [complete or rapid collaterals to entire tatives before randomization. The trial protocol is available in ischemic territory]). Supplement 2, the statistical analysis plan, in Supplement 3. The trial was monitored by an independent data and safety Randomization and Masking monitoring board. An independent clinical events committee Patients were randomized in a 1:1 ratio to either the endovas- validated adverse events, procedural-related complications, cular thrombectomy alone group or combined IV thromboly- and serious adverse events. All images were assessed in a sis and endovascular thrombectomy group. The randomiza- blinded manner by a core laboratory. The methods of this trial tion procedure was web-based, and competitive recruitment have been published previously.15 eFigure 1 in Supplement 4 was applied in this trial. Randomization allocations were cre- shows planned trial assessments and interventions. ated by an independent statistician with the use of SAS version 9.3 (SAS Institute Inc) to keep the study group blind. Four- Participating Centers and Patients block randomization was used. Personnel conducting clinical The study was conducted at 33 stroke centers in China. To examinations were qualified assessors who had not partici- qualify for participation, each center had to perform more than pated in the study procedures. 50 mechanical thrombectomies annually and each neurointerventionist, at least 10 thrombectomies per year. To ensure Intervention the quality of the trial, training of study protocol and endo- Patients in both groups received rapid endovascular treat- vascular treatment technique was held every 6 months in ment. In the endovascular thrombectomy alone group, Chongqing (eMethods 4 in Supplement 4). patients underwent endovascular treatment only, which jama.com (Reprinted) JAMA January 19, 2021 Volume 325, Number 3 235

© 2021 American Medical Association. All rights reserved. Research Original Investigation Effect of Endovascular Treatment With vs Without IV Alteplase on Functional Independence After Acute Ischemic Stroke

Figure 1. Eligibility, Randomization, and Follow-up of Patients Through the DEVT Randomized Clinical Trial of Intravenous Alteplase in Patients With Acute Ischemic Stroke

509 Adults with acute ischemic stroke were assessed for eligibility

274 Excluded 223 Did not meet inclusion criteria 133 Occlusion site 64 Contraindication to IV rt-PA 17 ≥4.5 h from stroke onset 4 IV delivered outside the hospital 2 Prestroke Rankin Scale score ≥2 1 Intracranial hemorrhage 1 Recent cardiac surgery 1 Advanced cancer 51 Declined participation

235 Randomized

117 Randomized to receive endovasculary 118 Randomized to receive combined IV and thrombectomy alone endovasculary thrombectomy 114 Underwent procedure as randomized 115 Underwent procedure and received 3 Did not receive treatment as IV as randomized randomizeda 3 Did not receive treatment as randomizedb

116 Included in the primary analysis 118 Included in the primary analysis 20 Died <90 d 21 Died <90 d 96 Evaluated at 90-d follow-upc 97 Evaluated at 90-d follow-upd 1 Not included (withdrew)

a One patient had expanded Thrombolysis in Cerebral Infarction (eTICI) 3 on d Of the survivors, 95 had video recording, 2 had voice recording, the first intracranial angiography; the other, eTICI 2c on first intracranial 0 outcomes determined by local investigators blinded to the treatment angiography. One patient withdrew immediately after randomization. assignments. b One patient had eTICI 2c on first intracranial angiography; 2 had eTICI 2b on DEVT indicates Direct Endovascular Thrombectomy vs Combined IV first intracranial angiography. Thrombolysis and Endovascular Thrombectomy for Patients With Acute Large c Of the survivors, 91 had video recording, 4 had voice recording, 1 outcome Vessel Occlusion in the Anterior Circulation Trial; IV indicates intravenous; determined by local investigators blinded to the treatment assignments rt-PA, recombinant tissue type plasminogen activator. because video or voice recording was unavailable.

included thrombectomy with stent retrievers, thromboaspi- ments. Disagreements were resolved through consensus ration, intraarterial thrombolysis, balloon angioplasty, stent- (eMethods 3 in Supplement 4). ing, or a combination of these approaches at the discretion of Secondary outcomes included the distribution of 90-day the treatment team. mRS scores and the rates of excellent functional outcome Patients in the combined treatment group underwent the (mRS score, 0-1), successful reperfusion on postprocedural endovascular procedure after receiving a standard dose of angiography ( grade 2b-3 on the expanded Thrombolysis in IV alteplase (0.9 mg/kg of body weight; 10% administered as Cerebral Infarction [eTICI] scale , indicating reperfusion of a bolus followed by 1-hour infusion of the remaining dose). ≥50% of the affected territory),16 vessel reperfusion on CT or Endovascular treatment was initiated as soon as possible with- MR angiography within 48 hours after treatment (successful out waiting for clinical response from IV alteplase. The full recanalization was defined by a core laboratory–adjudicated alteplase dose was infused even if successful reperfusion had modified Arterial Occlusive Lesion score of 2 or 3 on CT or already been established. MR angiography, indicating partial or complete recanalization of the occluded artery), the change of the National Insti- Outcome and Safety Measures tutes of Health Stroke Scale (NIHSS) score (range, 0 to 42, The primary outcome was the proportion of patients achiev- with higher values indicating more severe deficit) from base- ing functional independence (mRS score, 0-2) at 90 days line to 24 hours and 5 to 7 days (or discharge if earlier), and (+/− 14 days), with central evaluation by 2 blinded indepen- score of European Quality of Life 5-Dimension 5-level scale dent mRS-certified neurologists based on video or voice re- (EQ-5D-5L; range, −0.39 to 1, higher scores indicate a better cordings taken at the outpatient clinic, during a telephone or quality of life) at 90 days. The NIHSS assessment was based video call, or by the patient’s family. If video or voice record- on central evaluation through video recording or, if recording ings were unavailable, the outcomes were determined in per- was unavailable, by blinded local investigators. A post hoc son by local investigators blinded to the treatment assign- analysis evaluated the rates of successful reperfusion before

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endovascular treatment (defined as an eTICI score of 2b, 2c, ment group were reported as 90-day binary deaths. The post or 3 on the initial intracranial angiogram). hoc hierarchical modeling and sensitivity analyses were per- Adverse events, including incidence of symptomatic formed to assess site effects. intracranial hemorrhage within 48 hours, 90-day mortality, The missing values of baseline variables were imputed procedure-associated complications, and serious adverse with multiple imputation. Subgroup analyses were con- events, were adjudicated by an independent clinical events ducted for the primary effect variable, and the Wald χ2 test committee unaware of treatment assignment. Assessment of was used to test the interaction. All enrolled patients were intracranial hemorrhage was based on the Heidelberg analyzed according to their randomization group. Patients classification.17 A post hoc analysis investigated the rates of who actually received the assigned treatment and did not asymptomatic and symptomatic intracranial hemorrhage have major protocol violations were included in the per- using the European Cooperative Acute Stroke Study III protocol analysis. The rates of successful reperfusion before (ECASS III), ECASS II, the Safe Implementation of Thromboly- endovascular treatment was analyzed post hoc. All statistical sis in Stroke–Monitoring Study (SITS-MOST), and the tests were 2-sided with a significance level at .05 unless oth- National Institute of Neurological Disorders and Stroke erwise noted. Because of the potential for type I error due to (NINDS) definitions. multiple comparisons, findings for analyses of secondary end points should be interpreted as exploratory. Statistical analy- Statistical Analysis ses were performed using SAS version 9.4. Figures were The primary hypothesis was that the rate of 90-day func- drawn using Excel software 2019 (Microsoft). tional independence with endovascular treatment alone would be noninferior to IV alteplase plus endovascular treat- Trial Termination ment, the primary aim of the statistical analysis. Sample size The first interim analysis was performed as planned after 194 calculation was made assuming that 43% of patients in both patients (20% of the maximum sample size) had completed groups would achieve functional independence at the 90-day their 90-day follow-up on May 12, 2020. The proportion of follow-up according to previous studies.18-20 Among the patients achieving functional independence for the endovas- recent high-quality randomized clinical trials, the endovascular thrombectomy alone group (54.64%) exceeded that of cular group in the Multicenter Randomized Clinical Trial of the combined treatment group (47.42%) by 7.2% (1-sided Endovascular Treatment for Acute Ischemic Stroke in the 97.5% CI, −6.8% to ϱ). The noninferiority test demonstrated Netherlands (MR CLEAN)6 trial had the lowest proportion that endovascular thrombectomy alone was noninferior to (about 33%) of 90-day functional independence. We combined treatment (z = 2.4042, P for noninferiority = .008). assumed that the proportion of patients achieving 90-day Because this crossed the prespecified efficacy boundary functional independence of the endovascular thrombectomy (z = 2.35826, P for noninferiority = .009) that was prespeci- alone group could not be lower than 33%. Therefore, the non- fied for early termination, the steering committee accepted inferiority margin was set at −10.0% as the clinically relevant the recommendation from the data and safety monitoring limit for the outside bound of the CI. board of concluding the trial on May 14, 2020 (eMethods 2 A sample size of 918 patients (459 patients per group) and eFigure 2 in Supplement 4). would provide 80% statistical power to show noninferiority of endovascular thrombectomy alone group compared with combined treatment group including a 5-interim group- Results sequential analysis plan, using a 1-sided significance level of .025 and a noninferiority margin of 10% of the functional Patients and Baseline Characteristics independence proportion in the combined treatment From May 20, 2018, to May 2, 2020, a total of 509 patients group. To adjust for a 5% attrition rate, the total sample across 33 stroke centers in China were screened. Among size increased to 970. The evaluable sample size was 194 them, 235 qualified and were randomly enrolled in the trial. at each interim analysis (97 patients in each group). The One patient enrolled into the endovascular thrombectomy termination rule for efficacy was defined by using the alone group could not be included in the analysis because the Pocock analog boundaries on the binary outcome of func- legal representative withdrew consent immediately after ran- tional independence.21 domization. The median age of the 234 patients was 70 years The primary outcome was analyzed using a noninferior- (interquartile range [IQR], 60-78 years); 132 patients (56.4%) ity test for the difference of 2 proportions. The adjusted odds were men. Of 234 patients, 116 were randomized to the endo- ratio was estimated using a logistic regression model by tak- vascular thrombectomy alone group and 118 to combined ing the following variables into account: age, baseline NIHSS treatment group. No crossovers occurred, and no one was score, baseline Alberta Stroke Program Early Computed lost to the 90-day follow-up. Baseline characteristics were Tomography Score (ASPECTS), onset to randomization time, similar in both groups (Table 1;eTable1inSupplement 4). and occlusion site. Secondary outcomes were analyzed using The distribution of participating centers is illustrated on the a logistic, ordinal logistic, or linear regression model as map of China (eFigure 3), another map shows the number of appropriate. The Kaplan-Meier method was used to assess patients recruited at each center (eFigure 4), and the third the mortality. The log-rank test was applied to compare the 2 map shows the enrollment and follow-up of patients (eFig- treatment groups. Moreover, the death data of each treat- ure5inSupplement 4). jama.com (Reprinted) JAMA January 19, 2021 Volume 325, Number 3 237

Table 1. Baseline Characteristics and Workflow Measures

No. (%) of patients Combined IV thrombolysis Abbreviations: ASPECTS, Alberta Endovascular and endovascular Stroke Program Early Computed thrombectomy alone thrombectomy (n = 116) (n = 118) Tomography Score; CT, computed tomography; IQR, interquartile range; Demographic characteristics IV, intravenous; MR, magnetic Age, median (IQR), y 70 (60-77) 70 (60-78) resonance; NA, not applicable; Sex NIHSS, National Institutes of Health Stroke Scale. Men 66 (56.9) 66 (55.9) SI conversion factor: Toconvert glucose Women 50 (43.1) 52 (44.1) frommmol/Ltomg/dL,divideby0.0555. a Medical history a Patient self-report or family report. Hypertension 69 (59.5) 74 (62.7) b Included self-reported coronary Atrial fibrillation 62 (53.5) 62 (52.5) artery bypass grafting surgery, angina Coronary heart diseaseb 30 (25.9) 19 (16.1) pectoris (confirmed by angiogram), angioplasty, or coronary artery c Smoking 28 (24.1) 29 (24.6) stents, besides myocardial infarction. Diabetes 25 (21.6) 20 (17.0) c Current or within the prior 5 years. Hyperlipidemia 18 (15.5) 22 (18.6) d See the Methods section for Ischemic stroke 14 (12.1) 19 (16.1) functional disability ranges. A score of 2 or less indicates functional Prestroke score on the modified Rankin Scale of 1d 6 (5.2) 11 (9.3) independence. The score before Stroke etiology onset was evaluated with patients or Cardioembolism 65 (56.0) 69 (58.5) families through the specified Rankin Structured interview. Only patients Large artery atherosclerosis 32 (27.6) 28 (23.7) with scores of 0 or 1 were enrolled. Intracranial atherosclerosis 28 (24.1) 23 (19.5) e The Trial of ORG 10172 in Acute Unknown 15 (12.9) 20 (16.9) Stroke Treatment (TOAST) Othere 4 (3.4) 1 (0.8) classification assessed stroke etiology; other causes included small Imaging characteristicsf vessel occlusion, nonatherosclerotic Baseline ASPECTS, No.g 115 117 vasculopathies, hypercoagulable Median (IQR) 8 (7-9) 8 (7-9) states, and hematologic disorders. f Occlusion site on CT or MR angiography Imaging characteristics were assessed by the imaging core laboratory. Intracranial internal carotid artery 18 (15.5) 17 (14.4) g Imaging measures the extent of M1 middle cerebral artery segment 95 (81.9) 99 (83.9) ischemic stroke (range, 0-10, higher M2 middle cerebral artery segment 3 (2.6) 2 (1.7) scores indicate smaller infarct core). Clinical examination at arrival, median (IQR) Listed are values for the core laboratory assessment. NIHSS scoreh 16 (12-20) 16 (13-20) h National Institutes of Health Stroke i Systolic blood pressure, mm Hg 146 (129-165) 145 (128-168) Scale (NIHSS) score (range, 0-42, Glucose level, mmol/L 6.7 (5.7-8.1) 6.9 (5.9-8.9) lower scores indicate less severe No. of patients 114 115 neurological deficits). i Assessed at enrollment; Workflow times, median (IQR), min antihypertensives were not j Onset to randomization 170 (129-204) 168 (144-216) permitted prior to determination Arrival to intravenous alteplase NA 61 (49-81) of inclusion. Arrival to arterial puncture 101 (80-135) 105 (80-132) j Onset from patient or witness. Unknown times were the last known Onset to puncturej 200 (155-247) 210 (179-255) time well as reported by a proxy.

Primary Outcome of −10%. In addition, the noninferiority test demonstrated Among the patients who survived and were followed up to that the endovascular thrombectomy alone was noninferior 90 days, video materials were acquired from 186 patients and to the combined IV thrombolysis and endovascular throm- voice recordings from 6 patients. One patient’s assessment bectomy group (z = 2.7157, P for noninferiority = .003) since was determined by local investigators blinded to the treat- it crossed the efficacy boundary (z = 2.35826, P for noninferi- ment assignments because video or voice recording technol- ority = .009) that was prespecified for early termination. The ogy was unavailable. Sixty-three patients (54.3%) in the per-protocol analysis indicated that results were consistent endovascular thrombectomy alone group achieved func- with the primary analysis (eTable 3 and eTable 4 in Supple- tional independence vs 55 patients (46.6%) in the combined ment 4). Prespecified subgroup analyses are shown in eFig- treatment group (difference, 7.7%; 1-sided 97.5% CI, ures 6 and 7 (Supplement 4), and the post hoc hierarchical −5.1% to ϱ; Table 2). The lower boundary of the CI of −5.1% modeling and sensitivity analyses indicate that the site and was greater than the prespecified noninferiority margin effects were not significant (eTable 5 in Supplement 4).

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Table 2. Modified Rankin Scale Score at 90 Days and Secondary Outcomes

No. (%) Endovascular Combined IV thrombolysis thrombectomy and endovascular Unadjusted Unadjusted alone thrombectomy difference odds ratio Adjusted odds ratio (n = 116) (n = 118) (95% CI) (95% CI) (95% CI)a Primary efficacy outcomeb Functional independencec 63 (54.3) 55 (46.6) 7.7 (−5.1 to ϱ)d 1.36 (0.82 to 2.28) 1.48 (0.81 to 2.74) Secondary efficacy outcomes Excellent outcomec 44 (37.9) 37 (31.4) 6.6 (−5.6 to 18.7) 1.34 (0.78 to 2.30) 1.38 (0.75 to 2.56) Disability level, 2 (1 to 4) 3 (1 to 4) 0 (−1 to 0) 1.17 (0.75 to 1.84)e 1.13 (0.71 to 1.79)e median (IQR), mRS scorec Successful reperfusion 100 (88.5) 102 (87.2) 1.3 (−7.1 to 9.8) 1.13 (0.51 to 2.53) 1.14 (0.50 to 2.61) (eTICI 2b-3) at final angiogramf No. 113 117 Reperfusion on follow-up CT 96 (97.0) 94 (93.1) 3.9 (−2.1 to 9.9) 2.38 (0.64 to 11.31) 2.37 (0.63 to 11.34) or MR angiography ≤48 hg No. 99 101 NIHSS score, median (IQR), β Coefficient (95% CI)h change from baseline 24 hi −4 (−8 to 0) −3 (−6 to −1) −1 (−2 to 1) −0.14 (−1.97 to 1.69) −0.26 (−2.06 to 1.54) 5 to ≈7 d or early −7 (−11 to −1) −6 (−10 to −2) 0 (−2 to 2) 1.02 (−1.76 to 3.80) 0.77 (−1.96 to 3.50) dischargei Health–related qualify of life, 0.89 (0.22 to 1.00) 0.74 (0.26 to 0.96) 0.00 (0.00 to 0.05) 0.04 (−0.06 to 0.14) 0.04 (−0.04 to 0.13) EQ-5D-5L score, median (IQR)j Abbreviations: CT, computed tomography; EQ-5D-5L, European Quality of Life f The eTICI grade was determined at the final angiogram (range, 0 [no 5-Dimensions 5-Levels questionnaire; eTICI, Expanded Thrombolysis In reperfusion] to 3 [completed reperfusion]). A score of 2b to 3 indicates Cerebral Infarction, IQR, interquartile range; IV, intravenous; MR magnetic successful reperfusion. Data were missing from 3 patients in the endovascular resonance; mRS, modified Rankin Scale; NIHSS, National Institutes of Health thrombectomy alone group and 1 in the combined treatment group. Stroke Scale. A complete list of eTICI grades is provided in eTable 2 in Supplement 3. a Values were adjusted for age, baseline NIHSS and Alberta Stroke Program g Data were not available for 23 patients (12 in the endovascular thrombectomy Early Computed Tomography Score, occlusion site, and time from onset to alone group; 11 in the combined treatment group). Reperfusion failed in 11 randomization. patients (5 in the endovascular thrombectomy alone group and 6 in the b Noninferiority test for the difference of 2 proportions. combined treatment group). Vessel patency was adjudicated by 2 blinded independent neuroradiologists. Disagreements were resolved by consensus. c See the Methods section for mRS score ranges and evaluation criteria. h The β coefficient was estimated from a multivariable linear regression model. d Indicates 1-sided 97.5% CI. i Lower scores (range, 0-42), indicate less severe neurological deficits. e The common odds ratio was estimated from an ordinal logistic regression j model and indicates the odds of improvement of 1 point on the mRS, with a Higher scores (range, −0.39 to 1) indicate better quality of life; 0 is the value common odds ratio greater than 1 favoring the endovascular thrombectomy of a health state equivalent to death; negative values, worse than death; treatment alone group. 1, full health.

Secondary Outcomes bral hemorrhage in the 2 groups was 6.1% vs 6.8% (difference, The median of 90-day mRS scores for endovascular throm- −0.8%; 95% CI, −7.1% to 5.6%), respectively. Furthermore, in bectomy alone was 2 (IQR, 1-4) and for the combined treat- post hoc analyses, based on other definitions, the rate of symp- ment, 3 (IQR, 1-4). The unadjusted difference was 0 (95% CI, tomatic intracranial hemorrhage did not differ significantly be- −1 to 0). The adjusted common odds ratio was 1.13 (95% CI, 0.71- tween the 2 groups (Table 3). In a post hoc analysis, asymptom- 1.79). There were no significant differences in other second- atic intracerebral hemorrhage occurred in 15.7% vs 25.6% ary efficacy outcomes (Table 2). In a post hoc analysis, suc- (difference, −10.0%; 95% CI, −20.3% to 0.3%), respectively. Clot cessful reperfusion before endovascular treatment assessed on migration occurred in 20 patients (17.7%) of 113 in the endovas- initial angiography was observed for 2 patients in the endo- cular thrombectomy alone group vs 28 of 117 (23.9%) in com- vascular thrombectomy alone and 3 in the combined IV throm- bined treatment group. There were no significant differences bolysis and endovascular thrombectomy group (1.7% vs 2.6%). in proportions of procedures associated complications or seri- Further details are provided in the Table 2 and Figure 2. ous adverse events (Table 3). Kaplan-Meier estimates of the probability of death are provided in eFigure 5 in Supplement 4. Safety Outcomes The proportion of patients who died within 90 days was 17.2% among those in the endovascular thrombectomy alone group Discussion vs 17.8% among those in the combined treatment group (difference, −0.5%; 95% CI, −10.3% to 9.2%). According to the In this randomized clinical trial involving patients with ische- Heidelberg bleeding classification, the symptomatic intracere- mic stroke who presented within 4.5 hours from onset, had jama.com (Reprinted) JAMA January 19, 2021 Volume 325, Number 3 239

Figure 2. Distribution of the Modified Rankin Scale Score at 90 Days

Distribution of modified Rankin Scale score 0 1 2 3 4 5 6

No symptoms Death Endovascular thrombectomy 12.9 25.0 16.4 12.9 8.6 6.9 17.2 alone group (n = 116) Shown are scores on the modified Rankin Scale for patients in each Combined IV thrombolysis and group who were evaluated by means 15.3 16.1 15.3 17.0 11.9 6.8 17.8 endovascular thrombectomy group (n = 118) of video (186 patients) and voice (6 patients) recordings and by local 0 10 20 30 40 50 60 70 80 90 100 investigators (1 patient). Forty-one Patients, % patients died before 90 days. IV indicates intravenous.

proximal anterior circulation occlusion, and were eligible for A cohort study that used data from 2017 to 2019 and in- intravenous alteplase, endovascular thrombectomy alone, cluded 1526 patients showed that patients with asymptom- compared with combined IV alteplase and endovascular throm- atic intracranial hemorrhage have a worse functional out- bectomy, met the prespecified statistical threshold for nonin- come at 3 months than do those without it after endovascular feriority for achieving 90-day functional independence. Dif- treatment for acute ischemic stroke.27 This observation may ferent from the prior trials, this present trial excluded be attributed to the cytotoxic effect of the contrast agent and participants with middle cerebral artery M2 segment occlu- the mass effect caused by the destruction of the blood-brain sion and used a full dose of alteplase. barrier, compressing the adjacent healthy parenchyma with The rate of 90-day functional independence with com- subsequent impairment of the functional recovery.27 bined IV thrombolysis and endovascular thrombectomy in In comparing the results of this trial with those of the SKIP this trial was 46.6%, which is similar to the 46.4% observed and DIRECT-MT trials, the rate of intracranial hemorrhage was in the Highly Effective Reperfusion Using Multiple Endovas- similarly higher among patients in the combined treatment cular Devices (HERMES) meta-analysis.23 However, the over- group this trial and in the SKIP trial (34% vs 50%, P = .02), even all frequency of 90-day functional independence in this though patients in the SKIP trial received a lower dose of al- study was higher (50.4%) than that observed in the Direct teplase (0.6 mg/km) than did the patients in this study. Con- Intraarterial Thrombectomy in Order to Revascularize Acute versely, patients in the DIRECT-MT trial had similar rates of Ischemic Stroke Patients With Large Vessel Occlusion Effi- asymptomatic intracranial hemorrhage between treatment ciently in Chinese Tertiary Hospitals (DIRECT-MT) trial groups (33.3% vs 36.2%). This could be partially because in the (36.6%).13 The potential explanations for these differences DIRECT-MT trial’s combined IV thrombolysis and endovascu- include that the intracranial internal carotid artery occlusions lar thrombectomy group, 30 patients (9.1%) did not receive occurred more frequently in the DIRECT-MT trial (35%) than either the full dose (n = 20) or any dose (n = 10) of alteplase, in either this trial (15%) or the HERMES trial (21%), whereas and 37 patients (11.2%) did not undergo thrombectomy. More- the patients with favorable collateral status (defined as grade over, eTable 6 lists other important factors—including trial de- 2-3 on the ASITN/SIR scale) had fewer in the DIRECT-MT trial sign, inclusion criteria, primary end point—used in the (24%) than patients in either this trial (68.4%) or the HERMES DIRECT-MT and SKIP trials alongside those used in this trial trial (85%).13,24 (Supplement 4). More patients participating in both groups in this study achieved 90-day functional independence than patients in the Limitations DIRECT-MT trial. This provided an important supplement of This study has several limitations. First, the noninferiority mar- noninferiority despite the early termination and consequent gin used in this trial was not selected using the minimal clini- smaller sample size in the current study. That middle cere- cally important difference or fixed margin methods. The non- bral artery M2 occlusions were excluded from this trial, which inferior margin of 10% is broad, reaching no consensus in the are known to have a better response to IVT,25 may have con- clinical community, which may lead to concerns about the ro- tributed to the differences across the 2 trials. Indeed, higher bustness of study results. Second, the early termination of the rates of successful reperfusion prior to thrombectomy were trial does create potential for overestimation of the effect size. seen with combined IVT and endovascular thrombectomy in However, it followed a highly conservative prespecified sta- the DIRECT-MT trial but not in this trial. Some other factors tistical stopping rule. that may have theoretically favored endovascular thrombec- Third, the median time from hospital arrival to the start tomy alone in this trial include the lower proportions of both of IV alteplase of 61 minutes (IQR, 49-81 minutes) in this trial clot migration (17.7% vs 23.9%) and asymptomatic intracra- was similar to the 59 minutes (IQR, 45-78 minutes) in the nial hemorrhage (15.7% vs 25.6%) over combined IV throm- DIRECT-MT trial but was longer than what has been reported bolysis and endovascular thrombectomy because both these in the other recent thrombectomy trials.2-7 The main reason factors appear to be associated with worse functional out- for these differences is that alteplase could not be adminis- comes after endovascular stroke treatment.10,26 trated immediately after standard clinical and neuroimaging

240 JAMA January 19, 2021 Volume 325, Number 3 (Reprinted) jama.com

Table 3. Reported Severe Adverse Events and Procedure Associated Complications

No./total (%) Combined IV thrombolysis Endovascular thrombectomy and endovascular alone group thrombectomy group (n = 116) (n = 118) Patients with at least 1 serious adverse event 30 (25.9) 26 (22.0) Any intracranial hemorrhagea 25/115 (21.7) 38/117 (32.5) Symptomatic intracerebral hemorrhage definitions NINDSb 10/115 (8.7) 12/115 (10.3) ECASS IIc 9/115 (7.8) 10/117 (8.5) HBCd 7/115 (6.1) 8/117 (6.8) ECASS IIIe 5/115 (4.3) 7/117 (6.0) SITS-MOSTf 4/115 (3.5) 5/117 (4.3) Mortality at 90 d 20 (17.2) 21 (17.8) Acute respiratory failureg 14 (12.1) 12 (10.2) Large or malignant middle cerebral artery strokeh 13 (11.2) 9 (7.6) Acute heart failurei 12 (10.3) 9 (7.6) Hemicraniectomyj 3 (2.6) 5 (4.2) Patients with at least 1 procedure-associated complicationk 34/113 (30.1) 48/117 (41.0) Clot migrationl 20/113 (17.7) 28/117 (23.9) Distal occlusion present at procedure endm 19/113 (16.8) 21/117 (18.0) Contrast extravasationn 16/115 (13.9) 17/117 (14.5) Arterial perforation 2 (1.7) 6 (5.1) Puncture access complications 1 (0.9) 6 (5.1) Arterial dissection 0/113 1/117 (0.8) Abbreviations: ECASS, European Cooperative Acute Stroke Study; g Need for mechanical ventilation or oxygen through a reservoir mask or HBC, Heidelberg bleeding classification; NINDS, National Institute of a Pulmonary Severity Index greater than 130. Neurological Disorders and Stroke; SITS-MOST, Safe Implementation of h Any large infarction with mass effect observed on imaging that required Thrombolysis in Stroke–Monitoring Study. medical or surgical treatment of mass effect. a A complete list of intracranial hemorrhage classifications is provided in i Brain natriuretic peptide (BNP) concentration, changes in N-terminal pro-BNP eTable 7 and definitions of symptomatic intracerebral hemorrhage in eTable 8 (NT-pro-BNP) or Killip class II or higher. in Supplement 4. Data were not available for 1 patient in the endovascular j Surgical procedure to decompress the swollen hemisphere caused by large or thrombectomy alone group and 1 in the combined treatment group. malignant middle cerebral artery stroke. b Symptomatic if hemorrhage had not been seen on a previous computed k All procedure-associated complications were reported by the clinical events tomographic (CT) scan but either subsequent suspicion of hemorrhage or committee. decline in neurological status existed. l Clot observed to have moved before and or during the intervention at the c The ECASS II was the same as ECASS III, except that establishment of a causal occlusion site. Data were not available for 3 patients in the endovascular relationship between the hemorrhage and clinical deterioration or death was thrombectomy alone group and 1 in the combined treatment group. not a requirement. mOccurred after reperfusion of the primary occlusion site, any vessel occlusions d Symptomatic intracerebral hemorrhage detected by brain imaging as a distal from the primary occlusion site were considered emboli due to relevant change in neurological status; absence of another explanation for periprocedural thrombus fragmentation. deterioration; an event leading to intubation, hemicraniectomy, or external ventricular draining placement; or other major medical or surgical n Contrast extravasation is a hyperdense lesion with a maximum Hounsfield unit intervention. greater than 90 that persists on a follow-up CT scan.22 Data were not available for 1 patient in the endovascular thrombectomy alone group and 1 in the e Anyhemorrhagewithneurologicaldeteriorationidentifiedasthepredominantcause. combined treatment group. f Local or remote parenchymal hematoma type 2 on the imaging scan obtained 22 to 36 hours after treatment, plus neurological deterioration. screening as they were in the previous trials because addi- pital arrival to initiate IV alteplase times as short as those in tional time was required for study screening, obtaining pa- the previous trials with the absence of waiver of informed con- tient consent, and randomization in this and the DIRECT-MT sent is unlikely. trials. This explanation is supported by the findings of a recent In China, informed consent is required even before the multinational neuroprotection randomized trial. Despite hav- standard administration of IVT because patients or their ing one of most efficient workflows for IVT and thrombec- families often have to pay in advance before receiving tomy reported to date, the median time from hospital arrival alteplase. Relatedly, the median door-to-needle time was 62 to the initiation of the experimental drug in the Safety and minutes (IQR, 40-94 minutes) among 24 542 patients treated Efficacy of Nerinetide in Subjects Undergoing Endovascular with IV alteplase in a recent analysis of the Chinese Stroke Thrombectomy for Stroke (ESCAPE NA-1) trial was 64 min- Center Alliance Program,29 a finding that is fully consistent utes (IQR, 48-86 minutes).28 This highlights that achieving hos- with the times seen in this and the DIRECT-MT trials. jama.com (Reprinted) JAMA January 19, 2021 Volume 325, Number 3 241

Nevertheless, given the relatively long times from hospital ar- dence of intracranial atherosclerotic disease in Asian than in rival to alteplase initiation in this trial, it remains possible that Western populations. IV alteplase might still be beneficial in the presence of faster delivery times. Moreover, as bridging with tenecteplase vs alteplase was associated with higher rates of prethrombec- Conclusions tomy reperfusion and better 90-day functional outcomes in the Tenecteplase Versus Alteplase Before Endovascular Among patients with ischemic stroke due to proximal anterior Therapy for Ischemic Stroke (EXTEND-IA-TNK) trial,30 it is pos- circulation occlusion within 4.5 hours from onset, endovascu- sible that tenecteplase bridging might yield better results than lar treatment alone, compared with IV alteplase plus endovas- thrombectomy alone. cular treatment, met the prespecified statistical threshold for non- Fourth, because this, the DIRECT-MT, and the SKIP trials inferiority for the outcome of 90-day functional independence. only included Asian patients, the generalizability of their find- These findings should be interpreted in the context of the clini- ings is somewhat limited due to the significantly higher inci- cal acceptability of the selected noninferiority threshold.

ARTICLE INFORMATION People's Hospital, Chongzhou, China (Y. Wu); Administrative, technical, or material support: Zi, Accepted for Publication: December 3, 2020. Department of Neurology, Ganzhou People's Z. Qiu, F. Li, Sang, D. Wu, W. Luo, Shuai Liu, Yuan, Hospital, Zhanggong District, Ganzhou, China Song, Z. Shi, W. Huang, Min Zhang, W. Liu, Z. Guo, Author Affiliations: Department of Neurology, (Zeng); Department of Neurology, Yangluo District T. Qiu, Q. Shi, P. Zhou, L. Wang, Fu, Shudong Liu, Xinqiao Hospital and The Second Affiliated of Hubei Zhongshan Hospital, Qiaokou District, S. Yang, S. Zhang, Z. Zhou, X. Huang, Y. Wang, Hospital, Army Medical University (Third Military Wuhan, China (Wan); Department of Neurology, J. Luo, Bai, Min Zhang, Y. Wu, Zeng, Wan, C. Wen, Medical University), Shapingba District, Chongqing, Nanyang Central Hospital, Wolong District, H. Wen, Ling, Z. Chen, Peng, Ai, F. Guo, H. Li, J. Guo, China (Zi, Z. Qiu, F. Li, Sang, D. Wu, W. Luo, Nanyang, China (C. Wen); Department of Guan, Zhiyi Wang, Y. Liu, Pu, Zhen Wang, H. Liu, Shuai Liu, Yuan, Song, H. Liu, L. Chen, J. Huang, Neurology, Xiangyang Central Hospital, Xiangcheng L. Chen, J. Huang, G. Yang, Gong, Shuai, Q. Yang. G. Yang, Gong, Shuai, Q. Yang); Department of District, Xiangyang, China (H. Wen); Department of Supervision: Zi, Z. Qiu, F. Li, Sang, D. Wu, Shuai, Neurology, The 903rd Hospital of The Chinese Neurology, Zhongshan People's Hospital, Nogueira, Q. Yang. People’s Liberation Army, Xihu District, Hangzhou, Zhongshan, China (Ling); Department of China (Z. Qiu); Department of Neurology, Affiliated Conflict of Interest Disclosures: Dr Nogueira Neurology, Mianzhu People's Hospital, Mianzhu, reported receiving consulting fees for advisory Hangzhou First People’s Hospital, Zhejiang China (Z. Chen); Department of Neurology, Deyang University School of Medicine, Hangzhou, China roles with Anaconda, Biogen, Cerenovus, People’s Hospital, Jingyang District, Deyang, China Genentech, Imperative Care, Medtronic, Phenox, (Sang); Huaian Medical District of Jingling Hospital, (Peng); Department of Neurology, Taihe Affiliated Medical School of Nanjing University, Huaian, China Prolong Pharmaceuticals, and Stryker Hospital of Shiyan, Shiyan, China (Ai); Department Neurovascular and having stock options for (D. Wu); Department of Neurosurgery, The 904th of Neurology, Sichuan Provincial People’s Hospital, Hospital of The Chinese People’s Liberation Army, advisory roles with Astrocyte, Brainomix, Qingyang District, Chengdu, China (F. Guo); Cerebrotech, Ceretrieve, Corindus Vascular Wuxi, China (Z. Shi); Department of Neurology, Department of Neurology, Zhongnan Hospital of Maoming Traditional Chinese Medicine Hospital, Robotics, Vesalio, Viz-AI, and Perfuze. No other Wuhan University, Wuchang District, Wuhan, China disclosures were reported. Maonan District, Maoming, China (W. Huang, (H. Li); Department of Neurology, Chongqing Three Min Zhang); Department of Neurology, Wuhan No. 1 Gorges Central Hospital, Wanzhou District, Funding/Support: The study was supported by Hospital, Qiaokou District, Wuhan, China (W. Liu, Chongqing, China (J. Guo); Department of grants 81525008, 81901236, 81801157 from the Z. Guo); Department of Neurology, The First Neurology, The Third Affiliated Hospital of National Natural Science Foundation of China, People’s Hospital of Zigong, Da'an District, Zigong, Guangzhou Medical University, Liwan District, 2019ZX001 from the Chongqing Major Disease China (T. Qiu, Q. Shi); Department of Neurology, Guangzhou, China (Guan); Department of Prevention and Control Technology Research The First People’s Hospital of Xiangyang, Fancheng Neurology, Huazhou People’s Hospital, Hexi Project, 2019XLC2008 2019XLC3016 from the District, Xiangyang, China (P. Zhou); Department of District, Huazhou, China (Zhiyi Wang); Department Clinical Medical Research Talent Training Program Neurology, The Third People’s Hospital of Zigong, of Neurology, Lu'an People’s Hospital, Jin'an of Army Medical University, and 2018JSLC0017 Gongjing District, Zigong, China (L. Wang); District, Lu'an, China (Y. Liu); Department of from the Major Clinical Innovation Technology Department of Neurology, Xuzhou Central Hospital, Neurology, Hubei Provincial People's Hospital, Project of the Second Affiliated Hospital of Army Quanshan District, Xuzhou, China (Fu); Department Wuchang District, Wuhan, China (Pu); Department Medical University. of Neurology, Yongchuan Hospital of Chongqing of Neurology, Changsha Central Hospital, Yuhua Role of the Funder/Sponsor: The sponsors had no Medical University, Chongqing Key Laboratory of District, Changsha, China (Zhen Wang); role in the design and conduct of the study; Cerebrovascular Disease Research, Yongchuan Department of Neurology, Marcus Stroke & collection, management, analysis, and District, Chongqing, China (Shudong Liu); Neuroscience Center, Grady Memorial Hospital, interpretation of the data; preparation, review, or Department of Neurology, The 902nd Hospital of Emory University School of Medicine, Atlanta, approval of the manuscript; and decision to submit The Chinese People’s Liberation Army, Yuhui Georgia (Nogueira). the manuscript for publication. District, Bengbu, China (S. Yang); Department of Neurology, The Affiliated Hospital of Yangzhou Author Contributions: Drs Q. Yang and Nogueira Group Information: The DEVT Trial members are University, Guangling District, Yangzhou, China had full access to all of the data in the study and listed in Supplement 1. (S. Zhang); Department of Neurology, Yijishan take responsibility for the integrity of the data and Data Sharing Statement: See Supplement 5. Hospital of Wannan Medical College, Wuhu, China the accuracy of the data analysis. Drs Zi and Z. Qiu (Z. Zhou, X. Huang); Department of Neurology, The are co–first authors. Drs Q. Yang and Nogueira are REFERENCES Fifth People’s Hospital of Chengdu, Wenjiang co–corresponding authors. Concept and design: Zi, Z. Qiu, F. Li, Sang, D. Wu, 1. Bracard S, Ducrocq X, Mas JL, et al; THRACE District, Chengdu, China (Y. Wang); Department of investigators. Mechanical thrombectomy after Neurology, Sichuan Mianyang 404 Hospital, W. Liu, Shuai, Nogueira, Q. Yang. Acquisition, analysis, or interpretation of data: All intravenous alteplase versus alteplase alone after Fucheng District, Mianyang, China (J. Luo); stroke (THRACE): a randomised controlled trial. Department of Neurology, The First Affiliated authors. Drafting of the manuscript: All authors. Lancet Neurol. 2016;15(11):1138-1147. doi:10.1016/ Hospital of Henan Science and Technology S1474-4422(16)30177-6 University, Jianxi District, Luoyang, China (Bai); Critical revision of the manuscript for important Department of Neurology, Jiangmen Central intellectual content: Zi, Z. Qiu, F. Li, Sang, D. Wu, 2. Saver JL, Goyal M, Bonafe A, et al; SWIFT PRIME Hospital, Pengjiang District, Jiangmen, China W. Luo, W. Liu, Z. Zhou, Bai, Q. Yang. Investigators. Stent-retriever thrombectomy after (Min Zhang); Department of Neurology, Chongzhou Statistical analysis: W. Luo, Shuai Liu, X. Huang. intravenous t-PA vs t-PA alone in stroke. N Engl J Med. 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jama.com (Reprinted) JAMA January 19, 2021 Volume 325, Number 3 243

Xinqiao Hospital of Army Medical University: Qingwu Yang*, Wenjie Zi, Zhongming Qiu, Fengli Li, Hongfei Sang, Deping Wu, Weidong Luo, Shuai Liu, Junjie Yuan, Jiaxing Song, Hansheng Liu, Luming Chen, Jiacheng Huang, Guoqiang Yang, Zili Gong, Dong Zhang, and Jie Shuai*

The 904th Hospital of the Chinese People’s Liberation Army: Zhongming Shi*, Jiaming Cao, Mirui Qu, Zhizhong Yan, Chunlei Zhang, Xun Zhu, Xiaogang Hu, Qiaohua Huan

Maoming Traditional Chinese Medicine Hospital: Wenguo Huang*, Min Zhang* , Dongrun Yan, Songsheng Ye

Wuhan No. 1 Hospital: Wenhua Liu*, Zhangbao Guo*, Kun Tang, Zhenhui Duan, Houjie Ni, Xiangqian Xu

The First People's Hospital of Zigong: Tao Qiu*, Qiang Shi*, Zhaoyun Guo, Keting Liu, Xiaoyong Deng, Ming Chen

The First People's Hospital of Xiangyang: Peiyang Zhou*, Jincheng Liu, Pu Wang, Xiaojing Hu, Zhihua Cao, Guangzhi Liu, Chenglin Sun

The Third People's Hospital of Zigong: Li Wang*, Zhiguo Li, Yan Liu, Senlin He

Xuzhou Central Hospital: Xinmin Fu*, Qingqing Zhang, Qingfang Ma

Yongchuan Hospital of Chongqing Medical University: Shudong Liu*, Libo Zhao, Ge Tang, Yu Chen

The 902th Hospital of the Chinese People’s Liberation Army: Shiquan Yang*, Dongzhang Xue, Chunmei Xue, Yiqun Wang

The Affiliated Hospital of Yangzhou University: Shuai Zhang*, ZhenSheng Liu, Tieyu Tang

Yijishan Hospital of Wannan Medical College: Zhiming Zhou*, Xianjun Huang*, Xianhui Ding, Xiangjun Xu, Xianjin Shang

Sichuan Mianyang 404 Hospita: Jun Luo*, Zhenxuan Tian, Shuanglong Liu, Zongqin Li, Xuejie Xu

The Fifth People's Hospital of Chengdu: Yan Wang*, Pian Wang, Hongbo Zhang, Zheng Li, Qingbin Zhang

The First Affiliated Hospital of Henan Science and Technology University: Yongjie Bai*, Jisheng Qi, Lina Huang

Jiangmen Central Hospital: Min Zhang*, Weipeng Dai

Chongzhou People's Hospital: Youlin Wu*, Xiurong Zhu, Wenbin Wu, Xiyang Chen, Shifu Liang, Hong Zhao, Yanxue Zheng

Ganzhou People's Hospital: Guoyong Zeng*, Hongliang Zeng, Qingqing Fu

Yangluo District of Hubei Zhongshan Hospital: Yue Wan*, Jing Zuo, Yingbing Ke

Nanyang Central Hospital: Changming Wen*, Shuang Pei, Jun Sun, Fanghui Bai, Ning Wang, Yang Yu

Xiangyang Central Hospital: Hongbin Wen*, Xuan Liu, Jin Xu, Ping Yu

Zhongshan People's Hospital: Wentong Ling*, Huan Cai, Wenjun Wu

Mianzhu People's Hospital: Zhuo Chen*, Jingyu Tan, Xingju Zhong, Yong Wu

Deyang People's Hospital: Miao Peng*, Pan Huang, Duanxiu Liao, Hong Chen

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Taihe Hospital of Shiyan: Zhibing Ai*, Yueliang Zhang, Jiang Yuan, Chaohui Cheng

Sichuan Provincial People's Hospital: Fuqiang Guo*, Jianhong Wang, Shu Yang

Zhongnan Hospital of Wuhan University: Huagang Li*, Yumin Liu, Dong Sun, Fei Xie

Chongqing Three Gorges Central Hospital: Jing Guo*, Shengli Chen, Rong Deng

The Third Affiliated Hospital of Guangzhou Medical University: Haitao Guan*, Yanling Liang, Wei Li

Huazhou People's Hospital: Zhiyi Wang*, Zhiliang Li

Lu'an People's Hospital: Yong Liu*, Ping Jin, Hongjiang Zhai, Ran Chen

Hubei Provincial People's Hospital: Jie Pu*, Fei Zeng, Jian Jiang

Changsha Central Hospital: Zhen Wang*, Wei Xu, Tieqiao Feng

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6 Effect of Endovascular Treatment Alone Versus Intravenous Alteplase Plus

7 Endovascular Treatment on Functional Independence in Patients with

8 Acute Ischemic Stroke: The DEVT Randomized Clinical Trial

11 Trial Protocol

16 This supplement contains the following items:

17 1. Original Trial Protocol (page 2 to 33)

18 2. Final Trial Protocol (page 34 to 65)

19 3. Summary of changes (page 66 to 68)

22 Note: personal identifying information has been redacted from the protocol documents to comply with

23 international privacy legislation. Date: 30th March 2018 Version: 1.0

Sponsor

Army Medical University No. 30 Gaotanyan Main Street, Chongqing, China

Principle Investigators

Professor Qingwu Yang, Jie Shuai Professor Raul Gomes Nogueira 28 29

33 DEVT: A randomized, controlled, multicenter trial of direct endovascular treatment

34 versus standard bridging therapy for acute stroke patients with large vessel occlusion in

35 the anterior circulation

38 Protocol Version: 1.0

39 Issue Date: 30th March 2018 Date: 30th March 2018 Version: 1.0

40 CONTENTS 41 List of Abbreviations ...... 5 42 Study Synopsis ...... 7 43 Schedule of Assessments ...... 10 44 1. BACKGROUND INFORMATION ...... 11 45 2. TRIAL OBJECTIVES ...... 11 46 3. TRIAL DESIGN ...... 11 47 4. PATIENT POPULATION ...... 12 48 4.1. Inclusion criteria ...... 12 49 4.2. Exclusion criteria ...... 12 50 5. PARTICIPATING CENTER ELIGIBILITY ...... 13 51 6. RANDOMIZATION ...... 13 52 7. TREATMENTS ...... 13 53 8. OUTCOMES ...... 13 54 8.1. Primary Efficacy Outcome ...... 13 55 8.2. Secondary Efficacy Outcomes ...... 14 56 8.3 Safety Outcomes ...... 14 57 9. BLINDING AND MASKING ...... 14 58 10. ASSESSMENT OF EFFICACY ...... 15 59 10.1. The Modified Rankin Scale ...... 15 60 10.2. The National Institutes of Health Stroke Scale ...... 15 61 10.3. EQ-5D ...... 15 62 11. ASSESSMENT OF SAFETY ...... 15 63 11.1. Adverse Event Definitions ...... 15 64 11.1.1. Adverse Event ...... 15 65 11.1.2. Serious Adverse Event ...... 16 66 11.2. Definitions of AE-Related Terms ...... 16 67 12. CLINICAL MANAGEMENT OF ADVERSE EVENTS ...... 16 68 12.1. Identification of Adverse Events by the Investigator ...... 16 69 12.2. Reporting of Adverse Events ...... 17 70 12.3. Reporting of Serious Adverse Events ...... 17 71 12.4. Reporting by the Investigator ...... 17 72 12.5. Reporting SAEs to the Health Authorities and Ethics Committees ...... 17 73 13. DATA SAFETY MONITORING BOARD ...... 17 74 14. IMAGING CORE LABORATORY ...... 18 75 15. CLINICAL EVENTS COMMITTEE ...... 18 76 16. STATISTICS ...... 18 77 16.1. Sample size estimates ...... 18 78 16.2. Analysis Populations ...... 18 79 16.2.1. Intention-to-treat Population ...... 18 80 16.2.2. Per Protocol Population ...... 18 81 16.3. Analysis of Primary Efficacy Outcome ...... 18 82 16.4. Analysis of secondary efficacy outcomes ...... 19 83 16.5. Adjustment for covariates and subgroup analyses ...... 19 Date: 30th March 2018 Version: 1.0

84 16.6. Handling of Missing Data ...... 19 85 16.7. Analyses of Safety ...... 19 86 17. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...... 19 87 18. QUALITY CONTROL AND QUALITY ASSURANCE ...... 20 88 18.1. Audits and Inspections ...... 20 89 18.2. Protocol Amendments and Revisions ...... 21 90 19. ETHICAL CONSIDERATION ...... 21 91 20. DATA HANDLING AND RECORD KEEPING ...... 21 92 20.1. Data Handling ...... 21 93 20.2. Investigator Files/Retention of Documents ...... 21 94 20.3. Source Documents and Background Data ...... 22 95 20.4. Case Report Forms ...... 22 96 20.5. Confidentiality ...... 22 97 21. PUBLICATION AND PRESENTATION POLICY ...... 22 98 22. DATA-SHARING PLAN ...... 23 99 23. STUDY ORGANIZATION AND FUNDING ...... 23 100 Appendix 1 – Classification of Subtype of Acute Ischemic Stroke ...... 24 101 Appendix 2 - ASITN/SIR Collateral Vessel Grading System ...... 27 102 Appendix 3 - The Alberta Stroke Program Early Computed Tomography Score 103 (ASPECTS) ...... 28 104 Appendix 4 - Modified Rankin Scale (MRS) ...... 29 105 Appendix 5 - Modified Treatment In Cerebral Infarction (mTICI) Score ...... 30 106 Investigator’s Agreement ...... 31 107 REFERENCES ...... 32 108 Date: 30th March 2018 Version: 1.0

109 List of Abbreviations AE Adverse Event

AIS Acute Ischemia Stroke American Society of Interventional and Therapeutic Neuroradiology/Society of ASITN/SIR Interventional Radiology ASPECTS Alberta Stroke Program Early Computed Tomography Score

BP Blood Pressure

CEC Clinical Events Committee

CRF Case Report Form

CTA Computed Tomographic Angiography Direct Endovascular Treatment Versus Standard Bridging Therapy in Large Artery DEVT Anterior Circulation Stroke DSA Digital Subtraction Angiography

DSMB Data Safety Monitoring Board

ECG Electrocardiogram EQ-5D European Quality Five Dimensions EVT Endovascular Treatment

GCP Good Clinical Practice

HbA1c Hemoglobin A1c

HCG Human Chorionic Gonadotropin

HR Heart Rate

ICA Internal Carotid Artery

ICH-GCP International Conference on Harmonization-Good Clinical Practice

INR International Normalized Ratio

IRB Institutional Review Board

ITT Intention-To-Treat

IVT Intravenous Thrombolysis

LAR Legally Authorized Representative

LVO Large Vessel Occlusion

MCA Middle Cerebral Artery

MR Magnetic Resonance

MRA Magnetic Resonance Angiography

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mRS Modified Rankin Scale

NCCT Non-Contrast Computed Tomography

NIHSS National Institutes of Health Stroke Scale

PP Per-Protocol

QA Quality Assurance

RCT Randomized Controlled Trial

REB Research Ethics Board

rt-PA Recombinant Tissue-type Plasminogen Activator

SAE Serious Adverse Event

SICH Symptomatic Intracranial Hemorrhage

SOPs Standard Operating Procedures

Temp Temperature

TIA Transient Ischemic Attack

TOAST Trial of Org 10172 in Acute Stroke Treatment 110

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111 Study Synopsis Trial Objectives The objective is to determine whether endovascular treatment alone is non-inferior to intravenous thrombolysis bridging endovascular treatment in acute anterior circulation large vessel occlusive patients who are eligible for intravenous rt-PA. Trial Design This study is a randomized, controlled, multicenter trial with blinded outcome assessment. This trial uses a five-look group-sequential non-inferiority design. Up to 194 patients in each interim analysis will be consecutively randomized to endovascular treatment alone or rt-PA plus endovascular treatment group in 1:1 ratio over three years from about 35 hospitals in China. Subjects Inclusion criteria 1) Aged 18 years or older; 2) Presenting with acute ischemic stroke (AIS) symptom within 4.5 hours; 3) Eligible for IV rt-PA; 4) Occlusion of the intracranial internal carotid artery (ICA) or M1 segment of the middle cerebral artery (MCA) confirmed by CT or MR angiography (CTA or MRA); 5) Randomization no later than 4 hours 15 minutes after stroke symptom onset; 6) Informed consent obtained from patients or their legal representatives. Exclusion criteria 1) CT or MR evidence of hemorrhage (the presence of micro-bleeds is allowed); 2) Contraindications of IV rt-PA; 3) Pre-morbidity with a modified Rankin scale (mRS) score of ≥ 2; 4) Currently in pregnant or lactating or serum beta human chorionic gonadotrophin (HCG) test is positive on admission; 5) Contraindication to radiographic contrast agents, nickel, titanium metals or their alloys; 6) Arterial tortuosity and/or other arterial disease that would prevent the device from reaching the target vessel; 7) Patients with a preexisting neurological or psychiatric disease that would confound the neurological functional evaluations; 8) Subjects with occlusions in multiple vascular territories (e.g. bilateral anterior circulation, or anterior/posterior circulation); 9) CT or MRI evidence of mass effect or intracranial tumor (except small meningioma); 10) CT or MRI evidence of cerebral vasculitis; 11) CTA or MRA evidence of intracranial arteriovenous malformations or aneurysms; 12) Any terminal illness with life expectancy less than 6 months; 13) Unlikely to be available for 90-day follow-up; 14) Current participation in another clinical trial. Treatments Patients are assigned to receive either endovascular treatment (EVT) alone (primary-thrombectomy group) or rt-PA plus EVT (bridging-therapy group). In the bridging-therapy group, subjects will receive a single rt-PA dose of 0.9 mg/kg IV (maximum dose: 90 mg), with 10% given as a bolus, followed by continuous IV

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infusion of the rest dose within 1 hour. Simultaneously, EVT preparation should be initiated with or as soon as IV rt-PA administration. While in the primary-thrombectomy group, subjects will receive EVT directly without prior IV rt-PA. Subjects in both groups will undergo rapid EVT. EVT consisted of mechanical thrombectomy, thromboaspiration, balloon dilation, stenting, intra-arterial thrombolysis, or various combinations of these approaches. Consent Explicit written, signed informed consent from the subject or legally authorized representative will be obtained prior to any protocol specific procedures.

Randomization Subjects will be randomly assigned in a 1:1 fashion to receive EVT alone or IV Method rt-PA plus EVT. Randomization occurs immediately after baseline (at the EVT institution) CT/MR brain imaging and CT/MR angiography via a real-time, internet-based randomization method. The randomization was stratified by participating centers. Duration of This study consists of one 90-day study period for each subject. Treatment Subjects will be hospitalized for care after their acute stroke according to the current standard of care. Subjects are required to return to clinic on Day 90 for end-of-study procedures. Laboratory Tests In order to support the assessment of patient safety baseline, chemistry laboratory tests will be completed. At baseline, blood work will be evaluated which includes: Blood cell counts, triglyceride, cholesterol, low density lipoprotein, high density lipoprotein, homocysteine, glucose, procalcitonin, HbA1C, prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, D-dimer, international normalized ratio. If the subject is female and is of childbearing potential, a pregnancy test (urine or serum point-of-care pregnancy test) must be completed and a negative test result obtained prior to inclusion in the trial. Electrocardiograms will also be collected and reviewed at baseline. Assessment of The primary efficacy outcome is the overall proportion of subjects experiencing a Efficacy functional independence 90 days post randomization, defined as a score of 0 to 2 on the mRS. The secondary efficacy outcomes include: 1) Proportion of mRS score 0 to 1 at 90 days; 2) Shift in the distribution of mRS scores at 90 days in EVT alone versus rt-PA plus EVT (ordinal shift analysis); 3) Successful recanalization proportion immediate after EVT. Successful recanalization is defined as a modified Treatment in Cerebral Infarction score of 2b (50 to 99% reperfusion) or 3 (complete reperfusion) in the post-procedure angiography; 4) Vessel recanalization rate evaluated by CTA or MRA within 48 hours; 5) The change of the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours from baseline; 6) The change of the NIHSS score at 5-7 days or discharge if earlier from baseline;

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7) European Quality Five Dimensions (EQ-5D) scale score at 90 days. Assessment of Safety 1) Symptomatic intracerebral hemorrhage (sICH) rate within 48 hours; 2) Mortality at 90 days; 3) Procedure-related complications such as arterial perforation, iatrogenic arterial dissection, arterial access site hematoma, and retroperitoneal hematoma; 4) Incidence of serious adverse events. 112 113

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114 Schedule of Assessments Baseline Day 1 Day 2 Day 5 or Day 90 (±14 (24 ± 12 h (48 ± 8 h from discharge (±1 d) from randomization) d) randomization) Informed consent X History and examination X Weight X Vital Signs (BP, HR, X X X X Temp) Randomization X NIHSS X X X mRS X* X ASPECTS X EQ-5D X CBC, electrolytes, INR, X X aPTT, serum creatinine and serum glucose Pregnancy test‡ X NCCT/MR head X X** CTA/MRA X X ECG X Endovascular Procedure X sICH X Mortality X X AE assessment Collected to Day 30 visit SAE assessment Collected to Day 90 visit Prior medications X Concomitant medications Collected to Day 30 visit 115 * Historical (pre-stroke) score. 116 ** MR head may be supplanted by an NCCT head if MR is unavailable. 117 ‡ If the subject is female and is of childbearing potential a pregnancy test (urine or serum point-of-care 118 pregnancy test) must be completed and the result must be negative; this is the only mandatory laboratory test 119 prior to randomization 120

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121 1. BACKGROUND INFORMATION 122 Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) within 4.5 hours of symptom 123 onset is the first-line treatment for acute ischemic stroke(AIS)1,2. Several randomized controlled trials have 124 consistently demonstrated that intravenous thrombolysis bridging with endovascular treatment (namely bridging 125 therapy) is superior to intravenous thrombolysis alone for acute anterior large vessel occlusion(LVO)3-9. 126 Intravenous thrombolysis prior to endovascular treatment can be initiated earlier, help eliminate thrombi in distal 127 or small arteries which are inaccessible for revascularization devices, facilitate mechanical thrombectomy, and 128 thereby increasing the rate of reperfusion10,11. However, intravenous thrombolysis also has some drawbacks. For 129 instance, it may increase the risk of intracranial or systemic hemorrhage12, especially when anti-thrombotic 130 therapy is administrated after angioplasty and/or stenting. It may also postpone endovascular treatment and 131 increase medical expenditures13. The therapeutic time window of intravenous thrombolysis is very narrow, which 132 has largely limited its application. 133 It remains uncertain whether pretreated with intravenous rt-PA provides any additional benefits to the acute 134 anterior large vessel occlusive patients experiencing endovascular treatment. A meta-analysis revealed that 135 patients treated with bridging therapy have higher recanalization rates, fewer device passes, equal probabilities 136 of symptomatic intracerebral hemorrhage, better clinical neurological outcomes, and lower mortality rates 137 compared with patients treated with direct endovascular treatment14. Whereas, a propensity score matching 138 analysis based on the Chinese population suggested that direct endovascular treatment can achieve similar 139 efficacy to that of bridging therapy, and a lower proportion of asymptomatic intracranial hemorrhage12. However, 140 the baseline characteristics for the direct endovascular treatment group and bridging-therapy group of these 141 studies are lack of equipoise, which may have significant influence on the results. Prospective data on direct 142 endovascular treatment for acute anterior large vessel occlusion remains scarce. Thus, we propose the hypothesis 143 that EVT alone initiated within 4.5 h of stroke onset is not inferior to rt-PA plus EVT in acute stroke patients 144 with a proximal LVO in the anterior circulation. 145 146 2. TRIAL OBJECTIVES 147 Direct Endovascular Treatment Versus Standard Bridging Therapy in Large Artery Anterior Circulation Stroke 148 (DEVT) Trial aims to investigate whether EVT alone is non-inferior to rt-PA plus EVT in acute anterior 149 circulation large vessel occlusive patients who are eligible for intravenous rt-PA. 150 151 3. TRIAL DESIGN 152 DEVT trial is a multicenter, prospective, randomized, open-label controlled clinical trial with blinded endpoint 153 evaluation. It is an academic trial designed by the principal investigators and a steering committee consisting of 154 experts in cerebrovascular diseases and interventional neuroradiology. The study patient flow outline was shown 155 in Figure 1. 156 Figure 1 Study flowchart of DEVT trial.

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157 158 4. PATIENT POPULATION 159 4.1. Inclusion criteria 160 (1) Aged 18 years or older; 161 (2) Presenting with AIS symptom within 4.5 hours; 162 (3) Eligible for IV rt-PA; 163 (4) Occlusion of the intracranial internal carotid artery (ICA) or M1 segment of the middle cerebral artery 164 (MCA) confirmed by CT or MR angiography (CTA or MRA); 165 (5) Randomization no later than 4 hours 15 minutes after stroke symptom onset; 166 (6) Informed consent obtained from patients or their legal representatives. 167 4.2. Exclusion criteria 168 (1) CT or MR evidence of hemorrhage (the presence of micro-bleeds is allowed); 169 (2) Contraindications of IV rt-PA; 170 (3) Pre-morbidity with a modified Rankin scale (mRS) score of ≥ 2; 171 (4) Currently in pregnant or lactating or serum beta HCG test is positive on admission; 172 (5) Contraindication to radiographic contrast agents, nickel, titanium metals or their alloys; 173 (6) Arterial tortuosity and/or other arterial disease that would prevent the device from reaching the target 174 vessel; 175 (7) Patients with a preexisting neurological or psychiatric disease that would confound the neurological 176 functional evaluations; 177 (8) Subjects with occlusions in multiple vascular territories (e.g. bilateral anterior circulation, or 178 anterior/posterior circulation); 179 (9) CT or MRI evidence of mass effect or intracranial tumor (except small meningioma); 180 (10) CT or MRI evidence of cerebral vasculitis;

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181 (11) CTA or MRA evidence of intracranial arteriovenous malformations or aneurysms; 182 (12) Any terminal illness with life expectancy less than 6 months; 183 (13) Unlikely to be available for 90-day follow-up; 184 (14) Current participation in another clinical trial. 185 186 5. PARTICIPATING CENTER ELIGIBILITY 187 To be fully eligible for participation in this trial, study centers were required have performed at least 80 188 endovascular procedures annually, including at least 50 thrombectomy procedures with the stent-retriever 189 devices. Moreover, all neurointerventionists with more than five years’ experience in cerebrovascular 190 intervention and at least 10 cases of mechanical thrombectomy with stent retriever devices annually. 191 192 6. RANDOMIZATION 193 Subjects will be randomly assigned in a 1:1 fashion to receive EVT alone or IV rt-PA plus EVT. Randomization 194 occurs immediately after baseline (at the EVT institution) CT/MR brain imaging and CT/MR angiography via a 195 real-time, internet-based randomization method. The randomization was stratified by participating centers. The 196 time of randomization is defined as the time randomization occurred on the central server and this time is 197 considered time zero for the study. IV rt-PA will be infused immediately after randomization. 198 All subjects, investigators, their clinical staff, the clinical coordinating center, the data management group, and 199 the sponsor staff and delegates will be blinded to the randomization codes. The local laboratories will also be 200 blinded. 201 202 7. TREATMENTS 203 Patients are assigned to receive either EVT alone (primary-thrombectomy group) or rt-PA plus EVT 204 (bridging-therapy group). In the bridging-therapy group, subjects will receive a single rt-PA dose of 0.9 mg/kg 205 IV (maximum dose: 90 mg), with 10% given as a bolus, followed by continuous IV infusion of the rest dose 206 within 1 hour. Simultaneously, EVT preparation should be initiated with or as soon as IV rt-PA administration. 207 While in the primary-thrombectomy group, subjects will receive EVT alone without prior IV rt-PA. Subjects in 208 both groups will undergo rapid EVT. EVT consisted of mechanical thrombectomy, thromboaspiration, balloon 209 dilation, stenting, intra-arterial thrombolysis, or various combinations of these approaches. The choice of 210 technique is left to the discretion of the treating neurointerventionist. Additionally, stenting of the extracranial or 211 intracranial artery is permitted when absolutely necessary to obtain access to distal occlusion or to prevent acute 212 re-occlusion. This may require the use of thrombolytic agents to prevent acute stent thrombosis. After 213 recanalization of the target artery, all patients will get stroke unit care and postoperative management follows the 214 current American Heart Association/American Stroke Association guidelines15. 215 The use of conscious sedation or general anesthesia for the procedure to ensure the comfort and safety of patients 216 is at the discretion of the individual site neurointerventionalist. The steering committee will make 217 recommendations for dosages of thrombolytic agents, procedures, and for devices that will be considered in the 218 trial based on proposals by the executive committee or local investigators. The requirements for a device to be 219 considered in the trial should be approved by the China Food and Drug Administration or National Medical 220 Products Administration. 221 222 8. OUTCOMES 223 8.1. Primary Efficacy Outcome 224 The primary end-point is the overall proportion of subjects experiencing a functional independence 90 days post 225 randomization, defined as a score of 0 to 2 on the mRS. To ensure the reliability, evaluability, and traceability of

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226 the mRS score, we keep patients’ video or voice version of follow-up at 90 days except those who die or refuse 227 to take a video. The primary functional outcome is centrally assessed by two independent certified neurologists 228 in a blinded manner by the use of the video or voice recording. Disagreements are resolved by consensus. 229 8.2. Secondary Efficacy Outcomes 230 (1) Shift in the distribution of mRS scores at 90 days in EVT alone versus rt-PA plus EVT (ordinal shift 231 analysis); 232 (2) Proportion of mRS score 0 to 1 at 90 days; 233 (3) Successful recanalization proportion immediate after EVT. Successful recanalization is defined as a 234 modified Treatment in Cerebral Infarction score of 2b (50 to 99% reperfusion) or 3 (complete reperfusion) 235 in the post-procedure angiography16; 236 (4) Vessel recanalization rate evaluated by CTA or MRA within 48 hours; 237 (5) The change of the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours from baseline17; 238 (6) The change of the NIHSS score at 5-7 days or discharge if earlier from baseline; 239 (7) European Quality Five Dimensions (EQ-5D) scale score at 90 days. 240 8.3 Safety Outcomes 241 (1) Symptomatic intracerebral hemorrhage (sICH) rate within 48 hours. ICH will be evaluated according to the 242 Heidelberg Bleeding Classification18. sICH was diagnosed if the new observed ICH was associated with 243 any of the following conditions: 1) NIHSS score increased more than 4 points than that immediately before 244 worsening; 2) NIHSS score increased more than 2 points in one category; 3) Deterioration led to intubation, 245 hemicraniectomy, external ventricular drain placement or any other major interventions. Additionally, the 246 symptom deteriorations could not be explained by causes other than the observed ICH. Hemicraniectomy 247 will be defined as that surgical procedure used to decompress the swollen hemisphere; 248 (2) Mortality at 90 days. Mortality rates are defined as the number of deaths observed divided by the number of 249 subject observed over the 90-day study period. 250 (3) Procedure-related complications such as arterial perforation, iatrogenic arterial dissection, embolization in 251 previously uninvolved vascular territory, arterial access site hematoma, and retroperitoneal hematoma. 252 Arterial perforation will be defined at angiography by the operator and associated with subarachnoid 253 hemorrhage. Iatrogenic arterial dissection will be defined at angiography by the operator. Arterial access 254 site hematoma will be assessed as a complication of arterial access puncture and defined by clinical 255 examination and anatomic imaging. Retroperitoneal hematoma will be assessed as a complication of groin 256 puncture and defined by imaging (ultrasound or CTA or MR). The definition of embolization in previously 257 uninvolved vascular territory is noted after recanalization of the primary occlusion site, any vessel 258 occlusions distal from the primary occlusion site were considered emboli due to periprocedural thrombus 259 fragmentation. 260 (4) Incidence of serious adverse events. 261 262 9. BLINDING AND MASKING 263 Each site will designate one or more physician(s) to perform the follow-up evaluation at 24 hours, 5-7 days or 264 discharge if earlier and at 90 days who cannot be involved in care of the subjects and must remain blinded to 265 treatment assignment of each subject. 266 Regarding the NIHSS examination at baseline, 24 hours, 5-7 days or discharge if earlier and the primary 267 end-point, first, a local independent neurologist, not involved in the trial patient management, will evaluate the 268 scores in a face to face clinical visit, recording the examination by video with the consent of patient or the legal 269 representative; and second, two experienced and certified physicians will centrally evaluate the score by using

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270 the video recording. For cases with disagreement between the two assessors, decisions were made by the third 271 experienced neurologist. 272 All neuroimaging end-points including baseline Alberta Stroke Program Early Computed Tomography Score 273 (ASPECTS) score, recanalization within 48 hours, collateral circulation classification and hemorrhage will be 274 determined by the CT/MR core laboratory, which will be also blinded to treatment allocation. Another 275 independent angiographic core lab will review angiographic images from the procedure to determine clot 276 location and recanalization. Serious adverse events (SAEs) and procedure-related complications will be reviewed 277 and adjudicated by two individuals of the independent clinical events committee who will be blinded to 278 treatment allocation. 279 280 10. ASSESSMENT OF EFFICACY 281 10.1. The Modified Rankin Scale 282 The mRS is a valid and reliable clinician-reported measure of global disability that has been widely applied for 283 evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or 284 dependence in daily activities) of people who have suffered a stroke19,20. mRS scores range from 0 to 6, with 0 285 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death. The 286 mRS will be obtained at Day 90. Premorbid mRS status will also be obtained retrospectively at 24 Hours. The 287 mRS will only be scored by those trained and certified in the use of this scale. 288 10.2. The National Institutes of Health Stroke Scale 289 The NIHSS is a standardized neurological examination score that is a valid and reliable measure of disability and 290 recovery after acute stroke17. Scores range from 0 to 42, with higher scores indicating increasing severity. The 291 scale includes measures of level of consciousness, extra ocular movements, motor and sensory tests, 292 coordination, language and speech evaluations. The NIHSS will be administered at Baseline, at 24 hours from 293 baseline, Day 5-7or discharge. The NIHSS will only be scored by those trained and certified in the use of this 294 scale. 295 10.3. EQ-5D 296 The EQ-5D is a generic instrument for describing and valuing health. It is based on a descriptive system that 297 defines health in terms of five dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and 298 Anxiety/Depression21. Each dimension has five response categories corresponding to: no problems, slight, 299 moderate, severe and extreme problems22. The instrument is designed for self-completion, and respondents also 300 rate their overall health on the.day of the interview on a 0-100 hash-marked, vertical visual analogue scale. The 301 EQ- 5D will be administered on Day 90 by those trained in the use of this scale. 302 303 11. ASSESSMENT OF SAFETY 304 11.1. Adverse Event Definitions 305 11.1.1. Adverse Event 306 An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject 307 administered a pharmaceutical product and which does not necessarily have to have a causal relationship with 308 this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 309 finding, for example), symptom or disease temporally associated with the use of a medicinal product, whether or 310 not considered related to the medicinal product. 311 Therefore, an AE may be: A new illness; The worsening of a concomitant illness; An effect of vaccination, 312 including the comparator; A combination of the above. 313 Pre-existing medical conditions are not to be reported as AEs. However, if a pre-existing condition worsens in 314 frequency or intensity, or if in the assessment of the treating physician there is a change in its clinical

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315 significance, this change should be reported as an AE (exacerbation). This applies equally to recurring episodes 316 of pre-existing conditions (e.g., asthma) if the frequency or intensity increases post-randomization. 317 11.1.2. Serious Adverse Event 318 A serious adverse event (SAE) is any untoward medical occurrence that at any dose: Result in death; Are 319 life-threatening; Require or prolong inpatient hospitalization; Result in persistent or significant 320 disability/incapacity, or; Are a congenital/birth defect. 321 A SAE can also be an important medical event that may not result in death, be life-threatening, or require 322 hospitalization, but may jeopardize the subject and may require medical or surgical intervention to prevent one 323 of the outcomes listed in this definition. For example, any new diagnosis of cancer (made after study enrollment) 324 is considered an important medical event. Because our primary safety outcomes for the trial are also SAEs by 325 definition, they will be reported dually as SAEs and as outcomes. SAEs should be managed according to the best 326 current standard of care. 327 All deaths occurring during the follow up to Day 90 will be reported as an SAE. When reporting a death, the 328 event or condition that caused or contributed to the fatal outcome should be reported as a single medical concept. 329 AE occurring within 30 days of randomization and all SAEs will be reported in the CRF. Severity and 330 relationship definitions are presented below. 331 11.2. Definitions of AE-Related Terms AE Severity Mild Awareness of sign or symptom but easily tolerated Moderate Discomfort sufficient to cause interference with normal activities. Severe Incapacitating, with inability to perform normal activities. AE Relationship Related A clinical event, including laboratory test abnormality, where there is a “reasonable possibility” that the SAE was caused by the study drug, meaning that there is evidence or arguments to suggest a causal relationship. Probably A clinical event, including laboratory test abnormality, with a reasonable time sequence to drug administration, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal. Possibly A clinical event, including laboratory test abnormality, with a reasonable time sequence to drug administration, but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear. Unrelated This category is applicable to AEs which are judged to be clearly and incontrovertibly due to extraneous causes (diseases, environment, etc.) and do not meet the criteria for drug relationship listed for the above-mentioned conditions. 332 333 12. CLINICAL MANAGEMENT OF ADVERSE EVENTS 334 12.1. Identification of Adverse Events by the Investigator 335 AE monitoring and reporting will be followed-up until Day 30. SAEs will be followed through the final study 336 exit visit (Day 90 Visit or death or end of study whichever is sooner) or until the subject is deemed “lost to 337 follow-up”. 338 AE identification while the subject is admitted to the acute stroke hospital will be collected via acute stroke 339 hospital patient records and verbal histories from the subject or legally authorized representative (LAR). For

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340 follow up visits after discharge from the acute stroke hospital the subject (or LAR if the subject is not able to 341 respond to the questions) will be asked about the occurrence of AEs since the last contact, and if available, from 342 records at the acute stroke hospital. AEs that were ongoing at the last contact will be updated with a stop date or 343 confirmed as ongoing. AE collection will continue until Day 30, and SAE to Day 90 or the final contact. 344 A consistent methodology of eliciting AEs at all subject evaluation timepoints will be used. Non-directive 345 questions include: How have you felt since your last clinical visit/hospital discharge? Have you had any new or 346 changed health problems since you were last here? Have you had any unusual or unexpected worsening of your 347 underlying medical condition or overall health? Have there been any changes in the medicines you take since 348 your last clinical visit/hospital discharge? 349 Diagnosis versus signs and symptoms for the purpose of AE reporting: if known at the time of reporting, a 350 diagnosis should be reported rather than individual signs and symptoms. However, if a constellation of signs 351 and/or symptoms cannot be medically characterized as a single diagnosis it is acceptable to report the 352 information that is ultimately available. 353 12.2. Reporting of Adverse Events 354 AEs should be reported as they occur on the electronic Case Report Form (e-CRF). Documentation must be 355 supported by an entry in the subject’s file. Each event should be described in detail along with start and stop 356 dates, severity, relationship to investigational product as judged by the investigator, action taken and outcome. 357 12.3. Reporting of Serious Adverse Events 358 In order to comply with current regulations on SAE reporting to health authorities, the investigator must 359 document all SAEs regardless of causal relationship and notify the Sponsor. The Investigator will give access 360 and provide the Sponsor with all necessary information to allow the Sponsor to conduct a detailed analysis of the 361 safety of the investigational product. It is the responsibility of the Investigator to request all necessary 362 documentation (e.g., medical records, discharge summary, autopsy) in order to provide comprehensive safety 363 information. All relevant information must then be transcribed into the e-SAE Form. 364 12.4. Reporting by the Investigator 365 All SAEs must be reported to the Sponsor within 24 hours of the local Investigator’s first awareness of its 366 occurrence. SAEs will be reviewed by the trial medical monitor. 367 The investigator will report the SAEs using the e-SAE form in the e-CRF, which will send an immediate alert to 368 the Sponsor. If the e-CRF system is not available, a paper SAE form should be directed within 24 hours. 369 12.5. Reporting SAEs to the Health Authorities and Ethics Committees 370 The Sponsor will inform the relevant health authorities of any reportable SAEs according to the local regulatory 371 requirements. Reporting to the health authorities will be according to the Sponsor’s standard operating 372 procedures. 373 SAEs that are assessed by the Sponsor to be unexpected and related to study drug (expedited reporting SAEs) 374 will be reported to the regulatory agencies as per country requirements. All other SAEs will be reported to 375 regulatory agencies based upon local reporting requirements. 376 The Sponsor’s medical monitor or designee will notify the investigators in writing of the occurrence of any 377 reportable SAEs. The Sponsor or delegate will be responsible for reporting suspected unexpected serious adverse 378 reaction to any Central Ethics Committees in compliance with local current legislation. The investigators will be 379 responsible for informing their local ethics committees of any reportable SAEs as per their local requirements. 380 381 13. DATA SAFETY MONITORING BOARD 382 The independent Data safety monitoring board (DSMB) will be composed of an experienced neurologist, an 383 interventionalist, and a biostatistician, which are not involved in the trial. The DSMB will meet at least once a 384 year, and is provided with structured unmasked reports, prepared by the trial statistician, for their reference only.

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385 DSMB is responsible for recommendations to the executive committee regarding stopping or extending the trial. 386 In addition, the DSMB will review the occurrence of SAEs and make recommendations to the executive 387 committee regarding safety of the trial. 388 389 14. IMAGING CORE LABORATORY 390 Centralized imaging core laboratories will be used in this trial to provide consistent assessment of all the images. 391 CT/MR and angiographic images will be independently reviewed by two independent central imaging core 392 laboratories respectively. CT/MR core laboratory will review CT/MR images obtained at baseline and within 24 393 hours for confirmation of inclusion criteria, ASPECTS score, collateral circulation classification, and 394 presence/absence of hemorrhage. Angiographic core laboratory will review angiographic images from the 395 procedure to determine clot location and recanalization. CT/MR core laboratory will be independent from the 396 angiographic core laboratory to ensure the CT/MR core laboratory is blinded to the treatment allocation. 397 398 15. CLINICAL EVENTS COMMITTEE 399 The Clinical events committee (CEC) will be comprised of three expert physicians independent of the 400 investigational sites. This committee will validate all the complications that occur over the course of the study 401 and categorized for severity and relatedness according to the definition in the Adverse Event section in the CEC 402 Manual of Operations. The CEC can request any additional source information and images supporting the 403 adverse events to assist with the adjudication. 404 405 16. STATISTICS 406 16.1. Sample size estimates 407 According to the previous study data12,23-25, we hypothesis that the 90-day follow-up proportion of independent 408 functional outcome is 43% both in the primary-thrombectomy group and bridging-therapy group. The clinically 409 relevant non-inferiority margin was -10.0%. To maintain the alpha, Pocock Analog Alpha Spending Function 410 is used. Sample size and power are computed incorporating a five-look group-sequential analysis plan with a 411 one-sided at 0.025, 918 cases provide 80% power for testing the primary hypothesis of this trial; assuming the 412 attrition rate is 5% for the primary end-point, the total sample size is up to 970. The evaluable sample size is 194 413 at each interim analysis. Therefore, in each interim analysis, 97 cases should be enrolled in each treatment group. 414 16.2. Analysis Populations 415 16.2.1. Intention-to-treat Population 416 The primary efficacy analysis will be conducted in the intention-to-treat (ITT) population, defined as all subjects 417 randomized into the trial with grouping by randomized treatment, regardless of treatment actually received. 418 Deceased subject will be included in the ITT population with a mRS score of 6. 419 16.2.2. Per Protocol Population 420 The primary analysis will be repeated on the Per Protocol (PP) population, defined to be all subjects randomized 421 and treated, with no major protocol deviations. This population will be determined via blinded review of 422 protocol deviations at the end of the trial before database lock and unblinding. Prior to unblinding, the imaging 423 from each subject at the time of inclusion will be adjudicated to determine whether they have met the criteria for 424 endovascular intervention, and hence for the trial. This will include review of baseline NCCT and CTA. Subjects 425 who do not meet the imaging criteria outlined in the trial inclusion/exclusion criteria, will not be included in the 426 Per Protocol (PP) population. 427 Patients who withdraw informed consent immediately after randomization and are not to receive any treatment 428 should be excluded from all analysis populations. 429 16.3. Analysis of Primary Efficacy Outcome

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430 Non-inferiority test will be used to test the primary hypothesis that the proportion of patients with independent 431 functional outcome will be non-inferior in the primary-thrombectomy group compared to the bridging-therapy 432 group. We desired a maximum of 5 looks when approximately 20, 40, 60, 80, and 100% of the total sample size 433 finish the follow-up, monitoring and data cleaning processes. A group-sequential test strategy was designed to 434 have reasonable chances of stopping as early as possible, either because of efficacy or safety reasons. The 435 independent DSMB may recommend stopping the trial either for effectiveness, or safety in case the stopping 436 boundaries are crossed at interim analysis. For shedding cases, follow-up will be performed until the end of the 437 study, and the results will be included in the final analysis. Statistical analysis will be performed on the SAS 9.3 438 system. Details of these are provided in the Statistical Analysis Plan. 439 16.4. Analysis of secondary efficacy outcomes 440 The key secondary outcomes will be tested in the following order: 441 1.The Proportion of mRS score 0 to 1 at 90 days; 442 2.Shift in the distribution of mRS scores at 90 days in EVT alone versus rt-PA plus EVT (ordinal shift analysis); 443 3.Successful recanalization proportion immediate after EVT. 444 4.Vessel recanalization rate evaluated by CTA or MRA within 48 hours; 445 5.The change of the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours from baseline; 446 6.The change of the NIHSS score at 5-7 days or discharge if earlier from baseline; 447 7.European Quality Five Dimensions (EQ-5D) scale score at 90 days. 448 16.5. Adjustment for covariates and subgroup analyses 449 In addition to the primary and secondary analyses adjusting for age, sex, baseline NIHSS score, baseline 450 ASPECTS score, occlusion location, exploratory analyses will be conducted to determine the potential roles of 451 common baseline characteristics and assess potential heterogeneity of treatment effect across subgroups. Specific 452 subgroups of interest include the age >= 70 vs. < 70 years old, male vs. female, subject with different baseline 453 stroke severity (on NIHSS and measured radiologically on ASPECTS), baseline occlusion location (ICA 454 occlusion: no vs. yes), cause of stroke, onset to randomization time. Full details will be specified in detail in the 455 Statistical Analysis Plan. 456 16.6. Handling of Missing Data 457 Every effort will be made to keep missing data, particularly the Day 90 outcome assessments, to a minimum. 458 However, some missing data may be inevitable due to, for example, loss to follow-up. Deceased subject will 459 score 6 on the mRS and be counted as non-responders. For the primary analysis for regulatory submission, we 460 will assume that subject missing the primary endpoint data will be considered to be non-responders. Sensitivity 461 analyses using various imputation techniques will be specified prospectively in the Statistical Analysis Plan 462 before the database lock for the interim analysis if more than 5% of subject randomized are missing the primary 463 endpoint. 464 16.7. Analyses of Safety 465 The main analyses will be frequency of sICH and 90-day mortality. It is expected that the safety population and 466 the ITT population will be near-identical. Full details will be specified in detail in the Statistical Analysis Plan. 467 468 17. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 469 The sponsor or delegate will be permitted to visit the study facilities at any reasonable time in order to maintain 470 current, detailed knowledge of the study through review of the records, source documents, observation, and 471 discussion of the conduct and progress of the study. In addition, the sponsor will maintain regular telephone and 472 written communication with all investigators through the coordinating center. The sponsor (or delegate) will be 473 given complete access to all components of the study facility that pertain to the conduct of this study, and may be 474 present to observe any aspect of the conduct of the study by medical and paramedical staff, including but not

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475 limited to drug preparations, dosing, sample collections, and clinical observations. E-CRFs will be monitored 476 with sufficient frequency to assess the following: Subject randomization, compliance with protocol procedures, 477 the completeness and accuracy of data entered into the e-CRFs, verification of e-CRF data against original 478 source documents, and occurrence of AEs. Adequate time and all documents for these monitoring visits must be 479 made available by the investigators. The investigators will permit trial-related monitoring, audits, REB/IRB 480 review, and regulatory inspections, providing direct access to source data/documents. 481 482 18. QUALITY CONTROL AND QUALITY ASSURANCE 483 To ensure monitoring responsibilities are performed to the fullest extent possible, industry experienced study 484 monitors will perform on site data verification for the trial. All data monitored on site are verified for accuracy 485 and completeness using source documents for all subjects. In addition, 100% of subjects enrolled are monitored 486 for the presence of signed consent. 487 Monitoring of the investigational sites will be conducted by the sponsor or contracted to a qualified clinical 488 research organization. The sponsor will determine the extent, nature, and frequency of on-site visits that are 489 needed to ensure that the study is being conducted in accordance with the approved protocol (and any 490 amendments), Good Clinical Practice (GCP), and all applicable regulatory requirements. At site visits, the 491 monitor will, as required, assess the progress of the study; check that the study data chosen for verification are 492 authentic, accurate, and complete; verify that the safety and rights of patients are being protected; compare 493 original documents with data entered into the study database; and identify any issues and address their 494 resolution. 495 The investigator agrees to allow the monitor(s) direct access to all relevant documents, and to allocate his/her 496 time and the time of staff to discuss findings, corrective actions and any relevant issues. In addition to contacts 497 during the study, the monitor may also contact the site prior to the start of the study to discuss the protocol and 498 data collection procedures with site personnel. 499 Additional on-site monitoring verification includes: ongoing evaluation of the adequacy of site facilities and staff, 500 site recruitment, subject randomization, the presence of regulatory documents, and specific review of documents 501 and data. The initial performance-monitoring visit to a site takes place after the initial subject(s) are enrolled and 502 will continue according to enrolment for the duration of the trial. 503 During the monitoring visit, any omissions and corrections to data submitted to the database will be noted and 504 queries will be generated by the monitor and resolved by the site. 505 The close-out monitoring visit by the monitor will take place at the completion of subject enrollment and 506 protocol required follow-up visits at the performance site. At that visit, the monitor will again review the 507 presence of a regulatory file and verify documents for currency and completion as directed by the clinical 508 research unit. Sites will be instructed in the record retention of all trial documents. Principal Investigators are 509 directed to close the trial and issue a final report to the institutional review board. Finally, any additional special 510 considerations for the auditing of any additional safety issues are made during this final monitoring visit. 511 Except for an emergency situation in which proper care for the protection, safety and well- being of the study 512 subjects requires medical treatment, the study will be conducted as described in the approved protocol, 513 International Conference on Harmonization-Good Clinical Practice (ICH-GCP), Standard Operating Procedures 514 (SOPs) and regulatory requirements. All medical treatments will be recorded. Any deviation(s) from the protocol 515 will be recorded and presented in the final clinical study report. 516 18.1. Audits and Inspections 517 In accordance with the principles of ICH-GCP, the study site may be inspected by regulatory authorities. Quality 518 Assurance (QA) or their designates. The investigator and relevant clinical support staff will be required to be

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519 actively involved in audits and inspections, including staff interviews, and to make all necessary documentation 520 and data available upon request. 521 During the course of the study and/or after it has been completed, one or more investigator site audits may be 522 undertaken by auditors. The purpose of these audits is to determine whether or not the study is being/has been 523 conducted and monitored in compliance with recognized ICH-GCP, protocol and approved amendment 524 requirements, applicable local SOPs, and local laws and regulations. It is the responsibility of the investigator 525 and site staff to promptly address any deficiencies stemming out of regulatory inspections and delegate audits, 526 and to ensure that agreed-upon corrective and preventive actions are implemented as soon as possible. An 527 inspection by any regulatory authority may occur at any time during or after completion of the study. 528 18.2. Protocol Amendments and Revisions 529 Should amendments and/or revisions to the protocol be required, they will be originated and documented by the 530 sponsor. All amendments and/or revisions will be made in compliance with sponsor SOPs. All amendments will 531 be submitted to the research ethics board/Institutional Review Board (REB/IRB) for approval prior to 532 implementation. It is the sponsor’s responsibility to submit all revisions and amendments to regulatory 533 authorities when necessary. 534 535 19. ETHICAL CONSIDERATION 536 This research followed the ethical principles of the Helsinki Declaration. This protocol and the consent forms 537 will be submitted to each hospital’s REB/IRB. Before initiation of the study, a copy of the REB/IRBs’ approval 538 letters will be provided to the sponsor and the membership list of the REB/IRB will be kept on file. To make 539 sure the subjects fully understand about this trial, the investigators must provide the patients or their legal 540 representatives with detailed information about the clinical trial, including the purpose of the trial, possible 541 benefits and risks, and the rights/obligations. Subjects have the right to withdraw from the study at any time if 542 they wish to do so. The privacy protection of subjects has to be ensured. The patients or their legal 543 representatives give their written informed consent prior to the study. Each patient must leave contact 544 information to the investigator of the participating center. At the same time, the investigator must leave his own 545 phone number to the patient so that the patient can find the investigator at any time. Ethical approval for the 546 study was obtained by the Ethics Committee of the participating centers. SAEs will be reported to the REB/IRB 547 according to their requirements. 548 549 20. DATA HANDLING AND RECORD KEEPING 550 20.1. Data Handling 551 During the trial, clinical data reported in the e-CRFs will be integrated into the clinical database under the 552 responsibility of the Sponsor or their qualified representative. Quality control in the form of computerized logic 553 and/or consistency checks will be systematically applied in order to detect errors or omissions. In addition, safety 554 reviews may be performed several times by the Sponsor’s staff in the course of the trial. Any questions 555 pertaining to the reported clinical data will be submitted to the investigator for resolution. Each step of this 556 process will be monitored through the implementation of individual passwords to maintain appropriate database 557 access and to ensure database integrity. 558 After integration of all corrections in the complete set of data, the database will be released for statistical 559 analysis. 560 20.2. Investigator Files/Retention of Documents 561 The investigator must maintain adequate and accurate records to enable the conduct of the study to be fully 562 documented and the study data to be subsequently verified. These documents should be classified into two 563 different separate categories: Investigator's Study File; and Subject Clinical Source Documents.

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564 The Investigator's Study File will contain the Protocol/Amendments, CRFs, REB/IRB and governmental 565 approval with correspondence, all versions of ethics approved informed consent forms, staff curriculum vitae 566 and authorization forms and other appropriate documents/correspondence, etc. 567 Subject clinical source documents (usually defined by the project in advance to record efficacy/safety parameters 568 independent of the CRFs) would include subject hospital/clinic records, physician's and nurse's notes, 569 appointment book, original laboratory reports, ECG, image data, signed consent forms, consultant letters, and 570 source worksheets. The investigator must keep these two categories of documents on file according to local 571 clinical trial regulation. 572 The Investigator and the sponsor will maintain the records of disposition of the drug and the clinic records in 573 accordance with ICH-GCP and each applicable regulatory agency. Clinic records will be retained at the site until 574 informed by the sponsor to destroy the documents. If the clinical study must be terminated for any reason, the 575 investigator will return all study materials to the sponsor and provide a written statement as to why the 576 termination has taken place and notify the REB/IRB. 577 20.3. Source Documents and Background Data 578 Any investigators shall supply the sponsor, upon request, with any required background data from the study 579 documentation or clinic records. This is particularly important when e-CRFs are illegible or when errors in data 580 transcription are suspected. In case of special problems and/or governmental queries or requests for audit 581 inspections, it is also necessary to have access to the complete study records, provided that subject 582 confidentiality is protected. 583 20.4. Case Report Forms 584 For each subject randomized, an e-CRF must be completed and signed by the investigator. If a subject withdraws 585 from the study, the reason must be noted on the CRF. All forms should be completed within five business days 586 of subject visit. All corrections will be tracked in the e-CRF audit trail. The Investigator should ensure the 587 accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all 588 required reports. 589 20.5. Confidentiality 590 All imaging, evaluation forms, reports, and other records that leave the site are identified only by the site and 591 subject number to maintain subject confidentiality. All records are kept in a locked file cabinet. Clinical 592 information is not released without written permission of the subject, except as necessary for monitoring by 593 REB/IRB, health authorities, the sponsor, or the sponsor’s designee. 594 All study investigators at the clinical sites must ensure that the confidentiality of personal identity and all 595 personal medical information of study subjects are maintained at all times. clinical sites must conform to local 596 privacy and confidentiality law and custom. On the CRFs and other study documents or image materials 597 submitted to the CRU, the subjects are identified only by study identification codes. 598 Personal medical information may be reviewed for the purpose of verifying data recorded in the CRF by the site 599 monitors. Other properly authorized persons, such as the regulatory authorities, may also have access to these 600 records. Personal medical information is always treated as confidential. 601 602 21. PUBLICATION AND PRESENTATION POLICY 603 A trial executive committee shall be formed, and include at least the trial principal investigator and co-principal 604 investigator, the statistical consultant, and representatives of the Sponsor. The trial executive committee will be 605 co-authors on all publications and presentations. The primary author list for the primary publication will consist 606 of the executive committee and the site principal/qualified investigator at each of the sites. A formal publication 607 policy will be presented and developed by the trial executive. 608

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609 22. DATA-SHARING PLAN 610 The sponsor will permit any and all academic publications arising from the trial data provided that no publication 611 containing unblinded trial data precedes publication of the overall trial results in a peer-review journal, and are 612 (1) approved by the trial executive committee and (2) the publication authors notify the sponsor at least 30 days 613 prior to submittal for publication with a copy of such proposed publication for the sponsor’s review and 614 comment. Employees or consultants of the sponsor will only be named as authors in any such publication if the 615 parties agree that it is appropriate under the usual conventions used by academic institutions for naming authors 616 in scientific publications. Upon request of the sponsor the publication or disclosure shall be delayed for up to 60 617 days in order to allow for the filing of a patent application. The Executive Committee will make the trial results 618 available as free-access using PubMed and on Chinese Clinical Trials Registry. (www.chictr.org.cn). 619 620 23. STUDY ORGANIZATION AND FUNDING 621 DEVT trial is an investigator-initiated study which is organized by the second affiliated hospital of the Third 622 Military Medical University and conducted in about 30 comprehensive stroke centers in China. The authors 623 disclosed receipt of the following financial support: (1) National Science Fund for Distinguished Young Scholars 624 (No. 81525008), and (2) Major clinical innovation technology project of the Second Affiliated Hospital of the 625 Army Military Medical University (No. 2018JSLC0017). The funders had no involvement in the study design, 626 data collection, analysis and interpretation, writing or decision to submit the paper. 627

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628 Appendix 1 – Classification of Subtype of Acute Ischemic Stroke 629 The TOAST classification system includes five categories: 1) large-artery atherosclerosis, 2) cardioembolism, 3) 630 small-artery occlusion (lacunae), 4) stroke of other determined etiology, and 5) stroke of undetermined etiology 631 (Table 1)26. Diagnoses are based on clinical features and on data collected by tests such as brain imaging 632 (CT/MRI), cardiac imaging (echocardiography, etc.), duplex imaging of extracranial arteries, arteriography, and 633 laboratory assessments for a pro-thrombotic state. 634 The physician can apply the clinical and imaging findings when first assessing the patient and then consider the 635 results of other diagnostic tests later. An important part of the classification is the ability of the physician to 636 categorize a specific subtype diagnosis as probable or possible based on the degree of certainty. A "probable" 637 diagnosis is made if the clinical findings, neuroimaging data, and results of diagnostic studies are consistent with 638 one subtype and other etiologies have been excluded. A "possible" diagnosis is made when the clinical findings 639 and neuroimaging data suggest a specific subtype but other studies are not done. Because many patients will 640 have a limited number of diagnostic tests, the probable and possible subcategorizations allow the physician to 641 make as precise a subgroup diagnosis as can be achieved. 642 Large artery atherosclerosis 643 These patients will have clinical and brain imaging findings of either significant (>50%) stenosis or occlusion of 644 a major brain artery or branch cortical artery, presumably due to atherosclerosis (Table 2). Clinical findings 645 include those of cerebral cortical impairment (aphasia, neglect, restricted motor involvement, etc.) or brain stem 646 or cerebellar dysfunction. A history of intermittent claudication, transient ischemic attacks (TIAs) in the same 647 vascular territory, a carotid bruit, or diminished pulses helps support the clinical diagnosis. Cortical or cerebellar 648 lesions and brain stem or subcortical hemispheric infarcts greater than 1.5 cm in diameter on CT or MRI are 649 considered to be of potential large-artery atherosclerotic origin. Supportive evidence by duplex imaging or 650 arteriography of a stenosis of greater than 50% of an appropriate intracranial or extracranial artery is needed. 651 Diagnostic studies should exclude potential sources of cardiogenic embolism. The diagnosis of stroke secondary 652 to large artery atherosclerosis cannot be made if duplex or arteriographic studies are normal or show only 653 minimal changes. 654 Cardioembolism 655 This category includes patients with arterial occlusions presumably due to an embolus arising in the heart (Table 656 2). Cardiac sources are divided into high-risk and medium-risk groups based on the evidence of their relative 657 propensities for embolism (Table 3). At least one cardiac source for an embolus must be identified for a possible 658 or probable diagnosis of cardioembolic stroke. Clinical and brain imaging findings are similar to those described 659 for large-artery atherosclerosis. Evidence of a previous TIA or stroke in more than one vascular territory or 660 systemic embolism supports a clinical diagnosis of cardiogenic stroke. Potential large-artery atherosclerotic 661 sources of thrombosis or embolism should be eliminated. A stroke in a patient with a medium-risk cardiac source 662 of embolism and no other cause of stroke is classified as a possible cardioembolic stroke. 663 Small artery occlusion (lacunae) 664 This category includes patients whose strokes are often labeled as lacunar infarcts in other classifications (Table 665 2). The patient should have one of the traditional clinical lacunar syndromes and should not have evidence of 666 cerebral cortical dysfunction. A history of diabetes mellitus or hypertension supports the clinical diagnosis. The 667 patient should also have a normal CT/MRI examination or a relevant brain stem or subcortical hemispheric 668 lesion with a diameter of less than 1.5cm demonstrated. Potential cardiac sources for embolism should be absent, 669 and evaluation of the large extracranial arteries should not demonstrate a stenosis of greater than 50% in an 670 ipsilateral artery. 671 Acute stroke of other determined etiology

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672 This category includes patients with rare causes of stroke, such as nonatherosclerotic vasculopathies, 673 hypercoagulable states, or hematologic disorders. Patients in this group should have clinical and CT or MRI 674 findings of an acute ischemic stroke, regardless of the size or location. Diagnostic studies such as blood tests or 675 arteriography should reveal one of these unusual causes of stroke. Cardiac sources of embolism and large-artery 676 atherosclerosis should be excluded by other studies. 677 Stroke of undetermined etiology 678 In several instances, the cause of a stroke cannot be determined with any degree of confidence. Some patients 679 will have no likely etiology determined despite an extensive evaluation. In others, no cause is found but the 680 evaluation was cursory. This category also includes patients with two or more potential causes of stroke so that 681 the physician is unable to make a final diagnosis. For example, a patient with a medium-risk cardiac source of 682 embolism who also has another possible cause of stroke identified would be classified as having a stroke of 683 undetermined etiology. Other examples would be a patient who has atrial fibrillation and an ipsilateral stenosis 684 of 50%, or the patient with a traditional lacunar syndrome and an ipsilateral carotid stenosis of 50%. 685 686 TABLE 1. TOAST Classification of Subtypes of Acute Ischemic Stroke Large artery atherosclerosis (embolus/thrombosis)* Cardioembolism (high-risk/medium-risk)* Small-vessel occlusion (lacunae)* Stroke of other determined etiology* Stroke of undetermined etiology a. Two or more causes identified b. Negative evaluation c. Incomplete evaluation 687 TOAST denotes Trial of Org 10172 in Acute Stroke Treatment. 688 *Possible or probable depending on results of ancillary studies. 689 690 Table 2. Features of TOAST Classification of Subtypes of Ischemic Stroke Subtype Large artery Small artery Cardioembolism Other cause Features atherosclerosis occlusion (lacunae) Clinical Cortical or cerebellar + + - +/- dysfunction Lacunar - - + +/- syndrome Imaging Cortical, cerebellar, brain stem, or + + - +/- subcortical infarct > 1.5 cm

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Subcortical or brain stem - - +/- +/- infarct < 1.5 cm Tests Stenosis of extracranial + - - - internal carotid artery Cardiac source - + - - of emboli Other abnormality on - - - + tests 691 692 TABLE 3. TOAST Classification of High- and Medium-Risk Sources of Cardioembolism High-risk sources Mechanical prosthetic valve Mitral stenosis with atrial fibrillation Atrial fibrillation (other than lone atrial fibrillation) Left atrial/atrial appendage thrombus Sick sinus syndrome Recent myocardial infarction (<4 weeks) Left ventricular thrombus Dilated cardiomyopathy Akinetic left ventricular segment Atrial myxoma Infective endocarditis Medium-risk sources Mitral valve prolapse Mitral annulus calcification Mitral stenosis without atrial fibrillation Left atrial turbulence (smoke) Atrial septal aneurysm Patent foramen ovale Atrial flutter Lone atrial fibrillation Bioprosthetic cardiac valve Nonbacterial thrombotic endocarditis Congestive heart failure Hypokinetic left ventricular segment Myocardial infarction (> 4 weeks, < 6 months) 693

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694 Appendix 2 - ASITN/SIR Collateral Vessel Grading System 695 Collateral vessel status was evaluated by using the American Society of Interventional and Therapeutic 696 Neuroradiology/Society of Interventional Radiology (ASITN/SIR) collateral vessel grading system27. Collateral 697 vessel scores were categorized into ASITN/SIR grades 0 or 1, 2, and 3 or 4. The following scoring system 698 provides a guide. Grade Description 0 No collateral vessels visible to the ischemic site 1 Slow collateral vessels to the periphery of the ischemic site with persistence of some of the defect 2 Rapid collateral vessels to periphery of ischemic site with persistence of some of the defect and to only a portion of the ischemic territory 3 Collateral vessels with slow but complete angiographic blood flow of the ischemic bed by the late venous phase 4 Complete and rapid collateral blood flow to the vascular bed in the entire ischemic territory by retrograde perfusion 699 700

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701 Appendix 3 - The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) 702 NCCT shall be scored using ASPECTS, a 10-point score derived by examining each of 10 regions on the middle 703 cerebral artery territory28. Ischemic change present is scored as 0; ischemic change absent is score as 1. Adding 704 up the score gives a maximum of 10 (favorable scan) and minimum of 0 (unfavorable scan). The score is highly 705 reliable when trichotomized into 0-4 (severe ischemic change, large core), 5-7 (moderate ischemic change) and 706 8-10 (minimal ischemic change, small core). ASPECTS may be less reliable early in stroke (i.e. within 90 707 minutes of onset); however, at later time windows it should be easy to recognize large areas of irreversible 708 damage. Having a good quality scan and optimization of scanner is key to successful interpretation. Further 709 information is available at: ww.aspectsinstroke.com.

710 711

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712 Appendix 4 - Modified Rankin Scale (MRS) Grade Description29 0 No symptoms at all 1 No significant disability despite symptoms: able to carry out all usual duties and activities 2 Slight disability: unable to carry out all previous activities but able to look after own affairs without assistance 3 Moderate disability: requiring some help, but able to walk without assistance 4 Moderately severe disability: unable to walk without assistance, and unable to attend to own bodily needs without assistance 5 Severe disability: bedridden, incontinent, and requiring constant nursing care and attention 6 Death 713 714

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715 Appendix 5 - Modified Treatment In Cerebral Infarction (mTICI) Score Grade Description16 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 (e.g. in one major division of the middle cerebral artery (MCA) and its territory) 2b Antegrade reperfusion of more than half of the previously occluded target artery ischemic territory (e.g. in two 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 716 717

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718 Investigator’s Agreement 719 I have read the attached protocol: a randomized, controlled, multicenter trial of Direct Endovascular treatment 720 Versus standard bridging Therapy for acute stroke patients with large vessel occlusion in the anterior circulation 721 (DEVT Trial), Version 1.0 dated 30th March 2018 and agree to abide by all provisions set forth therein. I agree 722 to comply with the current International Conference on Harmonization Guidelines for Good Clinical Practice 723 and the laws, rules, regulations and guidelines of the community, country, state or locality relating to the conduct 724 of the clinical study. I also agree that persons debarred from conducting or working on clinical studies by any 725 court or regulatory agency will not be allowed to conduct or work on studies for the sponsor. 726 727 728 729 730 731 Name Site Principal Investigator Signature 732 733 734 Name of Clinical Site Date 735

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736 REFERENCES 737 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. 738 The New England journal of medicine 2008;359:1317-29. 739 2. National Institute of Neurological D, Stroke rt PASSG. Tissue plasminogen activator for acute ischemic 740 stroke. The New England journal of medicine 1995;333:1581-7. 741 3. Muir KW, Ford GA, Messow C-M, et al. Endovascular therapy for acute ischaemic stroke: the Pragmatic 742 Ischaemic Stroke Thrombectomy Evaluation (PISTE) randomised, controlled trial. Journal of neurology, 743 neurosurgery, and psychiatry 2017;88:38-44. 744 4. Bracard S, Ducrocq X, Mas JL, et al. Mechanical thrombectomy after intravenous alteplase versus alteplase 745 alone after stroke (THRACE): a randomised controlled trial. The Lancet Neurology 2016;15:1138-47. 746 5. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in 747 stroke. The New England journal of medicine 2015;372:2285-95. 748 6. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. 749 The New England journal of medicine 2015;372:2296-306. 750 7. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of 751 ischemic stroke. The New England journal of medicine 2015;372:1019-30. 752 8. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging 753 selection. The New England journal of medicine 2015;372:1009-18. 754 9. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute 755 ischemic stroke. The New England journal of medicine 2015;372:11-20. 756 10. Chandra RV, Lesliemazwi TM, Mehta BP, et al. Does the use of IV tPA in the current era of rapid and 757 predictable recanalization by mechanical embolectomy represent good value. Journal of neurointerventional 758 surgery 2016;8:443-6. 759 11. Grotta JC, Hacke W. Stroke Neurologist's Perspective on the New Endovascular Trials. Stroke; a journal of 760 cerebral circulation 2015;46:1447-52. 761 12. Wang H, Zi W, Hao Y, et al. Direct endovascular treatment: an alternative for bridging therapy in anterior 762 circulation large-vessel occlusion stroke. European journal of neurology : the official journal of the European 763 Federation of Neurological Societies 2017;24:935-43. 764 13. Rai AT, Boo S, Buseman C, et al. Intravenous thrombolysis before endovascular therapy for large vessel 765 strokes can lead to significantly higher hospital costs without improving outcomes. Journal of 766 neurointerventional surgery 2018;10:17-21. 767 14. Mistry EA, Mistry AM, Nakawah MO, et al. Mechanical Thrombectomy Outcomes With and Without 768 Intravenous Thrombolysis in Stroke Patients: A Meta-Analysis. Stroke; a journal of cerebral circulation 769 2017;48:2450-6. 770 15. Powers WJ, Derdeyn CP, Biller J, et al. 2015 American Heart Association/American Stroke Association 771 Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke 772 Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart 773 Association/American Stroke Association. Stroke; a journal of cerebral circulation 2015;46:3020-35. 774 16. Zaidat OO, Yoo AJ, Khatri P, et al. Recommendations on angiographic revascularization grading standards 775 for acute ischemic stroke: a consensus statement. Stroke; a journal of cerebral circulation 2013;44:2650-63. 776 17. Brott T, Adams HP, Jr., Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination 777 scale. Stroke; a journal of cerebral circulation 1989;20:864-70. 778 18. von Kummer R, Broderick JP, Campbell BC, et al. The Heidelberg Bleeding Classification: Classification of 779 Bleeding Events After Ischemic Stroke and Reperfusion Therapy. Stroke; a journal of cerebral circulation

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780 2015;46:2981-6. 781 19. Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke 782 clinical trials: a literature review and synthesis. Stroke; a journal of cerebral circulation 2007;38:1091-6. 783 20. Quinn TJ, Dawson J, Walters MR, Lees KR. Reliability of the modified Rankin Scale: a systematic review. 784 Stroke; a journal of cerebral circulation 2009;40:3393-5. 785 21. Brooks R. EuroQol: the current state of play. Health Policy 1996;37:53-72. 786 22. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of 787 EQ-5D (EQ-5D-5L). Quality of life research : an international journal of quality of life aspects of treatment, care 788 and rehabilitation 2011;20:1727-36. 789 23. Broeg-Morvay A, Mordasini P, Bernasconi C, et al. Direct Mechanical Intervention Versus Combined 790 Intravenous and Mechanical Intervention in Large Artery Anterior Circulation Stroke: A Matched-Pairs Analysis. 791 Stroke; a journal of cerebral circulation 2016;47:1037-44. 792 24. Bellwald S, Weber R, Dobrocky T, et al. Direct Mechanical Intervention Versus Bridging Therapy in Stroke 793 Patients Eligible for Intravenous Thrombolysis: A Pooled Analysis of 2 Registries. Stroke; a journal of cerebral 794 circulation 2017;48:3282-8. 795 25. Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized trial of intraarterial treatment for acute 796 ischemic stroke. The New England journal of medicine 2015;372:11-20. 797 26. Adams HP, Jr., Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. 798 Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke; a 799 journal of cerebral circulation 1993;24:35-41. 800 27. Zaidat OO, Yoo AJ, Khatri P, et al. Recommendations on angiographic revascularization grading standards 801 for acute ischemic stroke: a consensus statement. Stroke; a journal of cerebral circulation 2013;44:2650-63. 802 28. Pexman JH, Barber PA, Hill MD, et al. Use of the Alberta Stroke Program Early CT Score (ASPECTS) for 803 assessing CT scans in patients with acute stroke. AJNR American journal of neuroradiology 2001;22:1534-42. 804 29. Bonita R, Beaglehole R. Recovery of motor function after stroke. Stroke; a journal of cerebral circulation 805 1988;19:1497-500. 806807 808

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809 810 811 812

Sponsor

Army Medical University No. 30 Gaotanyan Main Street, Chongqing, China

Principle Investigators

Professor Qingwu Yang, Jie Shuai Professor Raul Gomes Nogueira 813 814 815 816 817 818 DEVT: A randomized, controlled, multicenter trial of direct endovascular treatment

819 versus standard bridging therapy for acute stroke patients with large vessel occlusion in

820 the anterior circulation

821

822

823 Protocol Version: 2.0

824 Issue Date: 1st August 2019

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825 CONTENTS 826 List of Abbreviations ...... 37 827 Study Synopsis ...... 39 828 Schedule of Assessments ...... 42 829 1. BACKGROUND INFORMATION ...... 43 830 2. TRIAL OBJECTIVES ...... 43 831 3. TRIAL DESIGN ...... 43 832 4. PATIENT POPULATION ...... 44 833 4.1. Inclusion criteria ...... 44 834 4.2. Exclusion criteria ...... 44 835 5. PARTICIPATING CENTER ELIGIBILITY ...... 45 836 6. RANDOMIZATION ...... 45 837 7. TREATMENTS ...... 45 838 8. OUTCOMES ...... 45 839 8.1. Primary Efficacy Outcome ...... 45 840 8.2. Secondary Efficacy Outcomes ...... 46 841 8.3 Safety Outcomes ...... 46 842 9. BLINDING AND MASKING ...... 46 843 10. ASSESSMENT OF EFFICACY ...... 47 844 10.1. The Modified Rankin Scale ...... 47 845 10.2. The National Institutes of Health Stroke Scale ...... 47 846 10.3. EQ-5D-5L ...... 47 847 11. ASSESSMENT OF SAFETY ...... 47 848 11.1. Adverse Event Definitions ...... 47 849 11.1.1. Adverse Event ...... 47 850 11.1.2. Serious Adverse Event ...... 48 851 11.2. Definitions of AE-Related Terms ...... 48 852 12. CLINICAL MANAGEMENT OF ADVERSE EVENTS ...... 48 853 12.1. Identification of Adverse Events by the Investigator ...... 48 854 12.2. Reporting of Adverse Events ...... 49 855 12.3. Reporting of Serious Adverse Events ...... 49 856 12.4. Reporting by the Investigator ...... 49 857 12.5. Reporting SAEs to the Health Authorities and Ethics Committees ...... 49 858 13. DATA SAFETY MONITORING BOARD ...... 49 859 14. IMAGING CORE LABORATORY ...... 50 860 15. CLINICAL EVENTS COMMITTEE ...... 50 861 16. STATISTICS ...... 50 862 16.1. Sample size estimates ...... 50 863 16.2. Analysis Populations ...... 50 864 16.2.1. Intention-to-treat Population ...... 50 865 16.2.2. Per-Protocol Population ...... 50 866 16.3. Analysis of Primary Efficacy Outcome ...... 50 867 16.4. Analysis of secondary efficacy outcomes ...... 51 868 16.5. Adjustment for covariates and subgroup analyses ...... 51

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869 16.6. Handling of Missing Data ...... 51 870 16.7. Analyses of Safety ...... 51 871 16.8. SAEs ...... 51 872 16.9. AEs ...... 52 873 17. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...... 52 874 18. QUALITY CONTROL AND QUALITY ASSURANCE ...... 52 875 18.1. Audits and Inspections ...... 53 876 18.2. Protocol Amendments and Revisions ...... 53 877 19. ETHICAL CONSIDERATION ...... 53 878 20. DATA HANDLING AND RECORD KEEPING ...... 53 879 20.1. Data Handling ...... 54 880 20.2. Investigator Files/Retention of Documents ...... 54 881 20.3. Source Documents and Background Data ...... 54 882 20.4. Case Report Forms ...... 54 883 20.5. Confidentiality ...... 54 884 21. PUBLICATION AND PRESENTATION POLICY ...... 55 885 22. DATA-SHARING PLAN ...... 55 886 23. STUDY ORGANIZATION AND FUNDING ...... 55 887 Appendix 1 - Classification of Subtype of Acute Ischemic Stroke ...... 56 888 Appendix 2 - ASITN/SIR Collateral Vessel Grading System ...... 59 889 Appendix 3 - The Alberta Stroke Program Early Computed Tomography Score 890 (ASPECTS) ...... 60 891 Appendix 4 - Modified Rankin Scale (MRS) ...... 61 892 Appendix 5 - Expanded Thrombolysis In Cerebral Infarction (eTICI) Scale ...... 62 893 Investigator’s Agreement ...... 63 894 REFERENCES ...... 64 895

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896 List of Abbreviations AE Adverse Event

BP Blood Pressure

CEC Clinical Events Committee

CRF Case Report Form

CTA Computed Tomographic Angiography Direct Endovascular Treatment Versus Standard Bridging Therapy in Large Artery DEVT Anterior Circulation Stroke DSA Digital Subtraction Angiography

DSMB Data Safety Monitoring Board

ECG Electrocardiogram EQ-5D-5L European Quality Five-Dimension Five-Level EVT Endovascular Treatment

GCP Good Clinical Practice

HbA1c Hemoglobin A1c

HCG Human Chorionic Gonadotropin

HR Heart Rate

ICA Internal Carotid Artery

ICH-GCP International Conference on Harmonization-Good Clinical Practice

INR International Normalized Ratio

IRB Institutional Review Board

ITT Intention-To-Treat

IVT Intravenous Thrombolysis

LAR Legally Authorized Representative

LVO Large Vessel Occlusion

MCA Middle Cerebral Artery

MedDRA Medical Dictionary for Regulatory Activities

MR Magnetic Resonance

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MRA Magnetic Resonance Angiography

mRS Modified Rankin Scale

NCCT Non-Contrast Computed Tomography

NIHSS National Institutes of Health Stroke Scale

PP Per-Protocol

QA Quality Assurance

RCT Randomized Controlled Trial

REB Research Ethics Board

rt-PA Recombinant Tissue-type Plasminogen Activator

SAE Serious Adverse Event

SICH Symptomatic Intracranial Hemorrhage

SOC System Organ Class

SOPs Standard Operating Procedures

Temp Temperature

TIA Transient Ischemic Attack

TOAST Trial of Org 10172 in Acute Stroke Treatment 897

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898 Study Synopsis Trial Objectives The objective is to determine whether endovascular treatment alone is non-inferior to intravenous thrombolysis bridging endovascular treatment in acute anterior circulation large vessel occlusive patients who are eligible for intravenous rt-PA. Trial Design This study is a randomized, controlled, multicenter trial with blinded outcome assessment. This trial uses a five-look group-sequential non-inferiority design. Up to 194 patients in each interim analysis will be consecutively randomized to endovascular treatment alone or rt-PA plus endovascular treatment group in 1:1 ratio over three years from about 35 hospitals in China. Subjects Inclusion criteria 1) Aged 18 years or older; 2) Presenting with acute ischemic stroke (AIS) symptom within 4.5 hours; 3) Eligible for IV rt-PA; 4) Occlusion of the intracranial internal carotid artery (ICA) or M1 segment of the middle cerebral artery (MCA) confirmed by CT or MR angiography (CTA or MRA); 5) Randomization no later than 4 hours 15 minutes after stroke symptom onset; 6) Informed consent obtained from patients or their legal representatives. Exclusion criteria 1) CT or MR evidence of hemorrhage (the presence of micro-bleeds is allowed); 2) Contraindications of IV rt-PA; 3) Pre-morbidity with a modified Rankin scale (mRS) score of ≥ 2; 4) Currently in pregnant or lactating or serum beta human chorionic gonadotrophin (HCG) test is positive on admission; 5) Contraindication to radiographic contrast agents, nickel, titanium metals or their alloys; 6) Arterial tortuosity and/or other arterial disease that would prevent the device from reaching the target vessel; 7) Patients with a preexisting neurological or psychiatric disease that would confound the neurological functional evaluations; 8) Subjects with occlusions in multiple vascular territories (e.g. bilateral anterior circulation, or anterior/posterior circulation); 9) CT or MRI evidence of mass effect or intracranial tumor (except small meningioma); 10) CT or MRI evidence of cerebral vasculitis; 11) CTA or MRA evidence of intracranial arteriovenous malformations or aneurysms; 12) Any terminal illness with life expectancy less than 6 months; 13) Unlikely to be available for 90-day follow-up; 14) Current participation in another clinical trial. Treatments Patients are assigned to receive either endovascular treatment (EVT) alone (primary-thrombectomy group) or rt-PA plus EVT (bridging-therapy group). In the bridging-therapy group, subjects will receive a single rt-PA dose of 0.9 mg/kg IV (maximum dose: 90 mg), with 10% given as a bolus, followed by continuous IV

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Randomization Subjects will be randomly assigned in a 1:1 fashion to receive EVT alone or rt-PA Method plus EVT. Randomization occurs immediately after baseline (at the EVT institution) CT/MR brain imaging and CT/MR angiography via a real-time, internet-based randomization method. The randomization was stratified by participating centers. Duration of This study consists of one 90-day study period for each subject. Treatment Subjects will be hospitalized for care after their acute stroke according to the current standard of care. Subjects are required to return to clinic on Day 90 for end-of-study procedures. Laboratory Tests In order to support the assessment of patient safety baseline, chemistry laboratory tests will be completed. At baseline, blood work will be evaluated which includes: Blood cell counts, triglyceride, cholesterol, low density lipoprotein, high density lipoprotein, homocysteine, glucose, procalcitonin, HbA1C, prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, D-dimer, international normalized ratio. If the subject is female and is of childbearing potential, a pregnancy test (urine or serum point-of-care pregnancy test) must be completed and a negative test result obtained prior to inclusion in the trial. Electrocardiograms will also be collected and reviewed at baseline. Assessment of The primary efficacy outcome is the overall proportion of subjects experiencing a Efficacy functional independence 90 days post randomization, defined as a score of 0 to 2 on the mRS. The secondary efficacy outcomes include: 1) Proportion of mRS score 0 to 1 at 90 days; 2) Shift in the distribution of mRS scores at 90 days in EVT alone versus rt-PA plus EVT (ordinal shift analysis); 3) Successful recanalization proportion immediate after EVT. Successful recanalization is defined as a modified Treatment in Cerebral Infarction score of 2b (substantial perfusion),2c (near-complete perfusion) or 3 (complete reperfusion) in the post-procedure angiography; 4) Vessel recanalization rate evaluated by CTA or MRA within 48 hours; 5) The change of the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours from baseline; 6) The change of the NIHSS score at 5-7 days or discharge if earlier from baseline; 7) European Quality Five-Dimension Five-Level (EQ-5D-5L) scale score at 90

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days. Assessment of Safety 1) Symptomatic intracerebral hemorrhage (sICH) rate within 48 hours; 2) Mortality at 90 days; 3) Procedure-related complications such as arterial perforation, iatrogenic arterial dissection, arterial access site hematoma, and retroperitoneal hematoma; 4) Incidence of serious adverse events. 899 900

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901 Schedule of Assessments Baseline Day 1 Day 2 Day 5 or Day 90 (±14 (24 ± 12 h (48 ± 8 h from discharge (±1 d) from randomization) d) randomization) Informed consent X History and examination X Weight X Vital Signs (BP, HR, X X X X Temp) Randomization X NIHSS X X X mRS X* X ASPECTS X EQ-5D-5L X CBC, electrolytes, INR, X X aPTT, serum creatinine and serum glucose Pregnancy test‡ X NCCT/MR head X X** CTA/MRA X X ECG X Endovascular Procedure X sICH X Mortality X X AE assessment Collected to Day 30 visit SAE assessment Collected to Day 90 visit Prior medications§ X Concomitant Collected to Day 30 visit medications§ 902 The subject’s actual weight will be measured in hospital using standard hospital scales (i.e., stand up or in-bed 903 scales if the subject is not ambulatory). If actual weight cannot be measured for any reason (due to, for 904 example severe illness or unavailability of in-bed scales at the site), weight will be determined by first asking 905 the subject, second asking a family member or third by estimation. 906 * Historical (pre-stroke) score. 907 ** MR head may be supplanted by an NCCT head if MR is unavailable. 908 ‡ If the subject is female and is of childbearing potential a pregnancy test (urine or serum point-of-care 909 pregnancy test) must be completed and the result must be negative; this is the only mandatory laboratory test 910 prior to randomization 911 § Prior and concomitant medications will be listed per patient, with the listings separated within treatment group. 912

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913 1. BACKGROUND INFORMATION 914 Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) within 4.5 hours of symptom 915 onset is the first-line treatment for acute ischemic stroke(AIS)1,2. Several randomized controlled trials have 916 consistently demonstrated that intravenous thrombolysis bridging with endovascular treatment (namely bridging 917 therapy) is superior to intravenous thrombolysis alone for acute anterior large vessel occlusion(LVO)3-9. 918 Intravenous thrombolysis prior to endovascular treatment can be initiated earlier, help eliminate thrombi in distal 919 or small arteries which are inaccessible for revascularization devices, facilitate mechanical thrombectomy, and 920 thereby increasing the rate of reperfusion10,11. However, intravenous thrombolysis also has some drawbacks. For 921 instance, it may increase the risk of intracranial or systemic hemorrhage12, especially when anti-thrombotic 922 therapy is administrated after angioplasty and/or stenting. It may also postpone endovascular treatment and 923 increase medical expenditures13. The therapeutic time window of intravenous thrombolysis is very narrow, which 924 has largely limited its application. In addition, IVT before EVT is associated with an increased incidence of clot 925 migration, resulting in an increased rate of clots inaccessibility by mechanical thrombectomy14. 926 It remains uncertain whether pretreated with intravenous rt-PA provides any additional benefits to the acute 927 anterior large vessel occlusive patients experiencing endovascular treatment. A meta-analysis revealed that 928 patients treated with bridging therapy have higher recanalization rates, fewer device passes, equal probabilities 929 of symptomatic intracerebral hemorrhage, better clinical neurological outcomes, and lower mortality rates 930 compared with patients treated with direct endovascular treatment15. Whereas, a propensity score matching 931 analysis based on the Chinese population suggested that direct endovascular treatment can achieve similar 932 efficacy to that of bridging therapy, and a lower proportion of asymptomatic intracranial hemorrhage12. Another 933 meta-analysis showed that direct endovascular treatment may carries comparable effectiveness and safety as 934 compared with bridging therapy by pooling studies with lower selection bias16. However, the baseline 935 characteristics for the direct endovascular treatment group and bridging-therapy group of these studies are lack 936 of equipoise, which may have significant influence on the results. Prospective data on direct endovascular 937 treatment for acute anterior large vessel occlusion remains scarce. Thus, we propose the hypothesis that EVT 938 alone initiated within 4.5 h of stroke onset is not inferior to rt-PA plus EVT in acute stroke patients with a 939 proximal LVO in the anterior circulation. 940 941 2. TRIAL OBJECTIVES 942 Direct Endovascular Treatment Versus Standard Bridging Therapy in Large Artery Anterior Circulation Stroke 943 (DEVT) Trial aims to investigate whether EVT alone is non-inferior to rt-PA plus EVT in acute anterior 944 circulation large vessel occlusive patients who are eligible for intravenous rt-PA. 945 946 3. TRIAL DESIGN 947 DEVT trial is a multicenter, prospective, randomized, open-label controlled clinical trial with blinded endpoint 948 evaluation. It is an academic trial designed by the principal investigators and a steering committee consisting of 949 experts in cerebrovascular diseases and interventional neuroradiology. The study patient flow outline was shown 950 in Figure 1. 951 Figure 1 Study flowchart of DEVT trial.

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952 953 4. PATIENT POPULATION 954 4.1. Inclusion criteria 955 (1) Aged 18 years or older; 956 (2) Presenting with AIS symptom within 4.5 hours; 957 (3) Eligible for IV rt-PA; 958 (4) Occlusion of the intracranial internal carotid artery (ICA) or M1 segment of the middle cerebral artery 959 (MCA) confirmed by CT or MR angiography (CTA or MRA); 960 (5) Randomization no later than 4 hours 15 minutes after stroke symptom onset; 961 (6) Informed consent obtained from patients or their legal representatives. 962 4.2. Exclusion criteria 963 (1) CT or MR evidence of hemorrhage (the presence of micro-bleeds is allowed); 964 (2) Contraindications of IV rt-PA; 965 (3) Pre-morbidity with a modified Rankin scale (mRS) score of ≥ 2; 966 (4) Currently in pregnant or lactating or serum beta HCG test is positive on admission; 967 (5) Contraindication to radiographic contrast agents, nickel, titanium metals or their alloys; 968 (6) Arterial tortuosity and/or other arterial disease that would prevent the device from reaching the target 969 vessel; 970 (7) Patients with a preexisting neurological or psychiatric disease that would confound the neurological 971 functional evaluations; 972 (8) Subjects with occlusions in multiple vascular territories (e.g. bilateral anterior circulation, or 973 anterior/posterior circulation); 974 (9) CT or MRI evidence of mass effect or intracranial tumor (except small meningioma); 975 (10) CT or MRI evidence of cerebral vasculitis;

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976 (11) CTA or MRA evidence of intracranial arteriovenous malformations or aneurysms; 977 (12) Any terminal illness with life expectancy less than 6 months; 978 (13) Unlikely to be available for 90-day follow-up; 979 (14) Current participation in another clinical trial. 980 981 5. PARTICIPATING CENTER ELIGIBILITY 982 To be fully eligible for participation in this trial, study centers are required have performed at least 80 983 endovascular procedures annually, including at least 50 thrombectomy procedures with the stent-retriever 984 devices. Moreover, all neurointerventionists with more than five years’ experience in cerebrovascular 985 intervention and at least 10 cases of mechanical thrombectomy with stent retriever devices annually. 986 987 6. RANDOMIZATION 988 Subjects will be randomly assigned in a 1:1 fashion to receive EVT alone or IV rt-PA plus EVT. Randomization 989 occurs immediately after baseline (at the EVT institution) CT/MR brain imaging and CT/MR angiography via a 990 real-time, internet-based randomization method. The randomization was stratified by participating centers. The 991 time of randomization is defined as the time randomization occurred on the central server and this time is 992 considered time zero for the study. IV rt-PA will be infused immediately after randomization. 993 All subjects, investigators, their clinical staff, the clinical coordinating center, the data management group, and 994 the sponsor staff and delegates will be blinded to the randomization codes. The local laboratories will also be 995 blinded. 996 997 7. TREATMENTS 998 Patients are assigned to receive either EVT alone (primary-thrombectomy group) or rt-PA plus EVT 999 (bridging-therapy group). In the bridging-therapy group, subjects will receive a single rt-PA dose of 0.9 mg/kg 1000 IV (maximum dose: 90 mg), with 10% given as a bolus, followed by continuous IV infusion of the rest dose 1001 within 1 hour. Simultaneously, EVT preparation should be initiated with or as soon as IV rt-PA administration. 1002 While in the primary-thrombectomy group, subjects will receive EVT alone without prior IV rt-PA. Subjects in 1003 both groups will undergo rapid EVT. EVT consisted of mechanical thrombectomy, thromboaspiration, balloon 1004 dilation, stenting, intra-arterial thrombolysis, or various combinations of these approaches. The choice of 1005 technique is left to the discretion of the treating neurointerventionist. Additionally, stenting of the extracranial or 1006 intracranial artery is permitted when absolutely necessary to obtain access to distal occlusion or to prevent acute 1007 re-occlusion. This may require the use of thrombolytic agents to prevent acute stent thrombosis. After 1008 recanalization of the target artery, all patients will get stroke unit care and postoperative management follows the 1009 current American Heart Association/American Stroke Association guidelines17. 1010 The use of conscious sedation or general anesthesia for the procedure to ensure the comfort and safety of patients 1011 is at the discretion of the individual site neurointerventionalist. The steering committee will make 1012 recommendations for dosages of thrombolytic agents, procedures, and for devices that will be considered in the 1013 trial based on proposals by the executive committee or local investigators. The requirements for a device to be 1014 considered in the trial should be approved by the China Food and Drug Administration or National Medical 1015 Products Administration. 1016 1017 8. OUTCOMES 1018 8.1. Primary Efficacy Outcome 1019 The primary end-point is the overall proportion of subjects experiencing a functional independence 90 days post 1020 randomization, defined as a score of 0 to 2 on the mRS. To ensure the reliability, evaluability, and traceability of

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1021 the mRS score, we keep patients’ video or voice version of follow-up at 90 days except those who die or refuse 1022 to take a video. The primary functional outcome is centrally assessed by two independent certified neurologists 1023 in a blinded manner by the use of the video or voice recording. Disagreements are resolved by consensus. 1024 8.2. Secondary Efficacy Outcomes 1025 (1) Shift in the distribution of mRS scores at 90 days in EVT alone versus rt-PA plus EVT (ordinal shift 1026 analysis); 1027 (2) Proportion of mRS score 0 to 1 at 90 days; 1028 (3) Successful recanalization proportion immediate after EVT. Successful recanalization is defined as an 1029 expanded Thrombolysis In Cerebral Infarction score of 2b (substantial perfusion),2c (near-complete 1030 perfusion) or 3 (complete reperfusion) in the post-procedure angiography18; 1031 (4) Vessel recanalization rate evaluated by CTA or MRA within 48 hours; 1032 (5) The change of the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours from baseline19; 1033 (6) The change of the NIHSS score at 5-7 days or discharge if earlier from baseline; 1034 (7) European Quality Five-Dimension Five-Level (EQ-5D-5L) scale score at 90 days. 1035 8.3 Safety Outcomes 1036 (1) Symptomatic intracerebral hemorrhage (sICH) rate within 48 hours. ICH will be evaluated according to the 1037 Heidelberg Bleeding Classification20. sICH was diagnosed if the new observed ICH was associated with 1038 any of the following conditions: 1) NIHSS score increased more than 4 points than that immediately before 1039 worsening; 2) NIHSS score increased more than 2 points in one category; 3) Deterioration led to intubation, 1040 hemicraniectomy, external ventricular drain placement or any other major interventions. Additionally, the 1041 symptom deteriorations could not be explained by causes other than the observed ICH. Hemicraniectomy 1042 will be defined as that surgical procedure used to decompress the swollen hemisphere; 1043 (2) Mortality at 90 days. Mortality rates are defined as the number of deaths observed divided by the number of 1044 subject observed over the 90-day study period; 1045 (3) Procedure-related complications such as arterial perforation, iatrogenic arterial dissection, embolization in 1046 previously uninvolved vascular territory, arterial access site hematoma, and retroperitoneal hematoma. 1047 Arterial perforation will be defined at angiography by the operator and associated with subarachnoid 1048 hemorrhage. Iatrogenic arterial dissection will be defined at angiography by the operator. Arterial access 1049 site hematoma will be assessed as a complication of arterial access puncture and defined by clinical 1050 examination and anatomic imaging. Retroperitoneal hematoma will be assessed as a complication of groin 1051 puncture and defined by imaging (ultrasound or CTA or MR). The definition of embolization in previously 1052 uninvolved vascular territory is noted after recanalization of the primary occlusion site, any vessel 1053 occlusions distal from the primary occlusion site are considered emboli due to periprocedural thrombus 1054 fragmentation. 1055 (4) Incidence of serious adverse events. 1056 1057 9. BLINDING AND MASKING 1058 Each site will designate one or more physician(s) to perform the follow-up evaluation at 24 hours, 5-7 days or 1059 discharge if earlier and at 90 days who cannot be involved in care of the subjects and must remain blinded to 1060 treatment assignment of each subject. 1061 Regarding the NIHSS examination at baseline, 24 hours, 5-7 days or discharge if earlier and the primary 1062 end-point, first, a local independent neurologist, not involved in the trial patient management, will evaluate the 1063 scores in a face to face clinical visit, recording the examination by video with the consent of patient or the legal 1064 representative; and second, two experienced and certified physicians will centrally evaluate the score by using

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1065 the video recording. For cases with disagreement between the two assessors, decisions are made by the third 1066 experienced neurologist. 1067 All neuroimaging end-points including baseline Alberta Stroke Program Early Computed Tomography Score 1068 (ASPECTS) score, recanalization within 48 hours, collateral circulation classification and hemorrhage will be 1069 determined by the CT/MR core laboratory, which will be also blinded to treatment allocation. Another 1070 independent angiographic core lab will review angiographic images from the procedure to determine clot 1071 location and recanalization. Serious adverse events (SAEs) and procedure-related complications will be reviewed 1072 and adjudicated by two individuals of the independent clinical events committee who will be blinded to 1073 treatment allocation. 1074 1075 10. ASSESSMENT OF EFFICACY 1076 10.1. The Modified Rankin Scale 1077 The mRS is a valid and reliable clinician-reported measure of global disability that has been widely applied for 1078 evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or 1079 dependence in daily activities) of people who have suffered a stroke21,22. mRS scores range from 0 to 6, with 0 1080 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death. The 1081 mRS will be obtained at Day 90. Premorbid mRS status will also be obtained retrospectively and reported on the 1082 24h CRF page. The mRS will only be scored by those trained and certified in the use of this scale. 1083 10.2. The National Institutes of Health Stroke Scale 1084 The NIHSS is a standardized neurological examination score that is a valid and reliable measure of disability and 1085 recovery after acute stroke19. Scores range from 0 to 42, with higher scores indicating increasing severity. The 1086 scale includes measures of level of consciousness, extra ocular movements, motor and sensory tests, 1087 coordination, language and speech evaluations. The NIHSS will be administered at Baseline, at 24 hours from 1088 baseline, Day 5-7or discharge. The NIHSS will only be scored by those trained and certified in the use of this 1089 scale. 1090 10.3. EQ-5D-5L 1091 The EQ-5D-5L is a generic instrument for describing and valuing health. It is based on a descriptive system that 1092 defines health in terms of five dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and 1093 Anxiety/Depression23. Each dimension has five response categories corresponding to: no problems, slight, 1094 moderate, severe and extreme problems. The instrument is designed for self-completion, and respondents also 1095 rate their overall health on the day of the interview on a 0-100 hash-marked, vertical visual analogue scale. The 1096 EQ-5D-5L will be administered on Day 90 by those trained in the use of this scale. 1097 1098 11. ASSESSMENT OF SAFETY 1099 11.1. Adverse Event Definitions 1100 11.1.1. Adverse Event 1101 An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject 1102 administered a pharmaceutical product and which does not necessarily have to have a causal relationship with 1103 this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 1104 finding, for example), symptom or disease temporally associated with the use of a medicinal product, whether or 1105 not considered related to the medicinal product. 1106 Therefore, an AE may be: A new illness; The worsening of a concomitant illness; An effect of vaccination, 1107 including the comparator; A combination of the above. 1108 Pre-existing medical conditions are not to be reported as AEs. However, if a pre-existing condition worsens in 1109 frequency or intensity, or if in the assessment of the treating physician there is a change in its clinical

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1110 significance, this change should be reported as an AE (exacerbation). This applies equally to recurring episodes 1111 of pre-existing conditions (e.g., asthma) if the frequency or intensity increases post-randomization. 1112 11.1.2. Serious Adverse Event 1113 A serious adverse event (SAE) is any untoward medical occurrence that at any dose: Result in death; Are 1114 life-threatening; Require or prolong inpatient hospitalization; Result in persistent or significant 1115 disability/incapacity, or; Are a congenital/birth defect. 1116 A SAE can also be an important medical event that may not result in death, be life-threatening, or require 1117 hospitalization, but may jeopardize the subject and may require medical or surgical intervention to prevent one 1118 of the outcomes listed in this definition. For example, any new diagnosis of cancer (made after study enrollment) 1119 is considered an important medical event. Because our primary safety outcomes for the trial are also SAEs by 1120 definition, they will be reported dually as SAEs and as outcomes. SAEs should be managed according to the best 1121 current standard of care. 1122 All deaths occurring during the follow up to Day 90 will be reported as an SAE. When reporting a death, the 1123 event or condition that caused or contributed to the fatal outcome should be reported as a single medical concept. 1124 AE occurring within 30 days of randomization and all SAEs will be reported in the CRF. Severity and 1125 relationship definitions are presented below. 1126 11.2. Definitions of AE-Related Terms AE Severity Mild Awareness of sign or symptom but easily tolerated Moderate Discomfort sufficient to cause interference with normal activities. Severe Incapacitating, with inability to perform normal activities. AE Relationship Related A clinical event, including laboratory test abnormality, where there is a “reasonable possibility” that the SAE was caused by the study drug, meaning that there is evidence or arguments to suggest a causal relationship. Probably A clinical event, including laboratory test abnormality, with a reasonable time sequence to drug administration, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal. Possibly A clinical event, including laboratory test abnormality, with a reasonable time sequence to drug administration, but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear. Unrelated This category is applicable to AEs which are judged to be clearly and incontrovertibly due to extraneous causes (diseases, environment, etc.) and do not meet the criteria for drug relationship listed for the above-mentioned conditions. 1127 1128 12. CLINICAL MANAGEMENT OF ADVERSE EVENTS 1129 12.1. Identification of Adverse Events by the Investigator 1130 AE monitoring and reporting will be followed-up until Day 30. SAEs will be followed through the final study 1131 exit visit (Day 90 Visit or death or end of study whichever is sooner) or until the subject is deemed “lost to 1132 follow-up”. 1133 AE identification while the subject is admitted to the acute stroke hospital will be collected via acute stroke 1134 hospital patient records and verbal histories from the subject or legally authorized representative (LAR). For

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1135 follow up visits after discharge from the acute stroke hospital the subject (or LAR if the subject is not able to 1136 respond to the questions) will be asked about the occurrence of AEs since the last contact, and if available, from 1137 records at the acute stroke hospital. AEs that were ongoing at the last contact will be updated with a stop date or 1138 confirmed as ongoing. AE collection will continue until Day 30, and SAE to Day 90 or the final contact. 1139 A consistent methodology of eliciting AEs at all subject evaluation timepoints will be used. Non-directive 1140 questions include: How have you felt since your last clinical visit/hospital discharge? Have you had any new or 1141 changed health problems since you were last here? Have you had any unusual or unexpected worsening of your 1142 underlying medical condition or overall health? Have there been any changes in the medicines you take since 1143 your last clinical visit/hospital discharge? 1144 Diagnosis versus signs and symptoms for the purpose of AE reporting: if known at the time of reporting, a 1145 diagnosis should be reported rather than individual signs and symptoms. However, if a constellation of signs 1146 and/or symptoms cannot be medically characterized as a single diagnosis it is acceptable to report the 1147 information that is ultimately available. 1148 12.2. Reporting of Adverse Events 1149 AEs should be reported as they occur on the electronic Case Report Form (e-CRF). Documentation must be 1150 supported by an entry in the subject’s file. Each event should be described in detail along with start and stop 1151 dates, severity, relationship to investigational product as judged by the investigator, action taken and outcome. 1152 12.3. Reporting of Serious Adverse Events 1153 In order to comply with current regulations on SAE reporting to health authorities, the investigator must 1154 document all SAEs regardless of causal relationship and notify the Sponsor. The Investigator will give access 1155 and provide the Sponsor with all necessary information to allow the Sponsor to conduct a detailed analysis of the 1156 safety of the investigational product. It is the responsibility of the Investigator to request all necessary 1157 documentation (e.g., medical records, discharge summary, autopsy) in order to provide comprehensive safety 1158 information. All relevant information must then be transcribed into the e-SAE Form. 1159 12.4. Reporting by the Investigator 1160 All SAEs must be reported to the Sponsor within 24 hours of the local Investigator’s first awareness of its 1161 occurrence. SAEs will be reviewed by the trial medical monitor. 1162 The investigator will report the SAEs using the e-SAE form in the e-CRF, which will send an immediate alert to 1163 the Sponsor. If the e-CRF system is not available, a paper SAE form should be directed within 24 hours. 1164 12.5. Reporting SAEs to the Health Authorities and Ethics Committees 1165 The Sponsor will inform the relevant health authorities of any reportable SAEs according to the local regulatory 1166 requirements. Reporting to the health authorities will be according to the Sponsor’s standard operating 1167 procedures. 1168 SAEs that are assessed by the Sponsor to be unexpected and related to study drug (expedited reporting SAEs) 1169 will be reported to the regulatory agencies as per country requirements. All other SAEs will be reported to 1170 regulatory agencies based upon local reporting requirements. 1171 The Sponsor’s medical monitor or designee will notify the investigators in writing of the occurrence of any 1172 reportable SAEs. The Sponsor or delegate will be responsible for reporting suspected unexpected serious adverse 1173 reaction to any Central Ethics Committees in compliance with local current legislation. The investigators will be 1174 responsible for informing their local ethics committees of any reportable SAEs as per their local requirements. 1175 1176 13. DATA SAFETY MONITORING BOARD 1177 The independent Data safety monitoring board (DSMB) will be composed of an experienced neurologist, an 1178 interventionalist, and a biostatistician, which are not involved in the trial. The DSMB will meet at least once a 1179 year, and is provided with structured unmasked reports, prepared by the trial statistician, for their reference only.

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1180 DSMB is responsible for recommendations to the executive committee regarding stopping or extending the trial. 1181 In addition, the DSMB will review the occurrence of SAEs and make recommendations to the executive 1182 committee regarding safety of the trial. 1183 1184 14. IMAGING CORE LABORATORY 1185 Centralized imaging core laboratories will be used in this trial to provide consistent assessment of all the images. 1186 CT/MR and angiographic images will be independently reviewed by two independent central imaging core 1187 laboratories respectively. CT/MR core laboratory will review CT/MR images obtained at baseline and within 24 1188 hours for confirmation of inclusion criteria, ASPECTS score, collateral circulation classification, and 1189 presence/absence of hemorrhage. Angiographic core laboratory will review angiographic images from the 1190 procedure to determine clot location and recanalization. CT/MR core laboratory will be independent from the 1191 angiographic core laboratory to ensure the CT/MR core laboratory is blinded to the treatment allocation. 1192 1193 15. CLINICAL EVENTS COMMITTEE 1194 The Clinical events committee (CEC) will be comprised of three expert physicians independent of the 1195 investigational sites. This committee will validate all the complications that occur over the course of the study 1196 and categorized for severity and relatedness according to the definition in the Adverse Event section in the CEC 1197 Manual of Operations. The CEC can request any additional source information and images supporting the 1198 adverse events to assist with the adjudication. 1199 1200 16. STATISTICS 1201 16.1. Sample size estimates 1202 According to the previous study data12,24-26, we hypothesis that the 90-day follow-up proportion of independent 1203 functional outcome is 43% both in the primary-thrombectomy group and bridging-therapy group. The clinically 1204 relevant non-inferiority margin was -10.0%. To maintain the alpha, Pocock Analog Alpha Spending Function 1205 is used. Sample size and power are computed incorporating a five-look group-sequential analysis plan with a 1206 one-sided at 0.025, 918 cases provide 80% power for testing the primary hypothesis of this trial; assuming the 1207 attrition rate is 5% for the primary end-point, the total sample size is up to 970. The evaluable sample size is 194 1208 at each interim analysis. Therefore, in each interim analysis, 97 cases should be enrolled in each treatment group. 1209 16.2. Analysis Populations 1210 16.2.1. Intention-to-treat Population 1211 The primary efficacy analysis will be conducted in the intention-to-treat (ITT) population, defined as all subjects 1212 randomized into the trial with grouping by randomized treatment, regardless of treatment actually received. 1213 Deceased subject will be included in the ITT population with a mRS score of 6. 1214 16.2.2. Per-Protocol Population 1215 The primary analysis will be repeated on the Per-Protocol (PP) population, defined to be all subjects randomized 1216 and treated, with no major protocol deviations. This population will be determined via blinded review of 1217 protocol deviations at the end of the trial before database lock and unblinding. Prior to unblinding, the imaging 1218 from each subject at the time of inclusion will be adjudicated to determine whether they have met the criteria for 1219 endovascular intervention, and hence for the trial. This will include review of baseline NCCT and CTA. Subjects 1220 who do not meet the imaging criteria outlined in the trial inclusion/exclusion criteria, will not be included in the 1221 PP population. 1222 Patients who withdraw informed consent immediately after randomization and are not to receive any treatment 1223 should be excluded from all analysis populations. 1224 16.3. Analysis of Primary Efficacy Outcome

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1225 Non-inferiority test will be used to test the primary hypothesis that the proportion of patients with independent 1226 functional outcome will be non-inferior in the primary-thrombectomy group compared to the bridging-therapy 1227 group. We desired a maximum of 5 looks when approximately 20, 40, 60, 80, and 100% of the total sample size 1228 finish the follow-up, monitoring and data cleaning processes. A group-sequential test strategy was designed to 1229 have reasonable chances of stopping as early as possible, either because of efficacy or safety reasons. The 1230 independent DSMB may recommend stopping the trial either for effectiveness, or safety in case the stopping 1231 boundaries are crossed at interim analysis. For shedding cases, follow-up will be performed until the end of the 1232 study, and the results will be included in the final analysis. Statistical analysis will be performed on the SAS 9.3 1233 system. Details of these are provided in the Statistical Analysis Plan. 1234 16.4. Analysis of secondary efficacy outcomes 1235 The key secondary outcomes will be tested in the following order: 1236 1.The Proportion of mRS score 0 to 1 at 90 days; 1237 2.Shift in the distribution of mRS scores at 90 days in EVT alone versus rt-PA plus EVT (ordinal shift analysis); 1238 3.Successful recanalization proportion immediate after EVT. 1239 4.Vessel recanalization rate evaluated by CTA or MRA within 48 hours; 1240 5.The change of the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours from baseline; 1241 6.The change of the NIHSS score at 5-7 days or discharge if earlier from baseline; 1242 7.European Quality Five-Dimension Five-Level (EQ-5D-5L) scale score at 90 days. 1243 16.5. Adjustment for covariates and subgroup analyses 1244 In addition to the primary and secondary analyses adjusting for age, sex, baseline NIHSS score, baseline 1245 ASPECTS score, occlusion location, exploratory analyses will be conducted to determine the potential roles of 1246 common baseline characteristics and assess potential heterogeneity of treatment effect across subgroups. Specific 1247 subgroups of interest include the age >= 70 vs. < 70 years old, male vs. female, subject with different baseline 1248 stroke severity (on NIHSS and measured radiologically on ASPECTS), baseline occlusion location (ICA 1249 occlusion: no vs. yes), cause of stroke, onset to randomization time. Full details will be specified in detail in the 1250 Statistical Analysis Plan. 1251 16.6. Handling of Missing Data 1252 Every effort will be made to keep missing data, particularly the Day 90 outcome assessments, to a minimum. 1253 However, some missing data may be inevitable due to, for example, loss to follow-up. Deceased subject will 1254 score 6 on the mRS and be counted as non-responders. For the primary analysis for regulatory submission, we 1255 will assume that subject missing the primary endpoint data will be considered to be non-responders. Sensitivity 1256 analyses using various imputation techniques will be specified prospectively in the Statistical Analysis Plan 1257 before the database lock for the interim analysis if more than 5% of subject randomized are missing the primary 1258 endpoint. 1259 16.7. Analyses of Safety 1260 The main analyses will be frequency of sICH and 90-day mortality. It is expected that the safety population and 1261 the ITT population will be near-identical. Full details will be specified in detail in the Statistical Analysis Plan. 1262 16.8. SAEs 1263 SAEs over the 90-day study period will be summarized by presenting, for each treatment group, the number and 1264 percentage of subjects having at least one SAE, having an SAE in each body system and preferred term, by 1265 severity and relatedness to study medication. The frequencies and incidences of SAEs occurring in subjects in 1266 the active and control groups will be summarized within treatment group by the Medical Dictionary for 1267 Regulatory Activities (MedDRA) System Organ Class (SOC). The frequencies and incidences of SAEs and 1268 discontinuations due to SAEs occurring in subjects in the active and control groups will be summarized within 1269 treatment group.

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1270 16.9. AEs 1271 Additional analyses will consider the frequency of AEs and discontinuations due to AEs. AEs will be 1272 summarized by presenting, for each treatment group, the number and percentage of subjects having any AE, 1273 having an AE in each body system and preferred term. Severity and relatedness to study medication will be 1274 recorded. The frequencies and incidences of AEs occurring in subjects in the active and control groups will be 1275 summarized within treatment group by the Medical Dictionary for Regulatory Activities (MedDRA) System 1276 Organ Class (SOC). 1277 1278 17. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 1279 The sponsor or delegate will be permitted to visit the study facilities at any reasonable time in order to maintain 1280 current, detailed knowledge of the study through review of the records, source documents, observation, and 1281 discussion of the conduct and progress of the study. In addition, the sponsor will maintain regular telephone and 1282 written communication with all investigators through the coordinating center. The sponsor (or delegate) will be 1283 given complete access to all components of the study facility that pertain to the conduct of this study, and may be 1284 present to observe any aspect of the conduct of the study by medical and paramedical staff, including but not 1285 limited to drug preparations, dosing, sample collections, and clinical observations. E-CRFs will be monitored 1286 with sufficient frequency to assess the following: Subject randomization, compliance with protocol procedures, 1287 the completeness and accuracy of data entered into the e-CRFs, verification of e-CRF data against original 1288 source documents, and occurrence of AEs. Adequate time and all documents for these monitoring visits must be 1289 made available by the investigators. The investigators will permit trial-related monitoring, audits, REB/IRB 1290 review, and regulatory inspections, providing direct access to source data/documents. 1291 1292 18. QUALITY CONTROL AND QUALITY ASSURANCE 1293 To ensure monitoring responsibilities are performed to the fullest extent possible, industry experienced study 1294 monitors will perform on site data verification for the trial. All data monitored on site are verified for accuracy 1295 and completeness using source documents for all subjects. In addition, 100% of subjects enrolled are monitored 1296 for the presence of signed consent. 1297 Monitoring of the investigational sites will be conducted by the sponsor or contracted to a qualified clinical 1298 research organization. The sponsor will determine the extent, nature, and frequency of on-site visits that are 1299 needed to ensure that the study is being conducted in accordance with the approved protocol (and any 1300 amendments), Good Clinical Practice (GCP), and all applicable regulatory requirements. At site visits, the 1301 monitor will, as required, assess the progress of the study; check that the study data chosen for verification are 1302 authentic, accurate, and complete; verify that the safety and rights of patients are being protected; compare 1303 original documents with data entered into the study database; and identify any issues and address their 1304 resolution. 1305 The investigator agrees to allow the monitor(s) direct access to all relevant documents, and to allocate his/her 1306 time and the time of staff to discuss findings, corrective actions and any relevant issues. In addition to contacts 1307 during the study, the monitor may also contact the site prior to the start of the study to discuss the protocol and 1308 data collection procedures with site personnel. 1309 Additional on-site monitoring verification includes: ongoing evaluation of the adequacy of site facilities and staff, 1310 site recruitment, subject randomization, the presence of regulatory documents, and specific review of documents 1311 and data. The initial performance-monitoring visit to a site takes place after the initial subject(s) are enrolled and 1312 will continue according to enrolment for the duration of the trial. 1313 During the monitoring visit, any omissions and corrections to data submitted to the database will be noted and 1314 queries will be generated by the monitor and resolved by the site.

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1315 The close-out monitoring visit by the monitor will take place at the completion of subject enrollment and 1316 protocol required follow-up visits at the performance site. At that visit, the monitor will again review the 1317 presence of a regulatory file and verify documents for currency and completion as directed by the clinical 1318 research unit. Sites will be instructed in the record retention of all trial documents. Principal Investigators are 1319 directed to close the trial and issue a final report to the institutional review board. Finally, any additional special 1320 considerations for the auditing of any additional safety issues are made during this final monitoring visit. 1321 Except for an emergency situation in which proper care for the protection, safety and well- being of the study 1322 subjects requires medical treatment, the study will be conducted as described in the approved protocol, 1323 International Conference on Harmonization-Good Clinical Practice (ICH-GCP), Standard Operating Procedures 1324 (SOPs) and regulatory requirements. All medical treatments will be recorded. Any deviation(s) from the protocol 1325 will be recorded and presented in the final clinical study report. 1326 18.1. Audits and Inspections 1327 In accordance with the principles of ICH-GCP, the study site may be inspected by regulatory authorities. Quality 1328 Assurance (QA) or their designates. The investigator and relevant clinical support staff will be required to be 1329 actively involved in audits and inspections, including staff interviews, and to make all necessary documentation 1330 and data available upon request. 1331 During the course of the study and/or after it has been completed, one or more investigator site audits may be 1332 undertaken by auditors. The purpose of these audits is to determine whether or not the study is being/has been 1333 conducted and monitored in compliance with recognized ICH-GCP, protocol and approved amendment 1334 requirements, applicable local SOPs, and local laws and regulations. It is the responsibility of the investigator 1335 and site staff to promptly address any deficiencies stemming out of regulatory inspections and delegate audits, 1336 and to ensure that agreed-upon corrective and preventive actions are implemented as soon as possible. 1337 An inspection by any regulatory authority may occur at any time during or after completion of the study. 1338 18.2. Protocol Amendments and Revisions 1339 Should amendments and/or revisions to the protocol be required, they will be originated and documented by the 1340 sponsor. All amendments and/or revisions will be made in compliance with sponsor SOPs. All amendments will 1341 be submitted to the research ethics board/Institutional Review Board (REB/IRB) for approval prior to 1342 implementation. It is the sponsor’s responsibility to submit all revisions and amendments to regulatory 1343 authorities when necessary. 1344 1345 19. ETHICAL CONSIDERATION 1346 This research followed the ethical principles of the Helsinki Declaration. This protocol and the consent forms 1347 will be submitted to each hospital’s REB/IRB. Before initiation of the study, a copy of the REB/IRBs’ approval 1348 letters will be provided to the sponsor and the membership list of the REB/IRB will be kept on file. To make 1349 sure the subjects fully understand about this trial, the investigators must provide the patients or their legal 1350 representatives with detailed information about the clinical trial, including the purpose of the trial, possible 1351 benefits and risks, and the rights/obligations. Subjects have the right to withdraw from the study at any time if 1352 they wish to do so. The privacy protection of subjects has to be ensured. The patients or their legal 1353 representatives give their written informed consent prior to the study. Each patient must leave contact 1354 information to the investigator of the participating center. At the same time, the investigator must leave his own 1355 phone number to the patient so that the patient can find the investigator at any time. Ethical approval for the 1356 study was obtained by the Ethics Committee of the participating centers. SAEs will be reported to the REB/IRB 1357 according to their requirements. 1358 1359 20. DATA HANDLING AND RECORD KEEPING

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1360 20.1. Data Handling 1361 During the trial, clinical data reported in the e-CRFs will be integrated into the clinical database under the 1362 responsibility of the Sponsor or their qualified representative. Quality control in the form of computerized logic 1363 and/or consistency checks will be systematically applied in order to detect errors or omissions. In addition, safety 1364 reviews may be performed several times by the Sponsor’s staff in the course of the trial. Any questions 1365 pertaining to the reported clinical data will be submitted to the investigator for resolution. Each step of this 1366 process will be monitored through the implementation of individual passwords to maintain appropriate database 1367 access and to ensure database integrity. 1368 After integration of all corrections in the complete set of data, the database will be released for statistical 1369 analysis. 1370 20.2. Investigator Files/Retention of Documents 1371 The investigator must maintain adequate and accurate records to enable the conduct of the study to be fully 1372 documented and the study data to be subsequently verified. These documents should be classified into two 1373 different separate categories: Investigator's Study File; and Subject Clinical Source Documents. 1374 The Investigator's Study File will contain the Protocol/Amendments, CRFs, REB/IRB and governmental 1375 approval with correspondence, all versions of ethics approved informed consent forms, staff curriculum vitae 1376 and authorization forms and other appropriate documents/correspondence, etc. 1377 Subject clinical source documents (usually defined by the project in advance to record efficacy/safety parameters 1378 independent of the CRFs) would include subject hospital/clinic records, physician's and nurse's notes, 1379 appointment book, original laboratory reports, ECG, image data, signed consent forms, consultant letters, and 1380 source worksheets. The investigator must keep these two categories of documents on file according to local 1381 clinical trial regulation. 1382 The Investigator and the sponsor will maintain the records of disposition of the drug and the clinic records in 1383 accordance with ICH-GCP and each applicable regulatory agency. Clinic records will be retained at the site until 1384 informed by the sponsor to destroy the documents. If the clinical study must be terminated for any reason, the 1385 investigator will return all study materials to the sponsor and provide a written statement as to why the 1386 termination has taken place and notify the REB/IRB. 1387 20.3. Source Documents and Background Data 1388 Any investigators shall supply the sponsor, upon request, with any required background data from the study 1389 documentation or clinic records. This is particularly important when e-CRFs are illegible or when errors in data 1390 transcription are suspected. In case of special problems and/or governmental queries or requests for audit 1391 inspections, it is also necessary to have access to the complete study records, provided that subject 1392 confidentiality is protected. 1393 20.4. Case Report Forms 1394 For each subject randomized, an e-CRF must be completed and signed by the investigator. If a subject withdraws 1395 from the study, the reason must be noted on the CRF. All forms should be completed within five business days 1396 of subject visit. All corrections will be tracked in the e-CRF audit trail. The Investigator should ensure the 1397 accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all 1398 required reports. 1399 20.5. Confidentiality 1400 All imaging, evaluation forms, reports, and other records that leave the site are identified only by the site and 1401 subject number to maintain subject confidentiality. All records are kept in a locked file cabinet. Clinical 1402 information is not released without written permission of the subject, except as necessary for monitoring by 1403 REB/IRB, health authorities, the sponsor, or the sponsor’s designee.

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1404 All study investigators at the clinical sites must ensure that the confidentiality of personal identity and all 1405 personal medical information of study subjects are maintained at all times. clinical sites must conform to local 1406 privacy and confidentiality law and custom. On the CRFs and other study documents or image materials 1407 submitted to the CRU, the subjects are identified only by study identification codes. 1408 Personal medical information may be reviewed for the purpose of verifying data recorded in the CRF by the site 1409 monitors. Other properly authorized persons, such as the regulatory authorities, may also have access to these 1410 records. Personal medical information is always treated as confidential. 1411 1412 21. PUBLICATION AND PRESENTATION POLICY 1413 A trial executive committee shall be formed, and include at least the trial principal investigator and co-principal 1414 investigator, the statistical consultant, and representatives of the Sponsor. The trial executive committee will be 1415 co-authors on all publications and presentations. The primary author list for the primary publication will consist 1416 of the executive committee and the site principal/qualified investigator at each of the sites. A formal publication 1417 policy will be presented and developed by the trial executive. 1418 1419 22. DATA-SHARING PLAN 1420 The sponsor will permit any and all academic publications arising from the trial data provided that no publication 1421 containing unblinded trial data precedes publication of the overall trial results in a peer-review journal, and are 1422 (1) approved by the trial executive committee and (2) the publication authors notify the sponsor at least 30 days 1423 prior to submittal for publication with a copy of such proposed publication for the sponsor’s review and 1424 comment. Employees or consultants of the sponsor will only be named as authors in any such publication if the 1425 parties agree that it is appropriate under the usual conventions used by academic institutions for naming authors 1426 in scientific publications. Upon request of the sponsor the publication or disclosure shall be delayed for up to 60 1427 days in order to allow for the filing of a patent application. The Executive Committee will make the trial results 1428 available as free-access using PubMed and on Chinese Clinical Trials Registry. (www.chictr.org.cn). 1429 1430 23. STUDY ORGANIZATION AND FUNDING 1431 DEVT trial is an investigator-initiated study which is organized by the second affiliated hospital of the Third 1432 Military Medical University and conducted in about 30 comprehensive stroke centers in China. The authors 1433 disclosed receipt of the following financial support: (1) National Natural Science Foundation of China (Nos. 1434 81525008, 81901236, 81801157), (2) Chongqing Major Disease Prevention and Control Technology Research 1435 Project (No. 2019ZX001), (3) Major clinical innovation technology project of the Second Affiliated Hospital of 1436 the Army Military Medical University (No. 2018JSLC0017), and (4) Clinical Medical Research Talent Training 1437 Program of Army Medical University (2019XLC2008, 2019XLC3016). The funders had no involvement in the 1438 study design, data collection, analysis and interpretation, writing or decision to submit the paper. 1439

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1440 Appendix 1 - Classification of Subtype of Acute Ischemic Stroke 1441 The TOAST classification system includes five categories: 1) large-artery atherosclerosis, 2) cardioembolism, 3) 1442 small-artery occlusion (lacunae), 4) stroke of other determined etiology, and 5) stroke of undetermined etiology 1443 (Table 1)27. Diagnoses are based on clinical features and on data collected by tests such as brain imaging 1444 (CT/MRI), cardiac imaging (echocardiography, etc.), duplex imaging of extracranial arteries, arteriography, and 1445 laboratory assessments for a pro-thrombotic state. 1446 The physician can apply the clinical and imaging findings when first assessing the patient and then consider the 1447 results of other diagnostic tests later. An important part of the classification is the ability of the physician to 1448 categorize a specific subtype diagnosis as probable or possible based on the degree of certainty. A "probable" 1449 diagnosis is made if the clinical findings, neuroimaging data, and results of diagnostic studies are consistent with 1450 one subtype and other etiologies have been excluded. A "possible" diagnosis is made when the clinical findings 1451 and neuroimaging data suggest a specific subtype but other studies are not done. Because many patients will 1452 have a limited number of diagnostic tests, the probable and possible subcategorizations allow the physician to 1453 make as precise a subgroup diagnosis as can be achieved. 1454 Large artery atherosclerosis 1455 These patients will have clinical and brain imaging findings of either significant (>50%) stenosis or occlusion of 1456 a major brain artery or branch cortical artery, presumably due to atherosclerosis (Table 2). Clinical findings 1457 include those of cerebral cortical impairment (aphasia, neglect, restricted motor involvement, etc.) or brain stem 1458 or cerebellar dysfunction. A history of intermittent claudication, transient ischemic attacks (TIAs) in the same 1459 vascular territory, a carotid bruit, or diminished pulses helps support the clinical diagnosis. Cortical or cerebellar 1460 lesions and brain stem or subcortical hemispheric infarcts greater than 1.5 cm in diameter on CT or MRI are 1461 considered to be of potential large-artery atherosclerotic origin. Supportive evidence by duplex imaging or 1462 arteriography of a stenosis of greater than 50% of an appropriate intracranial or extracranial artery is needed. 1463 Diagnostic studies should exclude potential sources of cardiogenic embolism. The diagnosis of stroke secondary 1464 to large artery atherosclerosis cannot be made if duplex or arteriographic studies are normal or show only 1465 minimal changes. 1466 Cardioembolism 1467 This category includes patients with arterial occlusions presumably due to an embolus arising in the heart (Table 1468 2). Cardiac sources are divided into high-risk and medium-risk groups based on the evidence of their relative 1469 propensities for embolism (Table 3). At least one cardiac source for an embolus must be identified for a possible 1470 or probable diagnosis of cardioembolic stroke. Clinical and brain imaging findings are similar to those described 1471 for large-artery atherosclerosis. Evidence of a previous TIA or stroke in more than one vascular territory or 1472 systemic embolism supports a clinical diagnosis of cardiogenic stroke. Potential large-artery atherosclerotic 1473 sources of thrombosis or embolism should be eliminated. A stroke in a patient with a medium-risk cardiac source 1474 of embolism and no other cause of stroke is classified as a possible cardioembolic stroke. 1475 Small artery occlusion (lacunae) 1476 This category includes patients whose strokes are often labeled as lacunar infarcts in other classifications (Table 1477 2). The patient should have one of the traditional clinical lacunar syndromes and should not have evidence of 1478 cerebral cortical dysfunction. A history of diabetes mellitus or hypertension supports the clinical diagnosis. The 1479 patient should also have a normal CT/MRI examination or a relevant brain stem or subcortical hemispheric 1480 lesion with a diameter of less than 1.5cm demonstrated. Potential cardiac sources for embolism should be absent, 1481 and evaluation of the large extracranial arteries should not demonstrate a stenosis of greater than 50% in an 1482 ipsilateral artery. 1483 Acute stroke of other determined etiology

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1484 This category includes patients with rare causes of stroke, such as nonatherosclerotic vasculopathies, 1485 hypercoagulable states, or hematologic disorders. Patients in this group should have clinical and CT or MRI 1486 findings of an acute ischemic stroke, regardless of the size or location. Diagnostic studies such as blood tests or 1487 arteriography should reveal one of these unusual causes of stroke. Cardiac sources of embolism and large-artery 1488 atherosclerosis should be excluded by other studies. 1489 Stroke of undetermined etiology 1490 In several instances, the cause of a stroke cannot be determined with any degree of confidence. Some patients 1491 will have no likely etiology determined despite an extensive evaluation. In others, no cause is found but the 1492 evaluation was cursory. This category also includes patients with two or more potential causes of stroke so that 1493 the physician is unable to make a final diagnosis. For example, a patient with a medium-risk cardiac source of 1494 embolism who also has another possible cause of stroke identified would be classified as having a stroke of 1495 undetermined etiology. Other examples would be a patient who has atrial fibrillation and an ipsilateral stenosis 1496 of 50%, or the patient with a traditional lacunar syndrome and an ipsilateral carotid stenosis of 50%. 1497 1498 Table 1. TOAST Classification of Subtypes of Acute Ischemic Stroke Large artery atherosclerosis (embolus/thrombosis)* Cardioembolism (high-risk/medium-risk)* Small-vessel occlusion (lacunae)* Stroke of other determined etiology* Stroke of undetermined etiology a. Two or more causes identified b. Negative evaluation c. Incomplete evaluation 1499 TOAST denotes Trial of Org 10172 in Acute Stroke Treatment. 1500 *Possible or probable depending on results of ancillary studies. 1501 1502 Table 2. Features of TOAST Classification of Subtypes of Ischemic Stroke Subtype Large artery Small artery Cardioembolism Other cause Features atherosclerosis occlusion (lacunae) Clinical Cortical or cerebellar + + - +/- dysfunction Lacunar - - + +/- syndrome Imaging Cortical, cerebellar, brain stem, or + + - +/- subcortical infarct > 1.5 cm

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Subcortical or brain stem - - +/- +/- infarct < 1.5 cm Tests Stenosis of extracranial + - - - internal carotid artery Cardiac source - + - - of emboli Other abnormality on - - - + tests 1503 1504 Table 3. TOAST Classification of High- and Medium-Risk Sources of Cardioembolism High-risk sources Mechanical prosthetic valve Mitral stenosis with atrial fibrillation Atrial fibrillation (other than lone atrial fibrillation) Left atrial/atrial appendage thrombus Sick sinus syndrome Recent myocardial infarction (<4 weeks) Left ventricular thrombus Dilated cardiomyopathy Akinetic left ventricular segment Atrial myxoma Infective endocarditis Medium-risk sources Mitral valve prolapse Mitral annulus calcification Mitral stenosis without atrial fibrillation Left atrial turbulence (smoke) Atrial septal aneurysm Patent foramen ovale Atrial flutter Lone atrial fibrillation Bioprosthetic cardiac valve Nonbacterial thrombotic endocarditis Congestive heart failure Hypokinetic left ventricular segment Myocardial infarction (> 4 weeks, < 6 months) 1505

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1506 Appendix 2 - ASITN/SIR Collateral Vessel Grading System 1507 Collateral vessel status was evaluated by using the American Society of Interventional and Therapeutic 1508 Neuroradiology/Society of Interventional Radiology (ASITN/SIR) collateral vessel grading system28. Collateral 1509 vessel scores are categorized into ASITN/SIR grades 0 or 1, 2, and 3 or 4. The following scoring system 1510 provides a guide. Grade Description 0 No collateral vessels visible to the ischemic site 1 Slow collateral vessels to the periphery of the ischemic site with persistence of some of the defect 2 Rapid collateral vessels to periphery of ischemic site with persistence of some of the defect and to only a portion of the ischemic territory 3 Collateral vessels with slow but complete angiographic blood flow of the ischemic bed by the late venous phase 4 Complete and rapid collateral blood flow to the vascular bed in the entire ischemic territory by retrograde perfusion 1511 1512

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1513 Appendix 3 - The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) 1514 NCCT shall be scored using ASPECTS, a 10-point score derived by examining each of 10 regions on the middle 1515 cerebral artery territory29. Ischemic change present is scored as 0; ischemic change absent is score as 1. Adding 1516 up the score gives a maximum of 10 (favorable scan) and minimum of 0 (unfavorable scan). The score is highly 1517 reliable when trichotomized into 0-4 (severe ischemic change, large core), 5-7 (moderate ischemic change) and 1518 8-10 (minimal ischemic change, small core). ASPECTS may be less reliable early in stroke (i.e. within 90 1519 minutes of onset); however, at later time windows it should be easy to recognize large areas of irreversible 1520 damage. Having a good quality scan and optimization of scanner is key to successful interpretation. Further 1521 information is available at: ww.aspectsinstroke.com.

1522 1523

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1524 Appendix 4 - Modified Rankin Scale (MRS) Grade Description30 0 No symptoms at all 1 No significant disability despite symptoms: able to carry out all usual duties and activities 2 Slight disability: unable to carry out all previous activities but able to look after own affairs without assistance 3 Moderate disability: requiring some help, but able to walk without assistance 4 Moderately severe disability: unable to walk without assistance, and unable to attend to own bodily needs without assistance 5 Severe disability: bedridden, incontinent, and requiring constant nursing care and attention 6 Death 1525 1526

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1527 Appendix 5 - Expanded Thrombolysis In Cerebral Infarction (eTICI) Scale Score Discription18 0 No perfusion or anterograde flow beyond site of occlusion 1 Penetration but not perfusion. Contrast penetration exists past the initial obstruction but with minimal filling of the normal territory 2 Incomplete perfusion wherein the contrast passes the occlusion and opacifies the distal arterial bed but rate of entry or clearance from the bed is slower or incomplete when compared with non-involved territories 2a Some perfusion with distal branch filling of < 50% of territory visualized 2b Substantial perfusion with distal branch filling of ≥ 50% of territory visualized 2c Near-complete perfusion except for slow flow in a few distal cortical vessels or presence of small distal cortical emboli 3 Complete perfusion with normal filling of all distal branches 1528 1529 1530

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1531 Investigator’s Agreement 1532 I have read the attached protocol: a randomized, controlled, multicenter trial of Direct Endovascular treatment 1533 Versus standard bridging Therapy for acute stroke patients with large vessel occlusion in the anterior circulation 1534 (DEVT Trial), Version 2.0 dated 1st August 2019 and agree to abide by all provisions set forth therein. I agree to 1535 comply with the current International Conference on Harmonization Guidelines for Good Clinical Practice and 1536 the laws, rules, regulations and guidelines of the community, country, state or locality relating to the conduct of 1537 the clinical study. I also agree that persons debarred from conducting or working on clinical studies by any court 1538 or regulatory agency will not be allowed to conduct or work on studies for the sponsor. 1539 1540 1541 1542 1543 1544 Name Site Principal Investigator Signature 1545 1546 1547 Name of Clinical Site Date 1548

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1549 REFERENCES 1550 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. 1551 The New England journal of medicine 2008;359:1317-29. 1552 2. National Institute of Neurological D, Stroke rt PASSG. Tissue plasminogen activator for acute ischemic 1553 stroke. The New England journal of medicine 1995;333:1581-7. 1554 3. Muir KW, Ford GA, Messow C-M, et al. Endovascular therapy for acute ischaemic stroke: the Pragmatic 1555 Ischaemic Stroke Thrombectomy Evaluation (PISTE) randomised, controlled trial. Journal of neurology, 1556 neurosurgery, and psychiatry 2017;88:38-44. 1557 4. Bracard S, Ducrocq X, Mas JL, et al. Mechanical thrombectomy after intravenous alteplase versus alteplase 1558 alone after stroke (THRACE): a randomised controlled trial. The Lancet Neurology 2016;15:1138-47. 1559 5. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in 1560 stroke. The New England journal of medicine 2015;372:2285-95. 1561 6. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. 1562 The New England journal of medicine 2015;372:2296-306. 1563 7. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of 1564 ischemic stroke. The New England journal of medicine 2015;372:1019-30. 1565 8. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging 1566 selection. The New England journal of medicine 2015;372:1009-18. 1567 9. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute 1568 ischemic stroke. The New England journal of medicine 2015;372:11-20. 1569 10. Chandra RV, Lesliemazwi TM, Mehta BP, et al. Does the use of IV tPA in the current era of rapid and 1570 predictable recanalization by mechanical embolectomy represent good value. Journal of neurointerventional 1571 surgery 2016;8:443-6. 1572 11. Grotta JC, Hacke W. Stroke Neurologist's Perspective on the New Endovascular Trials. Stroke; a journal of 1573 cerebral circulation 2015;46:1447-52. 1574 12. Wang H, Zi W, Hao Y, et al. Direct endovascular treatment: an alternative for bridging therapy in anterior 1575 circulation large-vessel occlusion stroke. European journal of neurology : the official journal of the European 1576 Federation of Neurological Societies 2017;24:935-43. 1577 13. Rai AT, Boo S, Buseman C, et al. Intravenous thrombolysis before endovascular therapy for large vessel 1578 strokes can lead to significantly higher hospital costs without improving outcomes. Journal of 1579 neurointerventional surgery 2018;10:17-21. 1580 14. Ren Y, Churilov L, Mitchell P, Dowling R, Bush S, Yan B. Clot Migration Is Associated With Intravenous 1581 Thrombolysis in the Setting of Acute Ischemic Stroke. Stroke; a journal of cerebral circulation 2018;49:3060-2. 1582 15. Mistry EA, Mistry AM, Nakawah MO, et al. Mechanical Thrombectomy Outcomes With and Without 1583 Intravenous Thrombolysis in Stroke Patients: A Meta-Analysis. Stroke; a journal of cerebral circulation 1584 2017;48:2450-6. 1585 16. Kaesmacher J, Mordasini P, Arnold M, et al. Direct mechanical thrombectomy in tPA-ineligible and -eligible 1586 patients versus the bridging approach: a meta-analysis. Journal of neurointerventional surgery 2019;11:20-7. 1587 17. Powers Wj Fau - Rabinstein AA, Rabinstein Aa Fau - Ackerson T, Ackerson T Fau - Adeoye OM, et al. 2018 1588 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare 1589 Professionals From the American Heart Association/American Stroke Association. stroke 2018;49. 1590 18. Liebeskind DS, Bracard S, Guillemin F, et al. eTICI reperfusion: defining success in endovascular stroke 1591 therapy. Journal of neurointerventional surgery 2019;11:433-8. 1592 19. Brott T, Adams HP, Jr., Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination

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1593 scale. Stroke; a journal of cerebral circulation 1989;20:864-70. 1594 20. von Kummer R, Broderick JP, Campbell BC, et al. The Heidelberg Bleeding Classification: Classification of 1595 Bleeding Events After Ischemic Stroke and Reperfusion Therapy. Stroke; a journal of cerebral circulation 1596 2015;46:2981-6. 1597 21. Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke 1598 clinical trials: a literature review and synthesis. Stroke; a journal of cerebral circulation 2007;38:1091-6. 1599 22. Quinn TJ, Dawson J, Walters MR, Lees KR. Reliability of the modified Rankin Scale: a systematic review. 1600 Stroke; a journal of cerebral circulation 2009;40:3393-5. 1601 23. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of 1602 EQ-5D (EQ-5D-5L). Quality of life research : an international journal of quality of life aspects of treatment, care 1603 and rehabilitation 2011;20:1727-36. 1604 24. Broeg-Morvay A, Mordasini P, Bernasconi C, et al. Direct Mechanical Intervention Versus Combined 1605 Intravenous and Mechanical Intervention in Large Artery Anterior Circulation Stroke: A Matched-Pairs Analysis. 1606 Stroke; a journal of cerebral circulation 2016;47:1037-44. 1607 25. Bellwald S, Weber R, Dobrocky T, et al. Direct Mechanical Intervention Versus Bridging Therapy in Stroke 1608 Patients Eligible for Intravenous Thrombolysis: A Pooled Analysis of 2 Registries. Stroke; a journal of cerebral 1609 circulation 2017;48:3282-8. 1610 26. Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized trial of intraarterial treatment for acute 1611 ischemic stroke. The New England journal of medicine 2015;372:11-20. 1612 27. Adams HP, Jr., Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. 1613 Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke; a 1614 journal of cerebral circulation 1993;24:35-41. 1615 28. Zaidat OO, Yoo AJ, Khatri P, et al. Recommendations on angiographic revascularization grading standards 1616 for acute ischemic stroke: a consensus statement. Stroke; a journal of cerebral circulation 2013;44:2650-63. 1617 29. Pexman JH, Barber PA, Hill MD, et al. Use of the Alberta Stroke Program Early CT Score (ASPECTS) for 1618 assessing CT scans in patients with acute stroke. AJNR American journal of neuroradiology 2001;22:1534-42. 1619 30. Bonita R, Beaglehole R. Recovery of motor function after stroke. Stroke; a journal of cerebral circulation 1620 1988;19:1497-500. 1621 1622

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1623 Summary of Changes - Protocol DEVT Version 1.0 to Version 2.0 1624 1625 Below is the table of changes. Deleted items are identified with Strikethrough font. Additional wording is in bold font Section(s) Protocol Version 1.0 Protocol Version 2.0 Rationale Change From: Change To: List of Abbreviations MedDRA-Medical Dictionary for Regulatory Activities Addition SOC-System Organ Class Schedule of Assessments Weight Weight Clarification The subject’s actual weight will be measured in hospital using standard hospital scales (i.e., stand up or in-bed scales if the subject is not ambulatory). If actual weight cannot be measured for any reason (due to, for example severe illness or unavailability of in-bed scales at the site), weight will be determined by first asking the subject, second asking a family member or third by estimation. Schedule of Assessments Prior medications Prior medications§ Clarification Concomitant medications Concomitant medications§ §Prior and concomitant medications will be listed per patient, with the listings separated within treatment group. Study Synopsis - Assessment Successful recanalization proportion Successful recanalization proportion immediate after EVT. Updated definition, in of Efficacy immediate after EVT. Successful Successful recanalization is defined as a expanded response to a comment & recanalization is defined as a modified Thrombolysis In Cerebral Infarction score of 2b received from the Research Section 8.2 Secondary Treatment in Cerebral Infarction score (substantial perfusion), 2c (near-complete perfusion) or 3 Committee Efficacy Outcomes of 2b (50 to 99% reperfusion) or 3 (complete reperfusion) in the post-procedure angiography (complete reperfusion) in the post-procedure angiography Section 1 BACKGROUND In addition, IVT before EVT is associated with an Addition INFORMATION increased incidence of clot migration, resulting in an

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Statistical Analysis Plan

increased rate of clots inaccessibility by mechanical thrombectomy. [reference: Stroke 2017;48:2450-6.]

Another meta-analysis showed that direct endovascular treatment may carries comparable effectiveness and safety as compared with bridging therapy by pooling studies with lower selection bias. [reference: Journal of neurointerventional surgery 2019;11:20-7.] Section 10.1 The Modified Premorbid mRS status will also be Premorbid mRS status will also be obtained retrospectively Clarification of the premorbid Rankin Scale obtained retrospectively at 24 Hours and reported on the 24h CRF page. mRS collection time and reporting on the CRF Section 16.8 SAEs SAEs over the 90-day study period will be summarized by Addition, presenting, for each treatment group, the number and To be consistent with the percentage of subjects having at least one SAE, having an Statistical Analysis Plan SAE in each body system and preferred term, by severity and relatedness to study medication. The frequencies and incidences of SAEs occurring in subjects in the active and control groups will be summarized within treatment group by the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). The frequencies and incidences of SAEs and discontinuations due to SAEs occurring in subjects in the active and control groups will be summarized within treatment group Section 16.9 AEs Additional analyses will consider the frequency of AEs and Addition, discontinuations due to AEs. AEs will be summarized by To be consistent with the presenting, for each treatment group, the number and Statistical Analysis Plan percentage of subjects having any AE, having an AE in each body system and preferred term. Severity and

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relatedness to study medication will be recorded. The frequencies and incidences of AEs occurring in subjects in the active and control groups will be summarized within treatment group by the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). Section 23. STUDY DEVT trial is an investigator-initiated DEVT trial is an investigator-initiated study which is Addition ORGANIZATION AND study which is organized by the second organized by the second affiliated hospital of the Third FUNDING affiliated hospital of the Third Military Military Medical University and conducted in about 30 Medical University and conducted in comprehensive stroke centers in China. The authors disclosed about 30 comprehensive stroke centers receipt of the following financial support: (1) National Natural in China. The authors disclosed receipt Science Foundation of China (Nos. 81525008, 81901236, of the following financial support: (1) 81801157), (2) Chongqing Major Disease Prevention and National Science Fund for Control Technology Research Project (No. 2019ZX001), Distinguished Young Scholars (No. (3) Major clinical innovation technology project of the Second 81525008), and (2) Major clinical Affiliated Hospital of the Army Military Medical University innovation technology project of the (No. 2018JSLC0017), and (4) Clinical Medical Research Second Affiliated Hospital of the Army Talent Training Program of Army Medical University Military Medical University (No. (2019XLC2008, 2019XLC3016). The funders had no 2018JSLC0017). The funders had no involvement in the study design, data collection, analysis and involvement in the study design, data interpretation, writing or decision to submit the paper. collection, analysis and interpretation, writing or decision to submit the paper. Appendix 5 - Modified Modified Treatment In Cerebral Expanded Thrombolysis in Cerebral Infarction Scale Updated definition, in Treatment In Cerebral Infarction (mTICI) Score response to a comment Infarction (mTICI) Score received from the Research Committee 1626

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Effect of Endovascular Treatment Alone Versus Intravenous Alteplase Plus

Endovascular Treatment on Functional Independence in Patients with

Acute Ischemic Stroke: The DEVT Randomized Clinical Trial

Statistical Analysis Plan

This supplement contains the Original/Final Statistical Analysis Plan (SAP). There were no substantive amendments between the Original SAP and the Final SAP which was finalized prior to database lock.

Note: personal identifying information has been redacted from the SAP documents to comply with international privacy legislation.

1st August 2019 Version 2.0 Statistical Analysis Plan

SIGNATURE PAGE

Wenjie Zi Date

Xinqiao Hospital of Army Medical University

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Statistical Analysis Plan

Contents

1. Overview ...... 4 2. Study Success Criteria ...... 4 3. Sample Size ...... 4 3.1. Non-inferiority Margin Evaluation ...... 4 3.2. Effectiveness Sample Size Evaluation ...... 4 3.3. Randomization and Allocation Concealment Methods ...... 7 3.4. Blinding ...... 7 4. Interim Analysis ...... 7 5. Analysis Populations ...... 7 5.1. Intention-to-treat set ...... 7 5.2. Per-protocol set ...... 7 5.3. Safety set ...... 7 6. Statistical Methods ...... 8 7. Baseline Characteristics ...... 8 8. Patient Disposition ...... 8 9. Effectiveness Analysis ...... 8 9.1. Primary Effectiveness Analysis ...... 8 9.2. Secondary Effectiveness Analysis ...... 9 9.3. Handling of Multiplicity ...... 9 9.4. Effectiveness Subgroup Analysis ...... 9 10. Safety Analysis ...... 10 10.1. Primary Safety Analysis ...... 10 10.2. Secondary Safety Analysis ...... 10 10.3. Analysis of Adverse Events ...... 10 10.4. Handling of Multiplicity ...... 11 10.5. Analysis of Deaths ...... 11 11. Pooling Across Centers ...... 11 12. Lost to Follow-Up and Missing Data ...... 11 13. Committees ...... 11 13.1. Clinical Events Committee/Data Safety Monitoring Board (CEC/DSMB) ...... 11 13.2. Imaging Core Laboratory ...... 12 14. Changed to Planned Analyses ...... 12 15. References ...... 13

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Statistical Analysis Plan

1. Overview This is a multicenter, prospective, randomized, open-label, blinded endpoint evaluation study designed to evaluate the efficacy and safety of endovascular treatment alone versus intravenous alteplase plus endovascular treatment for acute ischemic stroke patient with large artery occlusion in the anterior circulation both with eligible for treatment of intravenous alteplase. Up to 970 patients in total of all five interims will be enrolled over three years from approximately 35 hospitals in China. Each site will be limited to a maximum enrollment of about 194 patients (~20% of total enrollment). Patients will be randomized 1:1 to receive one of the following:  Intravenous alteplase plus endovascular treatment (control);  Endovascular treatment alone(test). This Statistical Analysis Plan will provide details to further elaborate statistical methods as outlined in the protocol and will describe analysis conventions. The Statistical Analysis Plan will be signed off prior to database lock.

2. Study Success Criteria The study will be considered a success if the primary efficacy non-inferiority criterion is met. Primary Effectiveness Non-Inferiority: The proportion of patients in the primary-thrombectomy group who achieve functional independence (defined as a modified Rankin scale score of 0 to 2) at 90-day follow-up is no more than 10% below that proportion of patients in the bridging-therapy group. Group Sequential Analysis: Interim analyses will be performed when 194 subjects from the intention-to-treat population have provided evaluable primary effectiveness data and then after each subsequent 194 subjects, to a maximum of 970 subjects with evaluable data (i.e. 194, 388, 582, 776, and 970). Table 3 provides the group sequential boundaries including minimum acceptable statistical criteria at each look (including the final analysis). Additional analyses conducted for secondary endpoints and subgroups will be presented.

3. Sample Size Up to 194 patients in each interim analysis and 970 in total of five interim analyses are to be randomized in a 1:1 ratio to bridging-therapy group or primary-thrombectomy group.

3.1. Non-inferiority Margin Evaluation The primary efficacy analysis will be performed by comparing the lower bound of a two-sided, 95% confidence interval, calculated using normal approximation, for the observed difference between endovascular treatment alone and intravenous alteplase plus endovascular treatment on the percentage of subjects that have functional independence with a pre-specified non-inferiority margin (-10%). According to the previous study data1-4, we hypothesis that the 90-day follow-up functional independence proportion of patients in the bridging-therapy group is 43%. We assumed that the functional independence of primary-thrombectomy group should not be less than that of bridging-therapy group of MR CLEAN trial which indicated that functional independence proportion is about 33%4. Therefore, the clinically relevant non-inferiority margin is estimated to be -10%. Should the lower limit of this difference be > -10%, it can be concluded that the endovascular treatment alone is non-inferior to intravenous alteplase plus endovascular treatment with respect to the primary efficacy measure.

3.2. Effectiveness Sample Size Evaluation The sample size calculations assume that 43% of intravenous alteplase plus endovascular treatment patients 4 / 13

Statistical Analysis Plan achieve functional independence at 90 days and 43% of endovascular treatment alone patients achieve functional independence at 90 days. The clinically relevant non-inferiority margin was -10.0%. A group-sequential test strategy was designed to have reasonable chances of stopping as early as possible, either because of efficacy or safety reasons. Sample size and power are computed incorporating a five-look group-sequential analysis plan with a two-sided at 0.05, 918 cases provide 80% power for testing the primary hypothesis of this trial; assuming the attrition rate is 5% for the primary end-point, the total sample size is up to 970. The evaluable sample size is 194 in each interim analysis and 970 in total of all five interim analyses. Therefore, in each interim analysis, 97 cases should be enrolled in each treatment group. PASS 15.0 (NCSS, LLC. Kaysville, Utah, USA) was used to calculate the sample size. See details in Table 1, Table 2, Table 3, Figure 1, and Figure 2.

Table 1. Effectiveness Sample Size Parameters Parameters Value Bridging-Therapy Proportion 0.43 Primary-Thrombectomy Proportion 0.43 Group Allocation (Bridging-Therapy : Primary-Thrombectomy) 1:1 Test Type Z-Test (Unpooled) Higher Proportions Are Better Simulations 5000 Power 80% Alpha 0.025 Number of Sides 1 Non-Inferiority Difference -0.10 Specification of Looks and Boundaries Simple Number of Equally Spaced Looks 5 Alpha Spending Function Pocock Analog Type of Futility Boundary None Estimated Attrition 5%

Table 2. Accumulated Information Details Accumulated Information Accumulated Sample Size Look Primary-thrombectomy Percent Bridging-therapy group Total group 1 20.0 97 97 194 2 40.0 194 194 388 3 60.0 291 291 582 4 80.0 388 388 776 5 100.0 485 485 970

Table 3. Boundaries Significance Boundary Look Z-value Scale P-Value Scale 1 2.35826 0.00918 2 2.45230 0.00710 3 2.35290 0.00931

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Look Significance Boundary 4 2.41629 0.00784 5 2.36354 0.00905

Figure 1. Boundary Plot - Z-Value

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Figure 2. Boundary Plot - P-Value

3.3. Randomization and Allocation Concealment Methods Subjects who are eligible based on inclusion and exclusion criteria and have had all pre- randomization screening procedures performed will be randomized by center in a 1:1 ratio to one of following two treatment groups:  Intravenous alteplase plus endovascular treatment (bridging-therapy, control);  Endovascular treatment alone (primary-thrombectomy, test). Randomization occurs immediately after baseline (at the endovascular treatment institution) CT/MR brain imaging and CT/MR angiography via a real-time, internet-based randomization method. The randomization was stratified by participating centers.

3.4. Blinding The investigators, and center study personnel will not be blinded to each patient's randomized treatment group throughout the course of the study. The study subjects, clinical data assessors and collectors, and the Independent Imaging Core Laboratory will be blinded to treatment assignment.

4. Interim Analysis We desired a maximum of 5 interim analyses when approximately 20, 40, 60, 80, and 100% of the total sample size finish the follow-up, monitoring and data cleaning processes. A group-sequential test strategy was designed to have reasonable chances of stopping as early as possible, either because of efficacy or safety reasons. See details in Table 2, Table 3, Figure 1, and Figure 2.

5. Analysis Populations All primary, secondary effectiveness, and safety endpoints will be performed for both the intention-to-treat population and per-protocol population. Patients who withdraw informed consent immediately after randomization and are not to receive any treatment should be excluded from all analysis populations.

5.1. Intention-to-treat set The intention-to-treat population will consist of all patients who signed the informed consent and are randomized in the study. The data from the intention-to-treat population will be analyzed by the treatment group assignment given at the time of randomization, even if the subject does not receive the correct treatment, or does not follow the protocol until completion. All randomized patients will be followed and assessed for 90 days post-procedure, even when no intravenous thrombolysis or endovascular treatment is performed.

5.2. Per-protocol set For the per-protocol analysis, only patients who actually received the assigned treatment and do not have major protocol violations will be included. Patients without intracranial large vessel occlusion, not meeting the inclusion criteria, not receiving standard dose alteplase in the alteplase-plus-intervention group, cross over to the alternative treatment will be removed from the per-protocol analysis.

5.3. Safety set For the safety analysis, patients will be analyzed according to the treatment they received. Any randomized subjects that did not meet the inclusion criteria, did not accept the relevant treatment, and did 7 / 13

Statistical Analysis Plan not have any evaluation results should be excluded from per-protocol analysis. The reason(s) for their exclusion from the study will be recorded. Listings will be provided for these patients, and they will be discussed in the clinical report.

6. Statistical Methods Summary tables (descriptive statistics and/or frequency tables) will be provided for all baseline variables, effectiveness variables, and safety variables, as appropriate. Continuous variables will be summarized with descriptive statistics (n, mean, standard deviation, median, and interquartile). Frequency counts and percentage of patients within each category will be provided for categorical data. The software used for all statistical analyses will be SAS® (SAS Institute, Inc.) version 9.3 or higher. Figures were drawn using MS Excel software 2019 (Microsoft).

7. Baseline Characteristics Baseline data will be analyzed to assess the comparability of treatment groups. Baseline data including, but not limited to demographics, clinical characteristics, baseline vessel characteristics, and imaging characteristics will be summarized using descriptive statistics. Differences between the treatment groups and their 95% confidence intervals will be calculated. Statistical testing will be performed as appropriate.

8. Patient Disposition The number of patients for each of the following categories will be summarized.  Assessed patients  Patients completing the study and not completing the study  Patients included in the intention-to-treat population  Patients included in the per-protocol population  Patients included in the safety population

9. Effectiveness Analysis 9.1. Primary Effectiveness Analysis The primary effectiveness variable is the proportion of patients with a modified Rankin scale score of 0 to 2 (functional independence) at 90 days. The proportion of patients in each group will be calculated based on this criterion. To ensure the reliability, evaluability, and traceability of the modified Rankin scale score, we keep patients’ video or voice recording of follow-up at 90 days. The primary functional outcome was centrally assessed by two independent certified neurologists in a blinded manner by the use of the video or voice recording. If video or voice recording is not available, the outcomes determined by the local investigator blindly in person are used as default. Disagreements were resolved by consensus. Electronic Data Capture System did not reveal the group assignment and patients were instructed not to reveal any relevant information that could potentially lead to disclosing their treatment group to the assessors. All recordings will be provided as supplementary material along with the main text. The primary effectiveness analysis will be the difference between bridging-therapy group (control) and primary-thrombectomy group (test). A binomial comparison will be used to test the one-sided null hypothesis that the difference in proportions is less than or equal to -0.10 (H0: Ptest - Pcontrol ≤ -0.10) versus the alternative

(H1: Ptest - Pcontrol > -0.10), where Pcontrol and Ptest are the proportions of functional independence for bridging-therapy (intravenous alteplase plus endovascular treatment) and primary-thrombectomy (endovascular treatment alone), respectively. This is equivalent to evaluating that the lower bound of the two-sided 95% confidence interval for the difference is above -0.10. The effect variable of this endpoint will be analyzed using a 8 / 13

Statistical Analysis Plan logistic regression model with the following terms in the model: age, baseline NIHSS score, baseline ASPECTS, stroke onset to randomization time, and occlusion site. The primary effectiveness analysis will be performed on the intention-to-treat population. The analysis based on the per-protocol population will be considered as supportive. Statistical analysis will be performed on the SAS 9.3 or higher system.

9.2. Secondary Effectiveness Analysis The secondary effectiveness variables:  Proportion of modified Rankin scale score 0 to 1 at 90 days;  Shift in the distribution of modified Rankin scale scores at 90 days in endovascular treatment alone versus intravenous alteplase plus endovascular treatment (ordinal shift analysis);  Successful recanalization proportion immediate after endovascular treatment. Successful recanalization is defined as an expanded Thrombolysis In Cerebral Infarction (eTICI) score of 2b (substantial reperfusion), 2c (near-complete perfusion) or 3 (complete reperfusion) in the post-procedure angiography;5  Vessel recanalization rate evaluated by CT or MR angiography within 48 hours;  The change of the National Institutes of Health Stroke Scale score at 24 hours from baseline;  The change of the National Institutes of Health Stroke Scale score at 5-7 days or discharge if earlier from baseline;  European Quality Five-Dimension Five-Level scale score at 90 days. Continuous variables will be summarized with descriptive statistics (n, mean, standard deviation, median, and interquartile). Frequency counts and percentage of patients within each category will be provided for categorical data. Estimates of the treatment differences and their 95% confidence intervals will be calculated. Subject rates will be compared between treatment groups with Chi-square test or Fisher's exact test. These endpoints will be analyzed using a logistic, ordinal logistic, or linear regression model as appropriate. The adjusted odds ratio, common odds ratio and beta coefficient were estimated by taking the following variables into account: age, baseline NIHSS score, baseline ASPECTS, stroke onset to randomization time, and occlusion site.

9.3. Handling of Multiplicity There will be no adjustment for multiple comparisons between intravenous alteplase plus endovascular treatment versus endovascular treatment alone on the primary effectiveness variable since the primary comparison is specified in the protocol. All other comparisons will be considered secondary analyses and will be adjusted using the Bonferroni correction.

9.4. Effectiveness Subgroup Analysis To evaluate the impact of baseline conditions on treatment effect, subgroup analyses will be performed for the primary effectiveness variable, modified Rankin scale score 0 to 2. The subgroups below will be used for these analyses: (1) Age (< median or ≥ median, years old) (2) Sex (Female or Male) (3) Baseline NIHSS score (< median or ≥ median) (4) Baseline ASPECTS (< median or ≥ median) (5) Stroke etiology (large artery atherosclerosis, cardioembolism, or others) (6) Site of occlusion (intracranial internal carotid artery or not) (7) Onset to randomization time (< median or ≥ median, minutes) The subgroup analysis will be conducted using a logistic regression with terms of treatment group and 9 / 13

Statistical Analysis Plan treatment-by-subgroup interaction. The primary statistical inference is the treatment- by-subgroup interaction, which is tested at the significance level of 0.100. These analyses will be performed on the intention-to-treat population. When the treatment-by-subgroup interaction is statistically significant (P ≤ 0.100) for a specific subgroup, the treatment group differences will be evaluated within each stratum of that subgroup.

10. Safety Analysis 10.1. Primary Safety Analysis The primary safety endpoint is the proportion of patients with symptomatic intracerebral hemorrhage (SICH) within 48 hours. ICH will be evaluated according to the Heidelberg Bleeding Classification.6 SICH was diagnosed if the new observed ICH was associated with any of the following conditions: 1) NIHSS score increased more than 4 points than that immediately before worsening; 2) NIHSS score increased more than 2 points in one category; 3) Deterioration led to intubation, hemicraniectomy, external ventricular drain placement or any other major interventions. Additionally, the symptom deteriorations could not be explained by causes other than the observed ICH; The proportion of patients in each group who experience a safety event based on these criteria will be calculated. The Clinical Events Committee/Data Safety Monitoring Board (CEC/DSMB) data supersede the investigator-reported data in all SICH. The primary null hypothesis for safety in this study is that there is no difference in SICH rates. This null hypothesis will be tested against the alternative hypothesis that there is a difference between the two groups. The null hypothesis will be rejected at the two-sided significance level of = 0.05. Frequency counts and percentage of patients within each category will be provided for categorical data. Estimates of the treatment differences and their 95% confidence intervals will be calculated. The primary analysis is an analysis of all patients according to treatment received. Subject rates will be compared between treatment groups with Chi-square test or Fisher's exact test.

10.2. Secondary Safety Analysis The secondary safety variables:  Mortality at 90 days  Procedure-related complications such as arterial perforation, arterial dissection, and embolization in previously uninvolved vascular territory The proportion of patients in each group who meet the safety endpoint based on this criterion will be calculated. The CEC/DSMB data supersede the investigator-reported data in all analyses. Frequency counts and percentage of patients within each category will be provided. Estimates of the treatment differences and their 95% confidence intervals will be calculated. Subject rates will be compared between treatment groups with Chi-square test or Fisher's exact test.

10.3. Analysis of Adverse Events The frequencies and incidences of Adverse events occurring in subjects in the intervention-alone and bridging-therapy groups will be summarized within treatment group by the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). Tabulations of adverse events will be presented with descriptive statistics at baseline hospitalization and follow-up visits. Adverse events will be categorized. Adverse event incidence rates will be summarized by category and severity of the adverse event. Each subject will be counted only once within a category by using the adverse event with the highest severity within each category. 10 / 13

Statistical Analysis Plan

All information pertaining to adverse events noted during the study will be listed by subject, detailing verbatim given by the investigator, category, date of onset, date of resolution, causality and severity. The onset of adverse events will also be shown relative (in number of days) to the day of procedure. A tabulation of Serious Adverse Events will be provided by subject. The specific categories analyzed will be those that are reported by at least three (3) percent of the patients. The CEC/DSMB adjudicated data supersedes the investigator reported data in all analyses of adverse events.

10.4. Handling of Multiplicity All safety variable comparisons between intravenous alteplase plus endovascular treatment versus endovascular treatment alone will be considered secondary analyses and will be adjusted using the Bonferroni correction.

10.5. Analysis of Deaths The Kaplan-Meier product-limit method will be the primary method utilized to assess the mortality. With the date of procedure set at day 0, any death occurring on or before calendar day 90 will be counted as a death. If clinical assessment is missing for a patient who has not died, the patient will be censored at the last follow-up date. Patients who are alive at day 90 will be censored at day 90. The log-rank test will be used to compare the groups. This comparison weights earlier and later differences equally. The time to death will be plotted with confidence intervals at monthly intervals. Additionally, the death data will be presented as 90-day binary deaths. The number of deaths will be presented for each group.

11. Pooling Across Centers The clinical study will be conducted under a common protocol for each investigational center with the intention of pooling the data for analysis. Every effort will be made to promote consistency in study execution at each investigational center. Analyses will be presented using data pooled across centers. Because the trial adopts a competitive recruitment approach, the number of participating centers is about 40 and the number of cases in each center may be small, and all centers share a random sequence table, the stratified analysis is not performed by center, and the center effect is not evaluated.

12. Lost to Follow-Up and Missing Data For sensitivity purposes, the following additional analyses will be conducted: • Analyze only patients with complete primary endpoint data. • The missing values of age, baseline NIHSS score, baseline ASPECTS, stroke onset to randomization time, and occlusion site which will be included in multivariable regression analysis are imputed with multiple imputation by fully conditional specification regression for continuous variables or by fully conditional specification logistic regression for binary and ordinal variables. • For subjects missing data for 90-day follow-up, missing values will be imputed by assuming the missing modified Rankin scale score at 90-day to be unfavorable. If the patient is known to be alive, we will impute a score of 5. Otherwise, we will impute a score of 6.

13. Committees 13.1. Clinical Events Committee/Data Safety Monitoring Board (CEC/DSMB) A CEC/DSMB will adjudicate serious adverse events for causality and attribution.

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13.2. Imaging Core Laboratory Centralized imaging core laboratories will be used in this trial to provide consistent assessment of all the images. CT/MR and angiographic images will be independently reviewed by two independent central imaging core laboratories respectively. The Imaging Core Laboratory will be blinded to treatment allocation.

14. Changed to Planned Analyses All changes to the statistical analysis plan will be documented in a revised statistical analysis plan or the clinical study report.

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15. References

1. Wang H, Zi W, Hao Y, et al. Direct endovascular treatment: an alternative for bridging therapy in anterior circulation large-vessel occlusion stroke. European journal of neurology 2017;24:935-43.

2. Broeg-Morvay A, Mordasini P, Bernasconi C, et al. Direct Mechanical Intervention Versus

Combined Intravenous and Mechanical Intervention in Large Artery Anterior Circulation Stroke: A

Matched-Pairs Analysis. Stroke 2016;47:1037-44.

3. Bellwald S, Weber R, Dobrocky T, et al. Direct Mechanical Intervention Versus Bridging Therapy in

Stroke Patients Eligible for Intravenous Thrombolysis: A Pooled Analysis of 2 Registries. Stroke

2017;48:3282-8.

4. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11-20.

5. Almekhlafi MA, Mishra S, Desai JA, et al. Not all "successful" angiographic reperfusion patients are an equal validation of a modified TICI scoring system. Interv Neuroradiol 2014;20:21-7.

6. von Kummer R, Broderick JP, Campbell BC, et al. The Heidelberg Bleeding Classification:

Classification of Bleeding Events After Ischemic Stroke and Reperfusion Therapy. Stroke; a journal of cerebral circulation 2015;46:2981-6.

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Supplemental Online Content

Zi W, Qui Z, Li F, et al. Effect of endovascular treatment alone versus intravenous alteplase plus endovascular treatment on functional independence in patients with acute ischemic stroke: the DEVT randomized clinical trial. JAMA. doi:10.1001/jama.2020.23523

CONSORT checklist eMethods eFigure 1. Overview of the DEVT trial eFigure 2. Analysis of the primary outcome in the first interim analysis (n=194) used by the DSMB to take the decision to stop the trial eFigure 3. Distribution of participating centers on the map of China eFigure 4. Number of patients recruited by each center eFigure 5. Kaplan-Meier estimates of the probability of death in patients eFigure 6. Analysis of functional independence at 90 days in prespecified subgroups eFigure 7. Distribution of modified Rankin scale scores at 90 days in prespecified subgroups eTable 1. Additional baseline characteristics eTable 2. Additional workflow metrics and procedural characteristics eTable 3. Primary and secondary outcomes in per-protocol analysis eTable 4. Safety outcomes in per-protocol analysis eTable 5. The hierarchical modeling and sensitivity analyses for assessment of site effects (post hoc analysis) eTable 6. Differences between DEVT, DIRECT-MT, and SKIP trial eTable 7. Assessment of intracranial hemorrhage based on Heidelberg classification eTable 8. Definitions of Symptomatic Intracerebral Hemorrhage eReferences

This supplemental material has been provided by the authors to give readers additional information about their work.

Item Section/Topic Checklist item Reported on page No No

Title and abstract 1a Identification as a randomised trial in the title 1 1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for 10-12 abstracts)

Introduction Background and 2a Scientific background and explanation of rationale 13-14 objectives 2b Specific objectives or hypotheses 14

Methods Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 14, 16 3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons Summary of Changes of protocol, page 66-68 in Supplement 2 Participants 4a Eligibility criteria for participants 15 4b Settings and locations where the data were collected 15 Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were 16-17 actually administered Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they were 17-19 assessed 6b Any changes to trial outcomes after the trial commenced, with reasons Page 66 in the Summary of Changes of trial protocol (Supplement 2) Sample size 7a How sample size was determined 19-20

© 2021 American Medical Association. All rights reserved. Item Section/Topic Checklist item Reported on page No No 7b When applicable, explanation of any interim analyses and stopping guidelines Page 5-6 in the Statistical Analysis Plan (Supplement 3) Randomisation: Sequence 8a Method used to generate the random allocation sequence 16 generation 8b Type of randomisation; details of any restriction (such as blocking and block size) 16 Allocation 9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), 16 concealment describing any steps taken to conceal the sequence until interventions were assigned mechanism Implementati 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to 16 on interventions Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those Page 7 in the Statistical assessing outcomes) and how Analysis Plan (Supplement 3) 11b If relevant, description of the similarity of interventions Not applicable Statistical 12a Statistical methods used to compare groups for primary and secondary outcomes 20 methods 12b Methods for additional analyses, such as subgroup analyses and adjusted analyses 20-21

Results Participant flow 13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were 22 and Figure 1 (a diagram is analysed for the primary outcome strongly 13b For each group, losses and exclusions after randomisation, together with reasons 22 and Figure 1 recommended) Recruitment 14a Dates defining the periods of recruitment and follow-up 22 14b Why the trial ended or was stopped 21-22 Baseline data 15 A table showing baseline demographic and clinical characteristics for each group 40-42

© 2021 American Medical Association. All rights reserved. Item Section/Topic Checklist item Reported on page No No Numbers 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was by 22-24 analysed original assigned groups Outcomes and 17a For each primary and secondary outcome, results for each group, and the estimated effect size and its precision 43-45 estimation (such as 95% confidence interval) 17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended 43-45 Ancillary 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre- eFigure 6, eFigure 7, eTable analyses specified from exploratory 3, eTable 4, and eTable 5 in Supplement 4 Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) 46-48

Discussion Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 28-30 Generalisability 21 Generalisability (external validity, applicability) of the trial findings 30 Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence 30

Other information Registration 23 Registration number and name of trial registry 12 Protocol 24 Where the full trial protocol can be accessed, if available Supplement 2 Or DOI: 10.1177/1747493020925349 Funding 25 Sources of funding and other support (such as supply of drugs), role of funders 32

© 2021 American Medical Association. All rights reserved. 4. eMethods 4.1. eMethod 1. Inclusion and exclusion criteria 4.1.1. Inclusion criteria (1) Aged 18 years or older; (2) Presenting with acute ischemic stroke symptom within 4.5 hours; (3) Eligible for intravenous alteplase; (4) Occlusion of the intracranial internal carotid artery or the first segment of the middle cerebral artery confirmed by CT or MR angiography; (5) Randomization no later than 4 hours 15 minutes after stroke symptom onset. Time of stroke onset was defined as time last known well; (6) Informed consent obtained from patients or their legal representatives. 4.1.2. Exclusion criteria (1) CT or MR evidence of hemorrhage (the presence of micro-bleeds is allowed); (2) Contraindications of intravenous alteplase; (3) Pre-morbidity with a modified Rankin scale score of 0 to 2; (4) Currently in pregnant or lactating or serum beta HCG test is positive on admission; (5) Contraindication to radiographic contrast agents, nickel, titanium metals or their alloys; (6) Arterial tortuosity and/or other arterial disease that would prevent the device from reaching the target vessel; (7) Patients with a preexisting neurological or psychiatric disease that would confound the neurological functional evaluations; (8) Patients with occlusions in multiple vascular territories (e.g. bilateral anterior circulation, or anterior/posterior circulation); (9) CT or MR evidence of mass effect or intracranial tumor (except small meningioma); (10) CT or MR evidence of cerebral vasculitis; (11) CT or MR angiography evidence of intracranial arteriovenous malformations or aneurysms; (12) Any terminal illness with life expectancy less than 6 months; (13) Unlikely to be available for 90-day follow-up; (14) Current participation in another clinical trial.

© 2021 American Medical Association. All rights reserved. 4.2 eMethod 2. Early termination of the trial The first interim analysis of DEVT was scheduled to occur after 194 patients had completed their 90-day clinical outcome. After the publication of the positive findings of the DIRECT-MT study1 on May 7th, 2020, DEVT had enrolled 235 patients but had not yet arrived at 194 patients with completed 90-day outcomes (the scheduled endpoint for our interim analysis). The steering committee made a decision to stop enrollment into the trial. After consultation with the Data and Safety Monitoring Board chairman (Dr. Anding Xu, The First Affiliated Hospital of Jinan University, Guangzhou, China) our interim analysis plan was accelerated by several weeks. Thus, the interim analysis was completed on 194 patients with completed 90-day outcomes on May 12th, 2020. The interim analysis was performed according to all prespecified criteria. For details, see Figure S2 in this file. At this point the Data and Safety Monitoring Board recommended to the Steering Committee early stopping of trial enrollment for efficacy. The last patient who completed 90-day follow-up on July 22th, 2020.

© 2021 American Medical Association. All rights reserved. 4.3. eMethod 3. Assessment of modified Rankin scale score at 90 days At the 90 days follow-up visits, a local neurologist who was unaware of group assignment recorded the modified Rankin scale score in a face to face structured clinical interview and recorded the interview using a portable camera or voice recorder (in case patient who was unwilling to take video recording). The primary functional outcome was centrally assessed by two independent certified neurologists in a blinded manner by the use of the video or voice recording. Disagreements were resolved by consensus. Electronic Data Capture System did not reveal the group assignment and patients were instructed not to reveal any relevant information that could potentially lead to disclosing their treatment group to the assessors. If video or voice recording is not available, the outcomes determined by the local investigator blindly in person are used as default. It was prespecified that the missing modified Rankin scale scores at 90 days were assumed the worst possible score. If the patient was identified to be alive, we imputed a modified Rankin scale score of 5. Otherwise, we imputed a score of 6.

© 2021 American Medical Association. All rights reserved. 4.4. eMethod 4. Investigator training The initiation meeting of the DEVT trial was held in Chongqing on April 21, 2018. The training of DEVT protocol, including the patient selection criteria, periprocedural clinical and imaging assessment, endovascular treatment technique, and the requirement of follow-up at 90 days, were conducted immediately after the initiation meeting. To speed up the enrollment progress, the steering committee recruited 6 more stroke centers and held a program training meeting in Beijing on June 30, 2018. In order to improve the endovascular treatment technique of investigators and ensure the quality of the trial, the training of study protocol and endovascular treatment technique and project promotion meeting was held once about every six months in Chongqing.

MRI denotes magnetic resonance imaging, NCCT non-contrast computed tomography.

© 2021 American Medical Association. All rights reserved. 5.2. eFigure 2. Analysis of the primary outcome in the first interim analysis (n=194) used by the DSMB to take the decision to stop the trial Distribution of the modified Rankin scale scores at 90 days was shown in eFigure2A. First interim analysis according to central evaluation through video (152 evaluations), voice (6 evaluations) recording or local investigators as default (1 evaluation); thirty-five patients died before 90 days. Efficacy Boundary Z-Value and P-Value Scale are the values such that statistics and P-Value outside this boundary at the corresponding interim indicate termination of the study and rejection of the null hypothesis, respectively. The proportion of functional independence for the endovascular thrombectomy alone group (54.64%) exceeded that of the combined IV thrombolysis and endovascular thrombectomy group (47.42%) by 7.2% (1- sided 97.5% CI, -6.8% to ∞). The non-inferiority test results demonstrated that the endovascular thrombectomy alone group was not inferior to the combined IV thrombolysis and endovascular thrombectomy group (Z=2.4042,

Pnon-inferiority=0.0081), which had crossed the efficacy boundary (Z=2.35826, Pnon-inferiority=0.00918) that was prespecified for early termination (eFigure 2B~C).

Distribution of modified Rankin scale score

0 1 2 3 4 5 6

Endovascular thrombectomy alone 14.4 22.7 17.5 12.4 7.2 8.2 17.5 group (n=97)

Combined IV thrombolysis and endovascular 17.5 15.5 14.4 15.5 10.3 8.3 18.6 thrombectomy group (n=97)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Patients (%) eFigure 2A

eFigure 2C

Log-Rank test: P = 0.998

Combined IV thrombolysis Endovascular No. of and endovascular P Value for Subgroup thrombectomy alone Odds Ratio (95% CI) patients thrombectomy group Interaction groupn=116 n=118 no. of functionally independent/total no. (% Overall 234 63/116(54.3) 55/118(46.6) 1.48(0.81 to 2.74) Age 0.743 <70 years 114 39/57(68.4) 37/57(65.0) 1.31(0.55 to 3.17) >=70 years 120 24/59(40.7) 18/61(29.6) 1.54(0.64 to 3.8) Sex 0.113 Female 102 22/50(44.0) 23/52(44.2) 0.88(0.36 to 2.15) Male 132 41/66(62.1) 32/66(48.5) 2.39(1 to 5.97) Baseline NIHSS score 0.252 < 16 110 39/57(68.4) 34/53(64.2) 1.02(0.41 to 2.53) >= 16 124 24/59(40.7) 21/65(32.3) 2.05(0.86 to 5.05) Baseline ASPECTS 0.280 < 8 102 18/50(36.0) 22/52(42.3) 0.98(0.38 to 2.58) >= 8 132 45/66(68.2) 33/66(50.1) 2.23(0.96 to 5.32) Stroke etiology 0.087 LAA 60 20/32(62.6) 13/28(46.4) 3.5(0.93 to 16.07) CE 134 34/65(52.3) 29/69(42.0) 1.31(0.53 to 3.27) Others 40 9/19(47.4) 13/21(61.9) 0.56(0.13 to 2.35) Occlusion site 0.075 intracranial ICA 35 8/18(44.4) 2/17(11.8) 9.15(1.24 to 135.49) MCA-M1 or M2 199 55/98(56.2) 53/101(52.4) 1.18(0.61 to 2.29) Onset to randomization time 0.222 < 169 min 117 36/59(61.0) 28/58(48.3) 0.97(0.41 to 2.3) >= 169 min 117 27/57(47.4) 27/60(45.0) 2.25(0.88 to 6.05)

0 1 10 100 Combined IV thrombolysis and endovascular thrombectomy better Endovascular thrombectomy alone better This forest plot shows that there was no evidence of heterogeneity of treatment effect across in most prespecified subgroups. The odds ratio was calculated by using logistic regression taking the following variables into account: age, baseline NIHSS score, baseline ASPECTS, occlusion site, and time from onset to randomization. Time of stroke onset was defined as time last known well. The thresholds for age, baseline NIHSS score, baseline ASPECTS, and onset to randomization time were chosen at the median. Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic deficits. The Alberta Stroke Program Early CT Score (ASPECTS) ranges from 0 to 10, with higher scores indicating a smaller infarct core. CE denotes cardioembolism, CI confidence interval, ICA internal carotid artery, LAA large artery atherosclerosis, MCA-M1 or M2 the first or second segment of middle cerebral artery.

© 2021 American Medical Association. All rights reserved. 5.7. eFigure 7. Distribution of modified Rankin scale scores at 90 days in prespecified subgroups These figures show the distribution of modified Rankin scale score at 90 days among the 7 prespecified subgroups. These groups and cut-points are:  age (< 70 or ≥ 70 years)  sex (female or male)  baseline NIHSS score (< 16 or ≥ 16)  baseline ASPECTS (< 8 or ≥ 8)  stroke etiology (large artery atherosclerosis, cardioembolism, or others)  occlusion site (intracranial internal carotid artery or not)  onset to randomization time (< 169 or ≥ 169 minutes)

There is no evidence of heterogeneity of treatment effect between these subgroups (Pinteraction=0.29, BreslowDay test).

Stratified by Age

Distribution of modified Rankin scale score

0 1 2 3 4 5 6

Endovascular thrombectomy alone group 8.5 18.6 13.6 15.3 11.9 8.5 23.7 (n=59) age >= 70 years

Combined IV thrombolysis and endovascular thrombectomy group 3.3 11.5 14.8 14.8 16.4 13.1 26.2 (n=61)

Endovascular thrombectomy alone group 17.5 31.6 19.3 10.5 5.3 5.3 10.5 (n=57) age < 70 years

Combined IV thrombolysis and endovascular thrombectomy group 28.1 21.1 15.8 19.3 7.0 0.0 8.8 (n=57)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Patients (%)

There is no evidence of heterogeneity of treatment effect between these subgroups (Pinteraction=0.14, BreslowDay test).

Stratified by Sex

Distribution of modified Rankin scale score

0 1 2 3 4 5 6

Endovascular thrombectomy alone group 12.1 33.3 16.7 7.6 9.1 7.6 13.6 (n=66) male

Combined IV thrombolysis and endovascular thrombectomy group 18.2 12.1 18.2 13.6 9.1 10.6 18.2 (n=66)

Endovascular thrombectomy alone group 14.0 14.0 16.0 20.0 8.0 6.0 22.0 (n=50) female

Combined IV thrombolysis and endovascular thrombectomy group 11.5 21.2 11.5 21.2 15.4 1.9 17.3 (n=52)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Patients (%)

NIHSS score. There is no evidence of heterogeneity of treatment effect between these subgroups (Pinteraction=0.91, BreslowDay test).

Stratified by baseline NIHSS score

Distribution of modified Rankin scale score

0 1 2 3 4 5 6

Endovascular thrombectomy alone group 6.8 15.3 18.6 13.6 10.2 10.2 25.4 (n=59) NIHSS >= 16

Combined IV thrombolysis and endovascular thrombectomy group 10.8 9.2 12.3 18.5 15.4 10.8 23.1 (n=65)

Endovascular thrombectomy alone group 19.3 35.1 14.0 12.3 7.0 3.5 8.8 (n=57) NIHSS < 16

Combined IV thrombolysis and endovascular thrombectomy group 20.8 24.5 18.9 15.1 7.5 1.9 11.3 (n=53)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Patients (%)

ASPECTS. There is no evidence of heterogeneity of treatment effect between these subgroups (Pinteraction=0.09, BreslowDay test).

Stratified by baseline ASPECTS score

Distribution of modified Rankin scale score

0 1 2 3 4 5 6

Endovascular thrombectomy alone group 19.7 27.3 21.2 6.1 7.6 4.5 13.6 (n=66) ASPECTS>= 8

Combined IV thrombolysis and endovascular thrombectomy group 19.7 15.2 15.2 22.7 9.1 4.5 13.6 (n=66)

Endovascular thrombectomy alone group 4.1 22.4 10.2 22.4 10.2 10.2 20.4 (n=49)

ASPECTS< 8 Combined IV thrombolysis and endovascular thrombectomy group 9.8 17.6 15.7 9.8 15.7 7.8 23.5 (n=51)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Patients (%)

© 2021 American Medical Association. All rights reserved. eFigure 7E: Distribution of modified Rankin scores at 90 days in the two groups in patients stratified by stroke etiology. There is no evidence of heterogeneity of treatment effect between these subgroups (Pinteraction=0.82, BreslowDay test).

Stratified by Stroke etiology

Distribution of modified Rankin scale score

0 1 2 3 4 5 6

Endovascular thrombectomy alone group 10.5 31.6 5.3 21.1 5.3 10.5 15.8 (n=19) Others

Combined IV thrombolysis and endovascular thrombectomy group 14.3 28.6 19.0 14.3 14.3 0.0 9.5 (n=21)

Endovascular thrombectomy alone group 16.9 18.5 16.9 9.2 12.3 7.7 18.5 (n=65) CE

Combined IV thrombolysis and endovascular thrombectomy group 11.6 14.5 15.9 15.9 14.5 8.7 18.8 (n=69)

Endovascular thrombectomy alone group 6.3 34.4 21.9 15.6 3.13.1 15.6 (n=32) LAA

Combined IV thrombolysis and endovascular thrombectomy group 25.0 10.7 10.7 21.4 3.6 7.1 21.4 (n=28)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Patients (%)

Others type contained stroke of undetermined cause and stroke of other determined cause. LAA denotes large artery atherosclerosis, CE cardioembolism.

© 2021 American Medical Association. All rights reserved. eFigure 7F: Distribution of modified Rankin scores at 90 days in the two groups in patients stratified by occlusion site (intracranial internal carotid artery occlusion or not). There is no evidence of heterogeneity of treatment effect between these subgroups (Pinteraction=0.06, BreslowDay test).

Stratified by ICA occlusion

Distribution of modified Rankin scale score

0 1 2 3 4 5 6

Endovascular thrombectomy alone group 13.3 27.6 15.3 13.3 10.2 6.1 14.3 (n=98) No

Combined IV thrombolysis and endovascular thrombectomy group 16.8 17.8 17.8 15.8 7.9 5.9 17.8 (n=101)

Endovascular thrombectomy alone group 11.1 11.1 22.2 11.1 0.0 11.1 33.3 (n=18) Ye s

Combined IV thrombolysis and endovascular thrombectomy group 5.9 5.90.0 23.5 35.3 11.8 17.6 (n=17)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Patients (%)

ICA denotes internal carotid artery.

© 2021 American Medical Association. All rights reserved. eFigure 7G: Distribution of modified Rankin scores at 90 days in the two groups in patients stratified by onset to randomization time. There is no evidence of heterogeneity of treatment effect between these subgroups

(Pinteraction=0.34, BreslowDay test).

Stratified by Onset to Randomization Time

Distribution of modified Rankin scale score

0 1 2 3 4 5 6

Endovascular thrombectomy alone group 15.3 22.0 23.7 11.9 6.8 1.7 18.6 (n=59) Time < 169 min

Combined IV thrombolysis and endovascular thrombectomy group 20.7 13.8 13.8 17.2 12.1 6.9 15.5 (n=58)

Endovascular thrombectomy alone group 10.5 28.1 8.8 14.0 10.5 12.3 15.8 (n=57) Time >= 169 min

Combined IV thrombolysis and endovascular thrombectomy group 10.0 18.3 16.7 16.7 11.7 6.7 20.0 (n=60)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Patients (%)

© 2021 American Medical Association. All rights reserved. 6. eTables 6.1. eTable 1. Additional baseline characteristics Endovascular Combined IV thrombectomy alone thrombolysis and group endovascular (N=116) thrombectomy group (N=118) Coronary heart disease - no./total no. (%) 30 (25.9) 19(16.1) Smoking - no./total no. (%) 28 (24.1) 29(24.6) Median platelet count in blood routine test (IQR), 185(146-224) 180(148-217) 10^9/La Median international normalized ratio (IQR) b 1.00(0.95-1.11) 1.02(0.95-1.10) Location of stroke in right hemisphere - no./total no. 58 (50.0) 61 (51.7) (%) Location of the atherosclerotic lesion - no./total no. (%) Intracranial 28 (24.1) 23 (19.5) Extracranial 4 (3.4) 5 (4.2) Collateral status, no./total no. (%) c ASITN/SIR grade 0 14/116(12.1) 8/118(6.8) ASITN/SIR grade 1 24/116(20.7) 28/118(23.7) ASITN/SIR grade 2 47/116(40.5) 48/118(40.7) ASITN/SIR grade 3 31/116(26.7) 34/118(28.8) ASITN/SIR grade 4 0 0 IQR denotes interquartile range, and ASITN/SIR American Society of Interventional and Therapeutic Neuroradiology / Society of Interventional Radiology. a Data were missing for 5 patients (3 in the endovascular thrombectomy alone group and 2 in the combined IV thrombolysis and endovascular thrombectomy group). b Data were missing for 6 patients (3 in the endovascular thrombectomy alone group and 3 in the combined IV thrombolysis and endovascular thrombectomy group). c The ASITN/SIR collateral flow grading system is a 5-point scale: with 0=no collaterals visible to the ischemic site; 1=slow collaterals to the periphery of the ischemic site with persistence of some of the defect; 2=rapid collaterals to the periphery of the ischemic site with persistence of some of the defect and to only a portion of the ischemic territory; 3=collaterals with slow but complete angiographic blood flow of the ischemic bed by late venous phase; and 4=complete and rapid collateral blood flow to the vascular bed in the entire ischemic territory by retrograde perfusion.

© 2021 American Medical Association. All rights reserved. 6.2. eTable 2. Additional workflow metrics and procedural characteristics Endovascular Combined IV thrombectomy alone thrombolysis and group endovascular (N=116) thrombectomy group (N=118) Workflow times Onset to hospital arrivala 90 (57-126) 100 (60-135) Hospital arrival to imaging 22 (16-32) 25 (15-32) Imaging to randomization 38 (27-56) 33 (25-60)) Onset to reperfusiona 289 (231-329) 285 (239-342) Onset to start of intravenous alteplasea NA 176 (153-225) Imaging to start of intravenous alteplase NA 40 (34-68) Randomization to start of intravenous alteplase NA 7 (5-10) Randomization to groin puncture 32 (17-50) 34 (20-53) Randomization to reperfusion or procedure 111 (84-150) 106 (75-154) completionb Groin puncture to reperfusion or procedure 72 (45-113) 68 (43-107) completionb Hospital arrival to start of intravenous alteplase, no./total no. (%) 0-90 min NA 99 (83.9) 90-180 min NA 18 (15.3) 180-270 min NA 1 (0.8) Total number of stent retriever passes (Median IQR) 1 (1-2) 1 (0-2) Total number of aspiration device passes (Median 0 (0-1) 0 (0-1) IQR) Procedures performed with stent-retriever only - 61 (52.6) 57 (48.3) no./total no. (%) Procedures performed with local aspiration only - 17 (14.7) 18 (15.3) no./total no. (%) Procedures performed with stent-retriever and local 17 (14.7) 16 (13.6) aspiration - no./total no. (%) Procedures performed with neither stent-retriever nor 7 (6) 11 (9.3) local aspiration - no./total no. (%) Intraarterial thrombolysis - no./total no. (%) Alteplase 2 (1.7) 5/116 (4.2) Urokinase 3 (2.6) 1 (0.8) Intraarterial tirofiban - no./total no. (%) 19 (16.4) 15 (12.7) Extracranial stenting - no./total no. (%) 0 (0.0) 1 (0.8) First pass effect - no./total no. (%) 51(44.0) 51 (43.2) Rescue therapy - no./total no. (%) 31(26.7) 33 (28.0)

© 2021 American Medical Association. All rights reserved. Balloon guide catheter - no./total no. (%) 1(0.9) 1 (0.8) eTICI Grade, no./total no. (%)c 0 1/113 (0.9) 3/117 (2.6) 1 0 2/117 (1.7) 2a 12/113 (10.6) 10/117 (8.6) 2b 35/113 (31.0) 31/117 (26.5) 2c 21/113 (18.6) 21/117 (17.9) 3 44/113 (38.9) 50/117 (42.7) a Time of stroke onset was defined as time last known well. b Revascularization was defined as the first visualization of successful reperfusion, as indicated by an extended Thrombolysis in Cerebral Infarction (eTICI) score of 2b, 2c, or 3 (on a scale from 0 [no reperfusion] to 3 [complete reperfusion]). End of time interval is time of first visualization of successful reperfusion (eTICI 2b-3) in patients with reperfusion and time of the last contrast bolus in patients without reperfusion (eTICI 0-2a). c The eTICI reperfusion grading system is a 6-point scale: with 0 = no reperfusion noted; 1 = reduction in thrombus without filling of distal arterial branches, 2a = reperfusion of < 50% of the territory, 2b = a reperfusion of ≥ 50% of the territory, 2c = near-complete perfusion with distal slow flow or presence of small cortical emboli, and 3 is a complete reperfusion.3 Data were missing for 4 patients (3 in the endovascular thrombectomy alone group and 1 in the combined IV thrombolysis and endovascular thrombectomy group).

© 2021 American Medical Association. All rights reserved. 6.3. eTable 3. Primary and secondary outcomes in per-protocol analysis Endovascular Combined IV Unadjusted Adjusted Odds Ratios thrombectomy alone thrombolysis and Difference (95% CI) b group endovascular (95% CI) (N=111) thrombectomy group (N=113) Primary efficacy outcome a Functional independence (mRS 0-2) at 90 days - no./total 59 (53.2) 52 (46.0) 7.1 (-5.9 to ∞)a 1.49(0.80-2.80) no. (%) Secondary efficacy outcomes Excellent outcome (mRS 0-1) at 90 days - no./total no. 43 (38.7) 35 (31.0) 7.8 (-4.7 to 1.55(0.82-2.94) (%) 20.2) Disability level (median mRS score) at 90 days (IQR) 2(1-5) 3(1-4) 0 (-1 to 0) 1.15(0.72-1.84) c eTICI level of 2b, 2c or 3 at final angiogram - no./total no. 95/108(88.0) 97/112(86.6) 1.4 (-7.4 to 1.15(0.51-2.64) (%)d 10.2) Reperfusion on follow-up CTA or MRA within 48 hours - 91/94(96.8) 89/96(92.7) 4.1 (-2.2 to 2.41(0.64-11.55) no./total no. (%)e 10.4) Adjusted Beta Coefficient (95% CI) f Median NIHSS score change from baseline at 24 hours -4(-9 to 0) -3(-6 to -1) -1(-2 to 1) -0.38(-2.24 to 1.48) (IQR)g Median NIHSS score change from baseline at 5~7 days or -7(-11 to -0) -6(-10 to -2) 0(-2 to 2) 0.88(-1.97 to 3.72) early discharge (IQR)g Median EQ-5D-5L scale score at 90 days (IQR)h 0.89(0.19-1.00) 0.91(0.62-1.00) 0(0 to 0.05) 0.03(-0.05 to 0.12) Patients achieved successful reperfusion before intervention assessed on initial digital substraction angiography (n=5, 2 in the endovascular thrombectomy alone group and 3 in the combined IV thrombolysis and endovascular thrombectomy group), and patients with occlusion in the second segment of middle cerebral artery (n=5, 3 in the endovascular thrombectomy alone group and 2 in the combined IV thrombolysis and endovascular thrombectomy group) had been removed from the per-protocol analysis.

© 2021 American Medical Association. All rights reserved. ASPECTS denotes Alberta Stroke Program Early CT Score, CI confidence interval, CTA computed tomography angiography, EQ-5D-5L European Quality of Life Five- Dimension Five-Level Self-Report Questionnaire, MRA magnetic resonance angiography, NA not applicable, and NIHSS National Institutes of Health Stroke Scale. a The confidence interval non-inferiority approach was used for the analysis of primary efficacy outcome. The absolute difference between the two groups was 0.071 (1-sided 97.5% CI, -0.059 to ∞). The lower boundary of 97.5% confidence interval was -0.059, and was greater than the non-inferiority margin -0.10 as prespecified. In addition, the non-inferiority test demonstrated that Z value and P value was 2.5711 and 0.0051, respectively, which had crossed the first-interim efficacy boundaries (Z-value Scale=2.3526, P-Value Scale=0.00918). Therefore, it could be concluded that endovascular treatment alone is non-inferior to intravenous alteplase plus endovascular treatment and the trial could be terminated early. b Values were adjusted for age, baseline NIHSS score, baseline ASPECTS, occlusion site, and time from Onset to randomization, as prespecified in the protocol and statistical analysis plan. c Common odds ratio: the analysis involved 116 patients in endovascular thrombectomy alone group and 118 patients in combined IV thrombolysis and endovascular thrombectomy group. The common odds ratio was estimated from an ordinal logistic regression model and indicates the odds of improvement of 1 point on the mRS, with a common odds ratio greater than 1 favoring the endovascular thrombectomy treatment alone. d The eTICI grade was determined at the final angiogram and ranged from 0 (no reperfusion) to 6 (completed reperfusion). An eTICI of 2b-3 indicates successful reperfusion. Four data were missing (3 in the endovascular thrombectomy alone group and 1 in the combined IV thrombolysis and endovascular thrombectomy group). A complete list of eTICI grade was provided in eTable 2 in the Supplement. e Data for follow-up CTA or MRA were not available for 23 patients (12 in the endovascular thrombectomy alone group and 11 in the combined IV thrombolysis and endovascular thrombectomy group). 11 patients failed in reperfusion (5 in the endovascular thrombectomy alone group and 6 in the combined IV thrombolysis and endovascular thrombectomy group). Vessel patency was adjudicated by two blinded independent neuro-radiologists in imaging core laboratory. Disagreements were resolved through consensus. f The Beta coefficient was estimated from a multivariable linear regression model. g Scores on NIHSS range from 0 to 42, with less scores indicating less severe neurologic deficits. h Scores on the EQ-5D-5L range from -0.39 (where 0 is the value of a health state equivalent to dead; negative values representing values as worse than dead) to 1 (full health), with higher scores indicating a better quality of life.

© 2021 American Medical Association. All rights reserved. 6.4. eTable 4. Safety outcomes in per-protocol analysis Endovascular Combined IV thrombectomy alone thrombolysis and group endovascular (N=111) thrombectomy group (N=113) Severe adverse events - no./total no. (%) Mortality at 90 days 20 (18.0) 20 (17.7) All intracranial hemorrhagea Symptomatic intracerebral hemorrhage 7/110(6.4) 7/112(6.3) Asymptomatic intracranial hemorrhage 18/110(16.4) 29/112(25.9) Other adjudicated severe adverse events within 90 days - no./total no. (%) Large or malignant middle cerebral artery stroke 13 (11.7) 9(8.0) Hemicraniectomyb 3(2.7) 5(4.4) Acute respiratory failure 14(12.6) 12(10.6) Acute heart failure 12(10.8) 9(8.0) Procedure associated complications - no./total no. (%)c Arterial perforation 2(1.8) 6(5.3) Arterial dissectiond 0/108(0) 1/112(0.9) Clot migration d 20/108(18.5) 28/112(25.0) Distal occlusion(s) present at procedure ende 19/108(17.6) 21/112(18.8) Contrast extravasationf 16/110(14.5) 17/112(15.2) Puncture access complications Groin hematoma 1(0.9) 1(0.9) Groin pseudoaneurysm 1(0.9) 5(4.4) a Symptomatic intracerebral hemorrhage was assessed by a clinical events committee according to the Heidelberg criteria.4 Data were not available for 2 patients (1 in the endovascular thrombectomy alone group and 1 in the combined IV thrombolysis and endovascular thrombectomy group). b The indication of hemicraniectomy procedure was large or malignant middle cerebral artery stroke. c All procedural-associated complications were reported by the clinical events committee. d Data were not available for 4 patients (3 in the endovascular thrombectomy alone group and 1 in the combined IV thrombolysis and endovascular thrombectomy group). e This item was defined as after Reperfusion of the primary occlusion site, any vessel occlusions distal from the primary occlusion site were considered emboli due to periprocedural thrombus fragmentation. Data were not available for 4 patients (3 in the endovascular thrombectomy alone group and 1 in the combined IV thrombolysis and endovascular thrombectomy group). f Data for follow-up computed tomography or magnetic resonance were not available for 2 patients (1 in the endovascular thrombectomy alone group and 1 in the combined IV thrombolysis and endovascular thrombectomy group).

© 2021 American Medical Association. All rights reserved. 6.5. eTable 5. The hierarchical modeling and sensitivity analyses for assessment of site effects (post hoc analysis) eTable 5-A. The hierarchical modeling analysis for site effects (post hoc analysis) Parameter Wald Chi- Pr > ChiSq Estimate 95% Confidence Limits of

Square Estimate

Intercept 2.2766 0.1313 2.4788 -0.7411 5.6987

group 0.6291 0.4277 0.3694 -0.5434 1.2822

group*affiliation 0.0039 0.9503 0.00250 -0.0761 0.0811

affiliation 0.7616 0.3828 0.0242 -0.0301 0.0785

age 11.4139 0.0007 -0.0491 -0.0776 -0.0206

Baseline NIHSS 22.6831 <.0001 -0.1803 -0.2546 -0.1061

Baseline ASPECTS 6.5452 0.0105 0.2119 0.0496 0.3742

Occlusion site 3.3123 0.0688 0.7579 -0.0583 1.5741

Time from onset to 0.3565 0.5504 0.00192 -0.00439 0.00824

randomization eTable 5-B. The sensitivity analysis for site effects after eliminating the affiliation with the largest number of enrolled patients (post hoc analysis) Parameter Wald Chi- Pr > ChiSq Estimate 95% Confidence Limits of

Square Estimate

Intercept 2.9608 0.0853 3.0440 -0.4233 6.5112

group 1.7720 0.1831 0.7281 -0.3439 1.8000

group*affiliation 0.1124 0.7374 -0.0146 -0.0998 0.0706

affiliation 0.7056 0.4009 0.0255 -0.0341 0.0852

age 9.0360 0.0026 -0.0482 -0.0796 -0.0168

Baseline NIHSS 22.7705 <.0001 -0.2067 -0.2917 -0.1218

Baseline ASPECTS 6.5362 0.0106 0.2315 0.0540 0.4090

Occlusion site 2.3640 0.1242 0.6740 -0.1852 1.5333

Time from onset to 0.0314 0.8594 0.000624 -0.00628 0.00752

randomization

© 2021 American Medical Association. All rights reserved. In this sensitivity analysis, the center (The 904th Hospital of CPLA) with the largest number (39 cases) of enrolled cases was eliminated. eTable 5-C. The sensitivity analysis for site effects after merging the affiliations with a small number of enrolled patients (post hoc analysis) Parameter Wald Chi- Pr > ChiSq Estimate 95% Confidence Limits of

Square Estimate

Intercept 2.2146 0.1367 2.4503 -0.7768 5.6774

group 0.4636 0.4959 0.3389 -0.6366 1.3143

group*affiliation 0.0168 0.8969 0.00633 -0.0894 0.1021

affiliation 0.4880 0.4848 0.0239 -0.0432 0.0911

age 11.2405 0.0008 -0.0487 -0.0771 -0.0202

Baseline NIHSS 22.6271 <.0001 -0.1800 -0.2541 -0.1058

Baseline ASPECTS 6.5561 0.0105 0.2123 0.0498 0.3747

Occlusion site 3.3178 0.0685 0.7572 -0.0576 1.5719

Time from onset to 0.3807 0.5372 0.00198 -0.00432 0.00828

randomization We merged 5 centers with only one patient into 1 center, 5 centers with 2 patients into 1 center, 3 centers with 3 patients into 1 center, and 4 centers with 4 patients were merged into two centers, respectively.

© 2021 American Medical Association. All rights reserved. 6.6. eTable 6. Differences between DEVT, DIRECT-MT, and SKIP trial DEVT DIRECT-MT SKIP Trial design Non-inferiority Change from superiority to non-inferiority Non-inferiority Sample size  assuming that the proportion of mRS score 0  assuming the proportion of mRS score 0 to 2  assuming the proportion of mRS score 0 to 2 calculation to 2 at 90 days of the endovascular treatment alone at 90 days of the endovascular treatment alone at 90 days of the endovascular treatment alone group and alteplase plus endovascular treatment group and alteplase plus endovascular treatment group and alteplase plus endovascular treatment group are 43% group is 37% and 33% group is 48.6% and 35.2%  non-inferiority margin is -10%  non-inferiority margin odds ratio is 0.8  non-inferiority margin odds ratio is 0.74  two-sided =0.05power=0.8  two-sided =0.05power=0.8  two-sided =0.05power=0.8  ratio between the two groups is 1:1  ratio between the two groups is 1:1  ratio between the two groups is 1:1  5-interim group-sequential trial, Pocock  710 cases. 15% reduction in the sample size  178 cases. function to determine spending and Z and P because of adjustment for major prognostic value boundary variables  attrition rate = 5%  dropout rate = 5%

97 cases/arm/interimin total of 970 cases of all 318 cases/arm, 636 cases in total 100 cases/arm, 200 cases in total five interims Inclusion Age ≥ 18 years old Age ≥ 18 years old Age ≥ 18 and < 86 years old criteria mRS of 0 or 1 before onseta mRS of 0 or 2 before onseta mRS of 0 or 2 before onseta ICA or MCA-M1 occlusion on CTA or MRA ICA, MCA-M1 or M2 occlusion on CTA ICA or MCA-M1 occlusion on CTA or MRA NIHSS: no limit NIHSS ≥ 2 NIHSS ≥ 6 ASPECTS: no limit ASPECTS: no limit ASPECTS: DWI ≥ 5 or CT ≥ 6 Onset to randomization ≤ 4 hours 15 minutes Onset to intravenous rt-PA ≤ 4 hours 30 minutes Onset to puncture < 4 hours Dose of 0.9 mg per kilogram of body weight 0.9 mg per kilogram of body weight 0.6 mg per kilogram of body weight intravenous alteplase Participation Academic tertiary hospital (9/33=27.3%) Academic tertiary hospital (41/41=100%) Unknown hospital Municipal tertiary hospital (21/33=63.6%

© 2021 American Medical Association. All rights reserved. County tertiary hospital (3/33=9.1%) Participation Neurology (32/33=97% Neurology (30/41=73.2%) Unknown department Neurosurgery (1/33=3%) Neurosurgery (8/41=19.5%) Radiology (3/41=7.3%) Geographical Mainly in central and western China Mainly in eastern China Japan distribution (see eFigure 8 next to this table) Primary Proportion of mRS score of 0-2 at 90 days mRS score at 90 days Proportion of mRS score of 0-2 at 90 days endpoint DIRECT-MT denotes Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke1, DWI diffusion weighted imaging, ICA internal carotid artery, MCA- M1 the first segment of middle cerebral artery, MCA-M2 the second segment of middle cerebral artery, NIHSS National Institutes of Health Stroke Scale, and SKIP The randomized study of endovascular therapy with versus without intravenous tissue plasminogen activator in acute stroke with ICA and M1 occlusion.5,6 a Time of stroke onset was defined as time last known well.

© 2021 American Medical Association. All rights reserved. 6.7. eTable 7. Assessment of intracranial hemorrhage based on Heidelberg classification Class type description4 Endovascular Combined IV thrombectomy alone thrombolysis and group endovascular thrombectomy group Hemorrhagic transformation of infarcted brain tissue, no (%) HI1 Scattered small petechiae, no mass effect 5(20.0) 7(18.4) HI2 Confluent petechiae, no mass effect 11(44.0) 19(50.0) PH1 Hematoma within infarcted tissue, 3(12.0) 2(5.3) occupying<30%, no substantive mass effect Intracerebral hemorrhage within and beyond infarcted brain tissue, no (%) PH2 Hematoma occupying 30% or more of the 1(4.0) 2(5.3) infarcted tissue, with obvious mass effect Intracerebral hemorrhage outside the infarcted brain tissue or intracranial–extracerebral hemorrhage, no (%) SAH Subarachnoid hemorrhage 2(8.0) 2(5.3) rPH Parenchymal hematoma remote from infarcted 1(4.0) 1(2.6) brain tissue IVH Intraventricular hemorrhage 0 0 SDH Subdural hemorrhage 0 0 Combined hemorrhage of the above types, no (%) 2(8.0) 6(13.0) Total, no (%) 25(100) 38(100) HI denotes hemorrhagic infarction, PH parenchymatous hematoma. Data for intracranial hemorrhage were not available for 2 patients (1 in the endovascular thrombectomy alone group and 1 in the combined IV thrombolysis and endovascular thrombectomy group).

© 2021 American Medical Association. All rights reserved. eTable 8. Definitions of Symptomatic Intracerebral Hemorrhage Clinical Radiographic Causality of Time Frame Neurological Deterioration NINDS7 definition Any clinical suspicion of hemorrhage or any Any hemorrhage on CT Regardless of causal CT required at 24 h and 7–10 d decline in neurological status relationship after stroke onset and with any clinical change suggestive of hemorrhage; primary analysis evaluated hemorrhage within 36 h ECASS II8 definition Clinical deterioration or adverse events indicating Any hemorrhage on CT Regardless of causal CT done at 22–36 h and 7 d clinical worsening (eg, drowsiness, increase relationship after stroke onset of hemiparesis) or causing an increase in NIHSS score of ≥4 points ECASS III9 definition Clinical deterioration defined by an increase of Any hemorrhage Hemorrhage as the CT/MRI required at 22–36 h ≥4 points in NIHSS score or that led to death predominant cause of after stroke onset the neurological deterioration SITS-MOST10 definition Neurological deterioration indicated by an Local or remote PH-2 Regardless of causal CT/MRI 22–36 h after stroke NIHSS score that was ≥4 points higher than relationship onset the baseline value or the lowest value between baseline and 24 h or hemorrhage leading to death CT indicates computed tomography; NINDS, National Institute of Neurological Diseases and Stroke; ECASS, European Cooperative Acute Stroke Study; NIHSS, National Institutes of Health Stroke Scale; MRI, magnetic resonance imaging; and SITS-MOST, Safe Implementation of Thrombolysis in Stroke: Monitoring Study.

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© 2021 American Medical Association. All rights reserved. 7. eReferences 1. Yang P, Zhang Y, Zhang L, et al. Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke. The New England journal of medicine. 2020;382(21):1981-1993. 2. Zaidat OO, Yoo AJ, Khatri P, et al. Recommendations on angiographic revascularization grading standards for acute ischemic stroke: a consensus statement. Stroke; a journal of cerebral circulation. 2013;44(9):2650-2663. 3. Almekhlafi MA, Mishra S, Desai JA, et al. Not all "successful" angiographic reperfusion patients are an equal validation of a modified TICI scoring system. Interv Neuroradiol. 2014;20(1):21-27. 4. von Kummer R, Broderick JP, Campbell BC, et al. The Heidelberg Bleeding Classification: Classification of Bleeding Events After Ischemic Stroke and Reperfusion Therapy. Stroke; a journal of cerebral circulation. 2015;46(10):2981-2986. 5. Suzuki K, Kimura K, Takeuchi M, et al. The randomized study of endovascular therapy with versus without intravenous tissue plasminogen activator in acute stroke with ica and m1 occlusion (skip study). International Stroke Conference. Accessed December 1, 2020. https://professional.heart.org/en/science- news/skip-study-clinical-trial-details 6. Suzuki K, Kimura K, Takeuchi M, et al. The randomized study of endovascular therapy with versus without intravenous tissue plasminogen activator in acute stroke with ICA and M1 occlusion (SKIP study). International journal of stroke : official journal of the International Stroke Society. 2019;14(7):752-755. 7. National Institute of Neurological D, Stroke rt PAS, Study G. Tissue plasminogen activator for acute ischemic stroke. The New England journal of medicine. 1995-12-14 1995;333(24):1581-7. doi:10.1056/nejm199512143332401 8. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet (London, England). 1998-Oct-17 1998;352(9136):1245-51. doi:10.1016/s0140-6736(98)08020-9 9. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. The New England journal of medicine. 2008-Sep-25 2008;359(13):1317-29. doi:10.1056/NEJMoa0804656104. 10. Wahlgren N, Ahmed N, Eriksson N, et al. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST). Stroke; a journal of cerebral circulation. 2008-Dec 2008;39(12):3316-22. doi:10.1161/ strokeaha.107.510768

Data Data available: Yes Data types: Deidentified participant data, Data dictionary How to access data: Please email [email protected] or [email protected]. When available: With publication

Supporting Documents Document types: Statistical/analytic code How to access documents: Please email [email protected] or [email protected]. When available: With publication

Additional Information Who can access the data: Qingwu Yang ([email protected]) or Wenjie Zi ([email protected]) Types of analyses: For a specified purpose Mechanisms of data availability: After approval of a proposal Research

JAMA | Original Investigation Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis on Functional Outcome Among Patients With Acute Ischemic Stroke The SKIP Randomized Clinical Trial

Kentaro Suzuki, MD, PhD; Yuji Matsumaru, MD, PhD; Masataka Takeuchi, MD; Masafumi Morimoto, MD, PhD; Ryuzaburo Kanazawa, MD, PhD; Yohei Takayama, MD; Yuki Kamiya, MD, PhD; Keigo Shigeta, MD, PhD; Seiji Okubo, MD, PhD; Mikito Hayakawa, MD; Norihiro Ishii, MD, PhD; Yorio Koguchi, MD, PhD; Tomoji Takigawa, MD, PhD; Masato Inoue, MD, PhD; Hiromichi Naito, MD; Takahiro Ota, MD, PhD; Teruyuki Hirano, MD, PhD; Noriyuki Kato, MD, PhD; Toshihiro Ueda, MD, PhD; Yasuyuki Iguchi, MD, PhD; Kazunori Akaji, MD, PhD; Wataro Tsuruta, MD, PhD; Kazunori Miki, MD, PhD; Shigeru Fujimoto, MD, PhD; Tetsuhiro Higashida, MD, PhD; Mitsuhiro Iwasaki, MD; Junya Aoki, MD, PhD; Yasuhiro Nishiyama, MD, PhD; Toshiaki Otsuka, MD, PhD; Kazumi Kimura, MD, PhD; for the SKIP Study Investigators

Visual Abstract

IMPORTANCE Whether intravenous thrombolysis is needed in combination with mechanical Editorial page 229 thrombectomy in patients with acute large vessel occlusion stroke is unclear. Related article page 234 OBJECTIVE To examine whether mechanical thrombectomy alone is noninferior to combined Supplemental content intravenous thrombolysis plus mechanical thrombectomy for favorable poststroke outcome. CME Quiz at DESIGN, SETTING, AND PARTICIPANTS Investigator-initiated, multicenter, randomized, jamacmelookup.com open-label, noninferiority clinical trial in 204 patients with acute ischemic stroke due to large vessel occlusion enrolled at 23 hospital networks in Japan from January 1, 2017, to July 31, 2019, with final follow-up on October 31, 2019.

INTERVENTIONS Patients were randomly assigned to mechanical thrombectomy alone (n = 101) or combined intravenous thrombolysis (alteplase at a 0.6-mg/kg dose) plus mechanical thrombectomy (n = 103).

MAIN OUTCOMES AND MEASURES The primary efficacy end point was a favorable outcome defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 2 at 90 days, with a noninferiority margin odds ratio of 0.74, assessed using a 1-sided significance threshold of .025 (97.5% CI). There were 7 prespecified secondary efficacy end points, including mortality by day 90. There were 4 prespecified safety end points, including any intracerebral hemorrhage and symptomatic intracerebral hemorrhage within 36 hours.

RESULTS Among 204 patients (median age, 74 years; 62.7% men; median National Institutes of Health Stroke Scale score, 18), all patients completed the trial. Favorable outcome occurred in 60 patients (59.4%) in the mechanical thrombectomy alone group and 59 patients (57.3%) in the combined intravenous thrombolysis plus mechanical thrombectomy group, with no significant between-group difference (difference, 2.1% [1-sided 97.5% CI, −11.4% to ϱ]; odds ratio, 1.09 [1-sided 97.5% CI, 0.63 to ϱ]; P = .18 for noninferiority). Among the 7 secondary efficacy end points and 4 safety end points, 10 were not significantly different, including mortality at 90 days (8 [7.9%] vs 9 [8.7%]; difference, –0.8% [95% CI, –9.5% to 7.8%]; odds ratio, 0.90 [95% CI, 0.33 to 2.43]; P > .99). Any intracerebral hemorrhage was observed less frequently in the mechanical thrombectomy alone group than in the combined group (34 [33.7%] vs 52 [50.5%]; difference, –16.8% [95% CI, –32.1% to –1.6%]; odds ratio, 0.50 [95% CI, 0.28 to 0.88]; P = .02). Symptomatic intracerebral hemorrhage was not significantly different between groups (6 [5.9%] vs 8 [7.7%]; difference, –1.8% [95% CI, –9.7% to 6.1%]; odds ratio, 0.75 [95% CI, 0.25 to 2.24]; P = .78). Author Affiliations: Author affiliations are listed at the end of this CONCLUSIONS AND RELEVANCE Among patients with acute large vessel occlusion stroke, article. mechanical thrombectomy alone, compared with combined intravenous thrombolysis plus Group Information: The SKIP Study mechanical thrombectomy, failed to demonstrate noninferiority regarding favorable Investigators are listed in the eAppendix in Supplement 3. functional outcome. However, the wide confidence intervals around the effect estimate also Corresponding Author: Kazumi did not allow a conclusion of inferiority. Kimura, MD, PhD, Department of Neurology, Nippon Medical TRIAL REGISTRATION umin.ac.jp/ctr Identifier: UMIN000021488 School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan JAMA. 2021;325(3):244-253. doi:10.1001/jama.2020.23522 ([email protected]).

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andomized trials have consistently shown that mechanical thrombectomy with or without intravenous Key Points thrombolysis using recombinant tissue plasminogen ac- R Question In patients with acute large vessel occlusion stroke, is tivator (rt-PA) can improve the outcome in patients with acute mechanical thrombectomy alone noninferior to combined stroke due to large vessel occlusion.1-7 Intravenous thromboly- intravenous thrombolysis using 0.6-mg/kg alteplase plus sis (with dosage of 0.9-mg/kg alteplase) prior to mechanical mechanical thrombectomy regarding functional outcomes? thrombectomy is recommended by national guidelines for pa- Findings In this randomized clinical trial of 204 patients, tients with large vessel occlusion, within 4.5 hours of symp- a favorable functional outcome occurred in 59.4% of those tom onset.8-10 randomized to mechanical thrombectomy alone and in 57.3% of A meta-analysis of 5 randomized clinical trials reported that those randomized to combined intravenous thrombolysis plus outcomes following mechanical thrombectomy did not dif- mechanical thrombectomy (odds ratio, 1.09 [95% confidence limit fer significantly between patients receiving and not receiving below the noninferiority margin of 0.74]). intravenous thrombolysis.11 However, this concerned an ob- Meaning The findings failed to demonstrate noninferiority of servational comparison because intravenous thrombolysis was mechanical thrombectomy alone, compared with combined withheld only in the presence of contraindications for rt-PA. intravenous thrombolysis plus mechanical thrombectomy, for A retrospective study also showed that the outcomes be- favorable functional outcome following acute large vessel occlusive ischemic stroke, although the wide confidence intervals tween mechanical thrombectomy alone and combined intra- around the effect estimate also did not allow a conclusion venous thrombolysis plus mechanical thrombectomy were not of inferiority. significantly different.12 However, a meta-analysis showed the combined intravenous thrombolysis plus mechanical thrombectomy was associated with favorable outcome compared Patients and Participating Centers with mechanical thrombectomy alone.13 This study was performed at 23 stroke centers capable of en- Intravenous thrombolysis performed in addition to me- dovascular therapy in Japan. Patients were allowed to be evalu- chanical thrombectomy in patients with large vessel occlusion ated in another hospital and transferred to one of the study cen- has some potential benefits, such as earlier therapy initiation ters. Eligible patients were 18 to 85 years old, had acute stroke and increased chance of reperfusion. However, intravenous with internal carotid artery (ICA) or M1 occlusion evaluated by thrombolysis in addition to mechanical thrombectomy may in- magnetic resonance angiography (MRA) or computed tomo- crease the risk of intracerebral hemorrhage and other bleeding graphic angiography (CTA), had a baseline Alberta Stroke Pro- complications.14 Noninferiority of mechanical thrombectomy gram Early CT Score (ASPECTS) (range, 0 to 10, with higher alone, compared with combined therapy, would have poten- scores indicating fewer early ischemic changes) of 6 to 10 or tial clinical consequences because the extra cost and stroke team Diffusion-Weighted Imaging (DWI)–ASPECTS (range, 0 to 10, labor associated with intravenous thrombolysis could be avoided with higher scores indicating fewer early ischemic changes) of if outcomes of mechanical thrombectomy alone were not worse 5 to 10, initial National Institutes of Health Stroke Scale (NIHSS) than outcomes of combined therapy. score (range, 0 [no symptoms] to 42 [most severe neurologic The Direct Mechanical Thrombectomy in Acute LVO deficits]) equal to 6 or greater, were functionally indepen- Stroke (SKIP) study was designed to evaluate whether the dent prior to stroke, with modified Rankin Scale (mRS) score outcomes with mechanical thrombectomy alone were nonin- (range, 0 [no symptoms] to 6 [death]) of 0 to 2 , and met the ferior than the outcomes with combined thrombolysis and criteria of the Japanese guidelines for treatment with the lower mechanical thrombectomy. dose of 0.6 mg/kg of alteplase as intravenous thrombolysis within 4.5 hours from onset.16 The NIHSS score was assessed at baseline. The mRS score was assessed at 90 days after on- Methods set. For detailed inclusion and exclusion criteria, see eBox 1 in Supplement 3. Trial Design and Oversight This trial was approved by the institutional review board (IRB) Randomization and Interventions of each hospital. Enrolled patients or their relatives provided Patients were randomly assigned in a 1:1 ratio to 1 of 2 treat- written informed consent. This trial was an investigator- ment groups using a web-based data management system: the initiated, multicenter, randomized, open-label, noninferior- mechanical thrombectomy alone group or the combined group. ity clinical trial. Detailed aspects of the study design are pro- Using a stratified permuted block method (a block size of 4), vided in the final trial protocol with summary of all changes we balanced the number of patients into the 2 treatment groups (Supplement 1), the final statistical analysis plan with sum- of each hospital. Alteplase was used at the only dosage mary of all changes (Supplement 2), and a prior trial design (0.6 mg/kg) approved by the Japanese government. Mechani- publication.15 The study was to test whether mechanical throm- cal thrombectomy was performed with any device approved bectomy alone was noninferior to combined intravenous by the Ministry of Health, Labour, and Welfare of Japan. Balloon thrombolysis plus mechanical thrombectomy with regard to guide catheter was selected as the guiding catheter on me- functional outcome in intravenous thrombolysis–eligible pa- chanical thrombectomy. Concomitant stenting and angio- tients. All patients were required to have large vessel occlu- plasty of cervical and intracranial ICA occlusive lesions were sion without large ischemic core lesions. permitted without device restrictions. All stroke centers were jama.com (Reprinted) JAMA January 19, 2021 Volume 325, Number 3 245

required to start mechanical thrombectomy within 30 min- for favorable outcome. Study investigators had not reviewed utes from randomization. rt-PA infusion was continued dur- any patient data before the primary outcome change. The study ing mechanical thrombectomy for those in the combined in- investigators included stroke neurologists, neurosurgeons, and travenous thrombolysis plus mechanical thrombectomy group. statisticians. This trial was monitored by an independent data monitoring committee and event evaluation committee. Radiologic Assessment At admission, the baseline clinical characteristics were Noninferiority Margin and Sample Size Calculations assessed by research physicians at each hospital, including In a retrospective analysis of patients eligible for intravenous the NIHSS score, occluded artery site17 at admission and start thrombolysis, Weber et al22 reported favorable functional out- of mechanical thrombectomy, ASPECTS on MRI or CT, and come (mRS score 0-2) in 48.6% of patients (n = 70) who had expanded Thrombolysis in Cerebral Infarction (eTICI) scale received mechanical thrombectomy alone and 35.2% of those score (range, 0-3, higher scores indicate better reperfusion) (n = 105) who received intravenous thrombolysis plus me- on digital subtraction angiography. After enrolling all chanical thrombectomy. As described in detail in the pub- patients, a core imaging assessment committee (2 expert lished study protocol for this study,15 the noninferiority mar- neurologists, S.F. and T. Hirano), who were blinded to the gin was set as the odds ratio of 0.74 using the fixed-margin intervention, independently reassessed the occlusion site, approach, which was derived from a previous meta-analysis ASPECTS, and presence of intracerebral hemorrhage as pre- of combined intravenous thrombolysis plus mechanical throm- specified adverse events. Clot migration was defined as bectomy compared with the best medical treatment.11 Based change of occlusion site on findings between initial MRA/CTA on those results, it was estimated that 178 patients (89 pa- and initial digital subtraction angiography. tients in each group) were needed to statistically show the noninferiority of the odds ratio for the primary outcome in the me- Outcome Measures chanical thrombectomy alone group compared with the The mRS score was assessed by physical examination or tele- intravenous thrombolysis plus mechanical thrombectomy phone interview at 90 days after onset by site personnel who group, based on comparison of the 2 proportions with a 1-sided were blinded to treatment group assignment. The primary out- α level of .025 and a power of 0.80. Therefore, the target en- come measure was favorable outcome defined as an mRS score rollment was set at 200 patients because of considering pos- of 0 to 2 at 90 days. In a sensitivity analysis, primary out- sible treatment failures, protocol violations, and dropouts. De- come results were analyzed using per-protocol analysis. tailed information on the calculation of sample size is described The prespecified secondary outcome measures were shift in the statistical analysis plan in Supplement 2. analysis of disability levels on the mRS; mRS score of 5 to 6; mRS score of 0 to 1; mRS score of 0 to 3; mortality at 90 days; Statistical Analysis successful reperfusion defined as an eTICI scale18 score of 2b All analyses were performed using the primary analysis set, to 3 on end-of-procedure catheter angiography; recanaliza- which was defined as all patients enrolled to the trial. tion, defined as modified Mori scale19 score of 2 to 3 (scale In the primary analysis, patients were analyzed according ranges from 0 [no recanalization] to 3 [nearly complete re- to the group to which they were randomized. The primary analy- canalization]) on 48-hour CTA/MRA. sis involved testing for noninferiority of the rate of a favorable The prespecified adverse events were any intracerebral outcome at 90 days of mechanical thrombectomy alone com- hemorrhage at 36 hours from onset; symptomatic intracere- pared with combined intravenous thrombolysis plus mechani- bral hemorrhage defined by the National Institute of Neuro- cal thrombectomy. Unadjusted logistic regression analysis was logical Disorders and Stroke (NINDS) criteria20; symptomatic used to test noninferiority. As described in detail in the intracerebral hemorrhage defined by Safe Implementation of protocol,15 we set an odds ratio of 0.74 as the noninferiority mar- Thrombolysis in Stroke–Monitoring Study (SITS-MOST) gin, using the fixed-margin approach, which was derived from criteria21; and other major bleeding events (eBox 2 in a previous meta-analysis of combined intravenous thromboly- Supplement 3). sis plus mechanical thrombectomy compared with the best In the initial protocol, the investigators requested that the medical treatment.11 As sensitivity analysis of the primary out- IRB allow use of mRS scores of 0 to 2 for noninferiority in the come, noninferiority analyses of a favorable outcome was also primary analysis. However, the IRB suggested to the investi- performed using the per-protocol analysis set, which ex- gators to change from an mRS score of 0 to 2 for noninferior- cluded patients with mRS scores prior to stroke higher than 2 ity to an mRS score of 5 to 6 for superiority in the primary analy- and a large volume infarct (ASPECTS of 0-5 or DWI-ASPECTS sis prior to study start because there were no confirmed data of 0-4) from the primary analysis set. to support the mRS score of 0 to 2 approach compared with In the prespecified secondary efficacy analysis, the mRS the mRS score of 5 to 6 approach. After 103 patients had been scores were compared between groups to test for the noninfe- enrolled in this trial, Weber et al22 reported an observational riority of mechanical thrombectomy compared with com- study that provided more data regarding the end point of an bined intravenous thrombolysis plus mechanical thrombec- mRS score of 0 to 2. Consequently, the IRB accepted the use tomy, using ordinal logistic regression (shift analysis). The of an mRS score of 0 to 2 for noninferiority in the primary analy- proportional odds assumption of the shift analysis was vali- sis. Therefore, on August 1, 2018, the primary outcome was dated by a Brant test. Furthermore, mortality at 90 days; reper- changed from superiority for poor outcome to noninferiority fusion rate of the occluded arteries; mRS score of 5 to 6, 0 to 1,

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or 0 to 3 at 90 days; and recanalization of modified Mori grade puncture time was not statistically significantly different of 2 or 3 at 72 hours after stroke onset were compared between between the 2 groups (mechanical thrombectomy alone vs the 2 groups using unadjusted logistic regression analysis. intravenous thrombolysis plus mechanical thrombectomy: 16 As prespecified adverse events, any and symptomatic in- minutes [IQR, 11-24] vs 19 minutes [13-27], P = .38). In the tracerebral hemorrhage and other bleeding events were as- combined group, the puncture was performed before the sessed for superiority of mechanical thrombectomy alone com- administration of rt-PA in 22 patients (21.4%). The rate of clot pared with combined therapy. In the post hoc analysis, mixed- migration was not significantly different between the 2 effect logistic regression analysis of the primary outcome was groups (25/100 [25%] vs 28/103 [27%], P > .99). performed with study site as a random effect. In addition, association between any intracerebral hemorrhage and clinical Primary Outcome outcome at 90 days, and subgroup plot–adjusted treatment ef- In the primary analysis set, a favorable outcome was ob- fect for favorable outcome were assessed. served in 60 of 101 patients (59.4%) in the mechanical throm- The primary noninferiority analysis used a 1-sided signifi- bectomy alone group and in 59 of 103 (57.3%) in the com- cance threshold of .025, as did all other noninferiority analy- bined group (difference, 2.1% [1-sided 97.5% CI, –11.4% to ϱ]; ses. Superiority analyses used a 2-sided significance thresh- odds ratio, 1.09 [1-sided 97.5% CI, 0.63 to ϱ]; 1-sided noninfe- old of .05. The heterogeneity of treatment effects on the riority P = .18). Therefore, noninferiority of mechanical throm- primary outcome across subgroups was examined using an in- bectomy alone to combined intravenous thrombolysis plus me- teraction test for the treatment × subgroup interaction. Be- chanical thrombectomy was not proven (Table 2 and Figure 2). cause of the potential for type I error due to multiple compari- In the per-protocol analysis, a favorable outcome was ob- sons, findings for analyses of secondary end points and served in 59 of 97 patients (60.8%) in the mechanical throm- subgroup analyses should be interpreted as exploratory. bectomy alone group and in 57 of 97 (58.8%) in the combined All data analyses were performed with JMP version 11 soft- group, and noninferiority of the primary outcome measure was ware (SAS Institute) and Stata version 14 software (StataCorp). not proven (difference, 2.1% [1-sided 97.5% CI, –13.7% to ϱ]; odds ratio, 1.06 [1-sided 97.5% CI, 0.60 to ϱ]; P = .22).

Results Secondary Outcome In the primary analysis set, we analyzed the overall distribu- Characteristics of the Patients tion of the mRS score at 90 days (shift analysis of the disabil- From January 2017 through July 2019, 204 patients were en- ity level). Mechanical thrombectomy alone was not associ- rolled. The median age was 74 years, 128 (62.7%) were men, ated with a favorable shift in the distribution of the mRS score and the median NIHSS score was 18 (interquartile range [IQR], at 90 days (odds ratio, 0.97 [1-sided 97.5% CI, 0.60 to ϱ]; non- 12-23) (Table 1). At admission, 181 (88.7%) and 23 (11.3%) pa- inferiority P = .27), without any violation of the proportional tients were assessed by MRI/MRA and CT/CTA, respectively. odds assumption (Brant test P = .90). The number of deaths The median ASPECTS was 8 (IQR, 6-9) and the occluded ves- within 90 days after onset was 8 (7.9%) in the mechanical sel site was ICA in 77 patients (37.7%), M1 proximal in 37 (18.1%), thrombectomy alone group and 9 (8.7%) in the combined group and M1 distal in 90 (44.1%). Patients were randomized into 2 (difference, –0.8% [95% CI, –9.5% to 7.8%]; odds ratio, 0.90 groups: 101 (49.5%) in the mechanical thrombectomy alone [95% CI, 0.33 to 2.43]; P > .99). The 2 groups did not signifi- group and 103 (50.5%) in the combined intravenous throm- cantly differ in rates of successful reperfusion after mechani- bolysis plus mechanical thrombectomy group. Ten patients did cal thrombectomy, defined as eTICI grade of 2b or greater (91 not fulfill the inclusion criteria (2 patients had a poor mRS score [90.1%] vs 96 [93.2%]; difference, –3.1% [95% CI, –11.8% to and 8 had a low ASPECTS. Therefore, 194 patients (97 in each 5.6%]; odds ratio, 0.66 [95% CI, 0.24 to 1.82]; P = .46) (Table 2). group) were included in the per-protocol analysis (Figure 1). Other prespecified secondary outcome data are described in No baseline covariate or outcome data were missing, except the eTable in Supplement 3. for 12 cases (5.9%) for modified Mori grade. Table 1 shows the demographic and clinical characteristics at baseline accord- Adverse Events ing to group. Intracerebral hemorrhage was assessed by only CT at 36 hours from onset. Of 86 patients with intracerebral hemor- Endovascular Therapy rhage, 16 patients showed parenchymal hematoma 2 defined Five patients did not undergo mechanical thrombectomy by European Cooperative Acute Stroke Study criteria. The because of aortic dissection (n = 2) and impossibility of rate of any intracerebral hemorrhage at 36 hours from onset approach (n = 1) in the mechanical thrombectomy alone was lower in the mechanical thrombectomy alone group than group and because of spontaneous recanalization (n = 1) and in the combined group (34 [33.7%] vs 52 [50.5%]; difference, impossibility of approach (n = 1) in the combined group. –16.8% [95% CI, –32.1% to –1.6%]; odds ratio, 0.50 [95% CI, Therefore, 199 patients (97.5%) underwent mechanical 0.28 to 0.88]; P = .02). However, the rate of symptomatic thrombectomy. The median door-to-randomization time was intracerebral hemorrhage was not significantly different 33 minutes (IQR, 23-48), randomization-to-puncture time between the 2 groups, based on the NINDS criteria (8 [7.9%] was 18 minutes (IQR, 11-25), and puncture-to-reperfusion vs 12 [11.7%]; difference, –3.7% [ 95% CI, –13.0% to 5.6%]; time was 34 minutes (IQR, 22-55). The randomization-to- odds ratio, 0.65 [95% CI, 0.25 to 1.67]; P = .48) and the jama.com (Reprinted) JAMA January 19, 2021 Volume 325, Number 3 247

Table 1. Characteristics of the Patients at Baseline

No. (%) Intravenous thrombolysis Mechanical thrombectomy alone plus mechanical thrombectomy Characteristic (n = 101) (n = 103) Age, median (IQR), y 74 (67-80) 76 (67-80) Sex Male 56 (55) 72 (70) Female 45 (45) 31 (30) Weight, median (IQR), kg 59 (52-66) 60 (53-68) Medical historya Hypertension 61 (60) 61 (59) Atrial fibrillation 57 (56) 64 (62) Smoking 42 (42) 54 (52) Dyslipidemia 30 (30) 37 (36) Diabetes 16 (16) 17 (17) Past stroke 12 (12) 14 (14) Past cardiovascular disease 7 (7) 7 (7) Antiplatelet agent 16 (16) 18 (17) Anticoagulant agent 19 (19) 17 (17) Blood glucose level at admission, mean (SD), mg/dL 135 (48) 135 (52) TOAST classificationb Large artery (atherosclerosis) 21 (21) 15 (15) Cardioembolism 67 (66) 72 (70) Other determined/undetermined etiology 13 (13) 16 (16) Blood pressure at admission, median (IQR), mm Hg Systolic 158 (132-172) 150 (134-171) Diastolic 83 (75-98) 86 (78-98) NIHSS score at admission, median (IQR)c 19 (13-23) 17 (12-22) Examination at admission MRI/MRA 86 (85) 95 (92) CT/CTA 15 (15) 8 (8) Occluded site by MRA/CTA ICA 41 (41) 36 (35) M1 proximald 19 (19) 18 (17) M1 distal 41 (41) 49 (48) Occluded site by DSA None 1 (1) 0 ICA origin 13 (13) 16 (16) ICA C4-5 6 (6) 6 (6) ICA C1-3 17 (17) 14 (14) M1 proximald 10 (10) 12 (12) M1 distal 44 (44) 35 (34) M2 10 (10) 20 (19) ASPECTSe 7 (6-9) 8 (6-9) ASPECTS of 0-4 4 (4) 4 (4) Tandem lesionf 9 (9) 13 (13) Modified Rankin Scale score before stroke 0 84 (83) 88 (85) 1 11 (11) 6 (6) 2 6 (6) 7 (7) 3 0 2 (2) Onset-to-door time, mean (SD), min 92 (57) 100 (55) Door-to-randomization time, mean (SD), min 37 (23) 36 (19)

(continued)

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Table 1. Characteristics of the Patients at Baseline (continued)

No. (%) Intravenous thrombolysis Mechanical thrombectomy alone plus mechanical thrombectomy Characteristic (n = 101) (n = 103) Randomization–to–rt-PA time, mean (SD), min 14 (10) Randomization-to-puncture time, mean (SD), min 20 (20) 22 (16) First procedural characteristics Clot retrieval by stent 58 (57) 59 (57) Aspiration 34 (34) 30 (30) Intra-arterial thrombolysis 1 (1) 0 Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; CT, computed atherosclerosis, (2) cardioembolism, (3) small vessel occlusion, (4) stroke of other tomography; CTA, computed tomographic angiography; DSA, digital determined etiology, and (5) stroke of undetermined etiology. The TOAST subtraction angiography; ICA, internal carotid artery; IQR, interquartile range; classification was based on clinical information and the radiological findings MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; M1, of MRI/CT. segment of the middle cerebral artery; M2, segment of the middle cerebral c Scores on the NIHSS range from 0 to 42, with higher scores indicating more artery; NIHSS, National Institutes of Health Stroke Scale; rt-PA, recombinant severe neurologic deficits. tissue plasminogen activator; TOAST, Trial of Org 10172 in Acute Stroke d M1 proximal occlusion is defined as occlusion within 5 mm from bifurcation Treatment for stroke type. according to a previous study.17 SI conversion factor: To convert glucose to mmol/L, multiply by 0.0555. e Scores on the ASPECTS range from 0 to 10, with lower scores indicating more a Medical history was based on self-report, with the exception of the presence severe ischemic core lesion. of atrial fibrillation, which was based on medical history and findings on f Cases in which an extracranial internal carotid occlusive lesion accompanied electrocardiography performed at admission. the intracranial lesion. b The TOAST classification23 denotes 5 subtypes of ischemic stroke: (1) large-artery

SIT-MOST criteria (6 [5.9%] vs 8 [7.8%]; difference, –1.8% Figure 1. Flowchart of Enrollment, Randomization, and Treatment [95% CI, –9.7% to 6.1%]; odds ratio, 0.75 [95% CI, 0.25 to of the SKIP Randomized Clinical Trial 2.24]; P = .78). In the post hoc analysis, patients with any intracerebral hemorrhage (symptomatic [n = 14] and asymp- 204 tomatic [n = 72]) had less frequently favorable outcomes than Randomized those without intracerebral hemorrhage (41.9% [36/86] vs 70.3% [83/118], P < .001). The incidence of other hemorrhagic 101 Randomized to receive 103 Randomized to receive events was not significantly different (1/101 [1%] and 4/103 mechanical thrombectomy alone intravenous thrombolysis plus 101 Received the intervention mechanical thrombectomy [4%], P = .37) (1 [1.0%] vs 4 [3.9%]; difference, –2.9% [95% CI, and were included in the 103 Received the intervention primary analysis set and were included in the –0.08 to 0.02]; odds ratio, 0.25 [95% CI, 0.03 to 2.25]; primary analysis set P = .37) between the 2 groups.

4 Excluded (ASPECTS too low)a 6 Excluded Subgroup Analysis and Post Hoc Analyses 4 ASPECTS too lowa 2 Pre-mRS score >2 There was no significant heterogeneity of effect on the primary outcome across the post hoc subgroups: age, sex, atrial 97 Included in the per-protocol 97 Included in the per-protocol fibrillation, blood glucose, antithrombotic agent, NIHSS score, analysis analysis ASPECTS, occluded artery at admission, and onset randomization time (Figure 3). Patients were randomly assigned in a 1:1 ratio to the mechanical thrombectomy The results for the primary outcome of the post hoc mixed- alone group or the intravenous thrombolysis plus mechanical thrombectomy effect logistic regression analysis with study site as a random group using a permuted block design stratified by site. Each site was not required to provide screening logs during the recruitment phase. Thus, the effect were similar (odds ratio, 1.09 [1-sided 97.5% CI, 0.63 to ϱ]; number of patients assessed for eligibility is not available. ASPECTS indicates P noninferiority = .17). Alberta Stroke Program Early CT Score; mRS, modified Rankin Scale. a ASPECTS too low indicates ASPECTS less than 5 on initial diffusion-weighted imaging or less than 6 on initial computed tomography. Discussion ingly, a larger trial or meta-analysis of trials is needed to con- This clinical trial of patients with acute large vessel occlusion clusively assess noninferiority. stroke failed to demonstrate noninferiority of mechanical Recent studies have evaluated the effectiveness of me- thrombectomy alone compared with combined intravenous chanical thrombectomy therapy compared with that thrombolysis plus mechanical thrombectomy with regard to for combined intravenous thrombolysis plus mechanical favorable functional outcome. Although this study hypoth- thrombectomy therapy in patients with acute large vessel oc- esis could not be proved, the point estimates of treatment ef- clusion stroke.1,5,12,13,22,24-31 A meta-analysis demonstrated that fect for mechanical thrombectomy alone was nominally slightly combined intravenous thrombolysis plus mechanical throm- better, not worse, compared with combined therapy. Accord- bectomy therapy was associated with a higher likelihood of jama.com (Reprinted) JAMA January 19, 2021 Volume 325, Number 3 249

Table 2. Primary and Secondary Efficacy End Points and Adverse Eventsa

Intravenous Noninferiority analysis Superiority analysis Mechanical thrombolysis Estimate thrombectomy plus mechanical of difference, Odds ratio Estimate alone thrombectomy % (97.5% (97.5% of difference, Odds ratio (n = 101) (n = 103) 1-sided CI) 1-sided CI)b P valuec % (95% CI) (95% CI) P valuec Primary outcome Modified Rankin Scale 60 (59.4) 59 (57.3) 2.1 (–11.4 to ϱ) 1.09 (0.63 to ϱ) .18 score 0-2 at 90 d, No. (%) Secondary outcomes Modified Rankin Scale 0.97 (0.60 to ϱ) .27 score reduction (shift analysis) Mortality at 90 d, No. (%) 8 (7.9) 9 (8.7) –0.8 (–9.5 to 7.8) 0.90 (0.33 to 2.43) >.99 TICI grade ≥2b, No. (%)d 91 (90.1) 96 (93.2) –3.1 (–11.8 to 5.6) 0.66 (0.24 to 1.82) .46 Adverse event outcomes Any ICH at 36 h 34 (33.7) 52 (50.5) –16.8 (–32.1 to –1.6) 0.50 (0.28 to 0.88) .02 from onset, No. (%) Symptomatic ICH 8 (7.9) 12 (11.7) –3.7 (–13.0 to 5.6) 0.65 (0.25 to 1.67) .48 (NINDS criteria) at 36 h from onset, No. (%)e Symptomatic ICH 6 (5.9) 8 (7.8) –1.8 (–9.7 to 6.1) 0.75 (0.25 to 2.24) .78 (SIT-MOST criteria) at 36 h from onset, No. (%)f Abbreviations: ICH, intracerebral hemorrhage; NIHSS, National Institutes of perfusion; 2a, only partial filling (<50%) of the entire vascular territory; Health Stroke Scale; NINDS, National Institute of Neurological Diseases and 2b, partial filling (Ն50%); 2c, near complete perfusion with the exception of Stroke; SITS-MOST, Safe Implementation of Thrombolysis in Stroke-Monitoring slow flow or a few distal cortical emboli; and 3, complete perfusion. Study; TICI, Thrombolysis in Cerebral Infarction. e Symptomatic ICH was also assessed according to NINDS trial criteria: any a All analyses were conducted using the primary analysis set. intracerebral hemorrhage with neurologic deterioration from baseline Ն b The noninferiority margin was an odds ratio of 0.74. (increase of 1 in the NIHSS score) or death within 36 hours. f c P values refer to the comparison between mechanical thrombectomy alone The main definition of symptomatic ICH was the definition from the and intravenous thrombolysis plus mechanical thrombectomy. SITS-MOST: a large local or remote parenchymal ICH (>30% of the infarcted area affected by hemorrhage with a mass effect or extension outside the d The TICI grading system was based on the angiographic appearances of the infarct) in combination with neurologic deterioration from baseline (increase treated occluded vessel and its distal branches: scores on the TICI grade range of Ն4 in the NIHSS score) or death within 36 hours. from 0 to 3, with 0 indicating no perfusion; 1, penetration with minimal

Figure 2. Functional Outcomes at 90 Days From Onset According to the Modified Rankin Scale Score

90-d Modified Rankin Scale score 0 1 2 3 4 5 6

Mechanical thrombectomy 19.8 20.8 18.8 13.9 10.9 7.9 7.9 alone group (n = 101) Scores on the modified Rankin Scale Intravenous thrombolysis plus range from 0 to 6, with 0 indicating 22.3 22.3 12.6 13.6 12.6 7.8 8.7 mechanical thrombectomy group (n = 103) no symptoms; 1, symptoms without clinical disability; 2, slight disability; 0 20 40 60 80 100 3, moderate disability; 4, moderately Patients, % severe disability; 5, severe disability; and 6, death.

functional independence compared with that for mechanical the mechanical thrombectomy alone group than in the com- thrombectomy alone therapy (odds ratio, 1.52 [95% CI, 1.32 to bined group. However, symptomatic intracerebral hemor- 1.76]).32 However, these results were obtained from retrospec- rhage did not significantly differ between the 2 groups. Intra- tive cohort studies, in which mechanical thrombectomy alone cerebral hemorrhage is associated with high morbidity and was performed on many rt-PA–ineligible patients.33 In con- mortality after mechanical thrombectomy therapy.35 Admin- trast, Kaesmacher et al34 reported that a meta-analysis using istration of rt-PA alone is known to increase the rate of symp- only rt-PA–eligible patients could not conclude that mechani- tomatic intracerebral hemorrhage 3- to 10-fold vs that with con- cal thrombectomy alone had more favorable outcome com- trols, though absolute numbers were low.14,20 In this trial, the pared with combined intravenous thrombolysis plus mechani- incidence of any intracerebral hemorrhage was significantly cal thrombectomy. higher in the combined group than in the mechanical throm- This study demonstrated that any intracerebral hemor- bectomy alone group. The higher frequency of any intracere- rhage within 36 hours from onset was significantly lower in bral hemorrhage may be caused by the administration of rt-PA.

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Figure 3. Subgroup Plot Showing the Adjusted Treatment Effect for Favorable Outcome, With P Values for Heterogeneity Across Subgroups

Intravenous Mechanical thrombolysis Favors Favors intravenous thrombectomy plus mechanical mechanical thrombolysis plus alone thrombectomy Odds ratio thrombectomy mechanical (n = 101) (n = 103) (95% CI) alone thrombectomy P value for Age, y interaction <70 24 (72.3) 21 (63.6) 1.52 (0.54-4.33) .45 ≥70 38 (52.9) 38 (54.3) 0.95 (0.49-1.85) Sex Male 33 (58.9) 43 (59.7) 0.97 (0.48-1.97) .53 Female 27 (60.0) 16 (51.6) 1.41 (0.56-3.54) Atrial fibrillation Yes 36 (63.2) 35 (54.7) 1.42 (0.68-2.95) .27 No 24 (54.6) 24 (61.5) 0.75 (0.31-1.80) Blood sugar, mg/dL <126 40 (65.6) 36 (59.0) 1.32 (0.63-2.76) .42 ≥126 20 (50.0) 23 (54.8) 0.83 (0.35-1.97) Use of antithrombotic agent Yes 16 (47.1) 18 (56.3) 0.69 (0.26-1.82) .25 No 44 (65.7) 41 (57.8) 1.40 (0.70-2.79) NIHSS score at admission >5 and <18 30 (73.2) 37 (69.8) 1.18 (0.48-2.92) .90 ≥18 30 (50.0) 22 (44.0) 1.27 (0.60-2.70) ASPECTS >4 and <8 30 (56.6) 20 (46.5) 1.50 (0.67-3.37) .37 ≥8 30 (62.5) 39 (65.0) 0.90 (0.41-1.98) Occluded artery Internal carotid artery 21 (51.2) 19 (52.8) 0.94 (0.38-2.30) MI proximal 11 (57.9) 9 (50.0) 1.38 (0.38-5.03) .99 MI distal 28 (68.3) 31 (63.3) 1.25 (0.52-3.01) Onset to randomization, min <120 34 (63.0) 31 (68.9) 0.77 (0.33-1.78) .35 ≥120 26 (55.3) 28 (48.3) 1.33 (0.61-2.87)

0.2 1 5.0 Odds ratio (95% CI)

ASPECTS indicates Alberta Stroke Program Early CT Score; M1, middle cerebral artery M1 segment; and NIHSS, National Institutes of Health Stroke Scale. To convert glucose to mmol/L, multiply by 0.0555.

Many reports have shown that symptomatic, but not asymp- Limitations tomatic, intracerebral hemorrhage is associated with poor This study has several limitations. First, this was an open- outcomes.36-38 Van Kranendonk et al39 reported that any in- label study regarding the use of rt-PA. Second, the sample tracerebral hemorrhage has a potential for poor outcome. In size and the noninferiority margin of 0.74 were calculated the post hoc analysis of this study, favorable outcomes were from previous studies using a dose of 0.9 mg/kg of alteplase. significantly less frequent in patients with any intracerebral In addition, the noninferiority margin was selected using hemorrhage than in those without intracerebral hemorrhage. the fixed-margin method rather than the minimal clini- Further studies are needed to clarify the relationship be- cally important difference. Third, favorable outcomes were tween any intracerebral hemorrhage and patient outcome. more frequent than expected, which may have resulted in a The combined intravenous thrombolysis plus mechani- reduction of study power. Recently, the Direct-MT trial40 in cal thrombectomy therapy might be considered to be disad- China, which was a similar randomized clinical trial to this vantaged by the delayed start of mechanical thrombectomy due trial, demonstrated noninferiority for mechanical thrombec- to the preparation of rt-PA administration. However, the ran- tomy alone compared with combined intravenous throm- domization-to-puncture time was not statistically signifi- bolysis and mechanical thrombectomy with regard to func- cantly different between the 2 groups. In 22 cases (21.4%) in tional outcome. In addition, 3 randomized clinical trials the combined group, groin puncture occurred before the start (MR CLEAN-NO IV [ISRCTN80619088], SWIFT DIRECT of intravenous thrombolysis. Therefore, rt-PA administra- [NCT03192332], and DIRECT-SAFE [NCT03494920]) similar tion might be not a disadvantage to the starting of mechani- to this trial are ongoing. Meta-analyses that include these cal thrombectomy therapy. trials may provide greater clarity. jama.com (Reprinted) JAMA January 19, 2021 Volume 325, Number 3 251

intravenous thrombolysis plus mechanical thrombectomy, Conclusions failed to demonstrate noninferiority regarding favorable functional outcome. However, the wide confidence inter- Among patients with acute large vessel occlusion stroke, vals around the effect estimate also did not allow a conclu- mechanical thrombectomy alone, compared with combined sion of inferiority.

ARTICLE INFORMATION Iguchi, Akaji, Tsuruta, Miki, Fujimoto, Higashida, from Daiichi Sankyo Co, personal fees from Bayer Accepted for Publication: November 18, 2020. Iwasaki, Aoki, Nishiyama, Otsuka, Kimura. Healthcare Co Ltd and personal fees from Nippon Drafting of the manuscript: Suzuki, Higashida, Boehringer Ingelheim Co Ltd and Bristol-Myers Author Affiliations: Department of Neurology, Kimura. Squibb Co Ltd outside the submitted work. No Nippon Medical School, Tokyo, Japan (Suzuki, Aoki, Critical revision of the manuscript for important other disclosures were reported. Nishiyama, Kimura); Division of Stroke Prevention intellectual content: Suzuki, Matsumaru, Takeuchi, and Treatment, Department of Neurosurgery, Funding/Support: Funding was provided by the Morimoto, Kanazawa, Takayama, Kamiya, Shigeta, Japanese Society for Neuroendovascular Therapy. Faculty of Medicine, University of Tsukuba, Ibaraki, Okubo, Hayakawa, Ishii, Koguchi, Takigawa, Inoue, Japan (Matsumaru, Hayakawa); Department of Naito, Ota, Hirano, Kato, Ueda, Iguchi, Akaji, Role of the Funder/Sponsor: The funding source Neurosurgery, Seisho Hospital, Kanagawa, Japan Tsuruta, Miki, Fujimoto, Iwasaki, Aoki, Nishiyama, had no role in the design and conduct of the study; (Takeuchi); Department of Neurosurgery, Otsuka, Kimura. collection, management, analysis, and Yokohama Shintoshi Neurosurgery Hospital, Statistical analysis: Suzuki, Higashida, Otsuka. interpretation of the data; preparation, review, or Kanagawa, Japan (Morimoto, Iwasaki); Department Obtained funding: Suzuki, Kimura. approval of the manuscript; and decision to submit of Neurosurgery, Nagareyama Central Hospital, Administrative, technical, or material support: the manuscript for publication. Chiba, Japan (Kanazawa, Higashida); Department Suzuki, Takeuchi, Morimoto, Kanazawa, Takayama, Group Information: The SKIP Study Investigators of Neurology, Akiyama Neurosurgical Hospital, Kamiya, Shigeta, Okubo, Ishii, Koguchi, Inoue, are listed in Supplement 3. Kanagawa, Japan (Takayama); Department of Naito, Ota, Hirano, Kato, Ueda, Iguchi, Akaji, Additional Contributions: We thank Akio Morita, Neurology, Showa University Koto Toyosu Hospital, Tsuruta, Miki, Higashida, Iwasaki, Aoki, Nishiyama, Tokyo, Japan (Kamiya); Department of MD, PhD (Department of Neurosurgery, Nippon Kimura. Medical School Hospital, Tokyo, Japan), as the Neurosurgery, National Hospital Organization Supervision: Matsumaru, Fujimoto, Otsuka, Kimura. Disaster Medical Center, Tokyo, Japan (Shigeta); independent data monitoring committee without Department of Cerebrovascular Medicine, NTT Conflict of Interest Disclosures: Dr Suzuki compensation and Hiroyuki Yokota, MD, PhD Medical Center Tokyo, Tokyo, Japan (Okubo); reported receiving grants from the Japanese (Department of Emergency and Critical Care Department of Neurosurgery, New Tokyo Hospital, Society for Neuroendovascular Therapy during the Medicine, Nippon Medical School Hospital, Tokyo, Chiba, Japan (Ishii); Department of Neurology and conduct of the study and a scholarship to study Japan), as the event evaluation committee without Neurosurgery, Chiba Emergency Medical Center, abroad from the Uehara Memorial Foundation. compensation. Chiba, Japan (Koguchi); Department of Dr Matsumaru reported receiving personal fees Data Sharing Statement: See Supplement 4. Neurosurgery, Dokkyo Medical University Saitama from Medtronic Co Ltd, Stryker Co Ltd, Sanofi Co Medical Center, Saitama, Japan (Takigawa); Ltd, Daiichi Sankyo Co Ltd, Otsuka Pharmaceutical REFERENCES Co Ltd, and Biomedical Solutions outside the Department of Neurosurgery, National Center for 1. Jovin TG, Chamorro A, Cobo E, et al; REVASCAT Global Health and Medicine, Tokyo, Japan (Inoue); submitted work. Dr Takeuchi reported receiving lecture fees from Stryker Co Ltd outside the Trial Investigators. Thrombectomy within 8 hours Department of Neurosurgery, Funabashi Municipal after symptom onset in ischemic stroke. N Engl J Med. Medical Center, Chiba, Japan (Naito); Department submitted work. 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Thrombectomy Evaluation (PISTE) randomised, 18. Goyal M, Fargen KM, Turk AS, et al. 2C or not multicenter study of Solitaire FR for controlled trial. J Neurol Neurosurg Psychiatry. 2C: defining an improved revascularization grading revascularization in the treatment of acute ischemic 2017;88(1):38-44. doi:10.1136/jnnp-2016-314117 scale and the need for standardization of stroke. Stroke. 2012;43(10):2699-2705. doi:10. 8. Jauch EC, Saver JL, Adams HP Jr, et al; American angiography outcomes in stroke trials. J Neurointerv 1161/STROKEAHA.112.663328 Heart Association Stroke Council; Council on Surg. 2014;6(2):83-86. doi:10.1136/neurintsurg- 30. Mulder MJ, Berkhemer OA, Fransen PS, et al; Cardiovascular Nursing; Council on Peripheral 2013-010665 MR CLEAN investigators. Treatment in patients Vascular Disease; Council on Clinical Cardiology. 19. Mori E, Minematsu K, Nakagawara J, Yamaguchi who are not eligible for intravenous alteplase: Guidelines for the early management of patients T, Sasaki M, Hirano T; Japan Alteplase Clinical Trial II MR CLEAN subgroup analysis. Int J Stroke. 2016;11 with acute ischemic stroke: a guideline for Group. Effects of 0.6 mg/kg intravenous alteplase (6):637-645. doi:10.1177/1747493016641969 healthcare professionals from the American Heart on vascular and clinical outcomes in middle cerebral 31. Nogueira RG, Gupta R, Jovin TG, et al. Association/American Stroke Association. Stroke. artery occlusion: Japan Alteplase Clinical Trial II Predictors and clinical relevance of hemorrhagic 2013;44(3):870-947. doi:10.1161/STR. (J-ACT II). Stroke. 2010;41(3):461-465. doi:10.1161/ transformation after endovascular therapy for 0b013e318284056a STROKEAHA.109.573477 anterior circulation large vessel occlusion strokes: 9. Turc G, Bhogal P, Fischer U, et al. European 20. National Institute of Neurological Disorders a multicenter retrospective analysis of 1122 Stroke Organisation (ESO)—European Society for and Stroke rt-PA Stroke Study Group. Tissue patients. J Neurointerv Surg. 2015;7(1):16-21. doi:10. Minimally Invasive Neurological Therapy (ESMINT) plasminogen activator for acute ischemic stroke. 1136/neurintsurg-2013-010743 Guidelines on Mechanical Thrombectomy in Acute N Engl J Med. 1995;333(24):1581-1587. doi:10.1056/ 32. Katsanos AH, Malhotra K, Goyal N, et al. Ischaemic StrokeEndorsed by Stroke Alliance for NEJM199512143332401 Intravenous thrombolysis prior to mechanical Europe (SAFE). Eur Stroke J. 2019;4(1):6-12. doi:10. 21. Wahlgren N, Ahmed N, Dávalos A, et al; thrombectomy in large vessel occlusions. Ann Neurol. 1177/2396987319832140 SITS-MOST investigators. Thrombolysis with 2019;86(3):395-406. doi:10.1002/ana.25544 10. Toyoda K, Koga M, Iguchi Y, et al. Guidelines for alteplase for acute ischaemic stroke in the Safe 33. Phan K, Dmytriw AA, Lloyd D, et al. Direct intravenous thrombolysis (recombinant tissue–type Implementation of Thrombolysis in endovascular thrombectomy and bridging plasminogen activator), the third edition, March Stroke-Monitoring Study (SITS-MOST): an strategies for acute ischemic stroke: a network 2019: a guideline from the Japan Stroke Society. observational study. Lancet. 2007;369(9558):275- meta-analysis. J Neurointerv Surg. 2019;11(5):443- Neurol Med Chir (Tokyo). 2019;59(12):449-491. doi: 282. doi:10.1016/S0140-6736(07)60149-4 449. doi:10.1136/neurintsurg-2018-014260 10.2176/nmc.st.2019-0177 22. Weber R, Nordmeyer H, Hadisurya J, et al. 34. Kaesmacher J, Mordasini P, Arnold M, et al. 11. Goyal M, Menon BK, van Zwam WH, et al; Comparison of outcome and interventional Direct mechanical thrombectomy in tPA-ineligible HERMES collaborators. Endovascular complication rate in patients with acute stroke and -eligible patients versus the bridging approach: thrombectomy after large-vessel ischaemic stroke: treated with mechanical thrombectomy with and a meta-analysis. J Neurointerv Surg. 2019;11(1):20-27. a meta-analysis of individual patient data from five without bridging thrombolysis. J Neurointerv Surg. doi:10.1136/neurintsurg-2018-013834 randomised trials. Lancet. 2016;387(10029):1723- 2017;9(3):229-233. doi:10.1136/neurintsurg-2015- 1731. doi:10.1016/S0140-6736(16)00163-X 012236 35. Fiorelli M, Bastianello S, von Kummer R, et al. Hemorrhagic transformation within 36 hours of 12. Broeg-Morvay A, Mordasini P, Bernasconi C, 23. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. a cerebral infarct: relationships with early clinical et al. Direct mechanical intervention versus Classification of subtype of acute ischemic stroke: deterioration and 3-month outcome in the combined intravenous and mechanical intervention definitions for use in a multicenter clinical trial: European Cooperative Acute Stroke Study I (ECASS in large artery anterior circulation stroke: TOAST, Trial of Org 10172 in Acute Stroke I) cohort. Stroke. 1999;30(11):2280-2284. doi:10. a matched-pairs analysis. Stroke. 2016;47(4):1037- Treatment. Stroke. 1993;24(1):35-41. doi:10.1161/01. 1161/01.STR.30.11.2280 1044. doi:10.1161/STROKEAHA.115.011134 STR.24.1.35 36. Molina CA, Alvarez-Sabín J, Montaner J, et al. 13. Mistry EA, Mistry AM, Nakawah MO, et al. 24. Leker RR, Pikis S, Gomori JM, Cohen JE. Thrombolysis-related hemorrhagic infarction: Mechanical thrombectomy outcomes with and Is bridging necessary? a pilot study of bridging a marker of early reperfusion, reduced infarct without intravenous thrombolysis in stroke versus primary stentriever-based endovascular size, and improved outcome in patients with patients: a meta-analysis. Stroke. 2017;48(9):2450- reperfusion in large anterior circulation strokes. proximal middle cerebral artery occlusion. Stroke. 2456. doi:10.1161/STROKEAHA.117.017320 J Stroke Cerebrovasc Dis. 2015;24(6):1163-1167. doi: 2002;33(6):1551-1556. doi:10.1161/01.STR. 14. Hacke W, Donnan G, Fieschi C, et al; ATLANTIS 10.1016/j.jstrokecerebrovasdis.2015.01.008 0000016323.13456.E5 Trials Investigators; ECASS Trials Investigators; 25. Rai AT, Boo S, Buseman C, et al. Intravenous 37. Dzialowski I, Pexman JH, Barber PA, Demchuk NINDS rt-PA Study Group Investigators. Association thrombolysis before endovascular therapy for large AM, Buchan AM, Hill MD; CASES Investigators. of outcome with early stroke treatment: pooled vessel strokes can lead to significantly higher Asymptomatic hemorrhage after thrombolysis may analysis of ATLANTIS, ECASS, and NINDS rt-PA hospital costs without improving outcomes. not be benign: prognosis by hemorrhage type in the stroke trials. Lancet. 2004;363(9411):768-774. doi: J Neurointerv Surg. 2018;10(1):17-21. doi:10.1136/ Canadian alteplase for stroke effectiveness study 10.1016/S0140-6736(04)15692-4 neurintsurg-2016-012830 registry. Stroke. 2007;38(1):75-79. doi:10.1161/01. 15. Suzuki K, Kimura K, Takeuchi M, et al. The 26. Coutinho JM, Liebeskind DS, Slater LA, et al. STR.0000251644.76546.62 randomized study of endovascular therapy with Combined intravenous thrombolysis and 38. Lei C, Wu B, Liu M, Chen Y. Asymptomatic versus without intravenous tissue plasminogen thrombectomy vs thrombectomy alone for acute hemorrhagic transformation after acute ischemic activator in acute stroke with ICA and M1 occlusion ischemic stroke: a pooled analysis of the SWIFT and stroke: is it clinically innocuous? J Stroke (SKIP study). Int J Stroke. 2019;14(7):752-755. doi: STAR studies. JAMA Neurol. 2017;74(3):268-274. Cerebrovasc Dis. 2014;23(10):2767-2772. doi:10. 10.1177/1747493019840932 doi:10.1001/jamaneurol.2016.5374 1016/j.jstrokecerebrovasdis.2014.06.024 16. Yamaguchi T, Mori E, Minematsu K, et al; Japan 27. Abilleira S, Ribera A, Cardona P, et al; Catalan 39. van Kranendonk KR, Treurniet KM, Boers AMM, Alteplase Clinical Trial (J-ACT) Group. Alteplase at Stroke Code and Reperfusion Consortium. et al; MR CLEAN investigators. Hemorrhagic 0.6 mg/kg for acute ischemic stroke within 3 hours Outcomes after direct thrombectomy or combined transformation is associated with poor functional of onset: Japan Alteplase Clinical Trial (J-ACT). Stroke. intravenous and endovascular treatment are not outcome in patients with acute ischemic stroke due 2006;37(7):1810-1815. doi:10.1161/01.STR. different. Stroke. 2017;48(2):375-378. doi:10.1161/ to a large vessel occlusion. J Neurointerv Surg. 0000227191.01792.e3 STROKEAHA.116.015857 2019;11(5):464-468. doi:10.1136/neurintsurg-2018- 17. Hirano T, Sasaki M, Mori E, Minematsu K, 28. Minnerup J, Wersching H, Teuber A, et al; 014141 Nakagawara J, Yamaguchi T; Japan Alteplase Clinical REVASK Investigators. Outcome after 40. Yang P, Zhang Y, Zhang L, et al; DIRECT-MT Trial II Group. Residual vessel length on magnetic thrombectomy and intravenous thrombolysis in Investigators. Endovascular Thrombectomy with or resonance angiography identifies poor responders patients with acute ischemic stroke: a prospective without Intravenous Alteplase in Acute Stroke. to alteplase in acute middle cerebral artery observational study. Stroke. 2016;47(6):1584-1592. N Engl J Med. 2020;382(21):1981-1993. doi:10. occlusion patients: exploratory analysis of the doi:10.1161/STROKEAHA.116.012619 1056/NEJMoa2001123 Japan Alteplase Clinical Trial II. Stroke. 2010;41(12): 29. Dávalos A, Pereira VM, Chapot R, Bonafé A, 2828-2833. doi:10.1161/STROKEAHA.110.594333 Andersson T, Gralla J; Solitaire Group. Retrospective jama.com (Reprinted) JAMA January 19, 2021 Volume 325, Number 3 253

Supplement 1

Initial protocol

Direct mechanical thrombectomy in acute LVO stroke (SKIP study): a randomized controlled trial

Research Plan UMIN 000021488

Principal Investigator: Kazumi Kimura, Department of Neurology, Nippon Medical School

113-8603 1-1-5, Sendagi, Bunkyo-ku, Tokyo Tel: 03-3822-2131 (extension 4050) Fax: 03-3822-4865 E-mail: [email protected]

Planned Study period: From November 1st, 2016 to October 30th, 2019 This research plan has created May 2nd, 2016 This research plan has accepted November 1st, 2016

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Table of Contents

Initial protocol 1. Study Organization ...... 5

2. Introduction and Rationale ...... 7

3. Purpose of the study ...... 7

4. Study period ...... 8

5. Study site ...... 8

6. Sample size ...... 8

7. Drugs and devices used in the study ...... 8

8. Patient population ...... 8

9. Informed consent ...... 10

10 Study design...... 11 11 Study outcome………………………………………………………………………………… 12

12. Observational items and examinations ...... 13

13. Study discontinuation ...... 15

14. Adverse events ...... 16

15. Statistical Analysis Plan...... 17

16. Privacy policy ...... 17

17. Consideration for safety or disadvantage ...... 17

18. Publish policy about the results of the study ...... 18

19. Cost burden for participants ...... 18

20. Compensation for health hazards...... 18

21. Monitoring and auditing ...... 19

22. Response to ethical guidelines and the Declaration of Helsinki ...... 19

23. Storage and disposal of samples and information ...... 19

24. Registration of research plan and publication of research results ...... 20

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25. Information on research funding sources and conflicts of interest...... 20

26. Attribution of intellectual property rights ...... 20

27. Content and method of reporting to the director of the institution ...... 20

28. References and materials ...... 20

Final protocol 1. Study Organization ...... 24

2. Introduction and Rationale ...... 26

3. Purpose of the study ...... 26

4. Study period ...... 27

5. Study site ...... 27

6. Sample size ...... 27

7. Drugs and devices used in the study ...... 27

8. Patient population ...... 27

9. Informed consent ...... 29

10 Study design...... 30

11. Study outcome ...... 31

12. Observational items and examinations ...... 32

13. Study discontinuation ...... 34

14. Adverse events ...... 35

15. Statistical Analysis Plan...... 36

16. Privacy policy ...... 36

17. Consideration for safety or disadvantage ...... 37

18. Publish policy about the results of the study ...... 37

19. Cost burden for participants ...... 37

20. Compensation for health hazards...... 37

21. Monitoring and auditing ...... 38

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22. Response to ethical guidelines and the Declaration of Helsinki ...... 38

23. Storage and disposal of samples and information ...... 38

24. Registration of research plan and publication of research results ...... 39

25. Information on research funding sources and conflicts of interest...... 39

26. Attribution of intellectual property rights ...... 39

27. Content and method of reporting to the director of the institution ...... 39

28. References and materials ...... 40

A summary of all protocol changes……………………………………………………………… 42

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Tranomon Hospital Wataro Tsuruta Chief 03-3588-1111 Tokyo Metropolitan Tama Medical Center Takahiro Ota Chief 042-323-5111 Masayuki Ueda Chief The Jikei University Yasuyuki Iguchi Professor 03-3433-1111 Toshihiro Ishibashi Asssociate Professor Kyorin University Teruyuki Hirano Professor 0422-47-5511 Tatsuo Amano Assistant Professor Tsukuba University Yuji Matsumaru Professor 029-893-3900 Mikito Hayakawa Lecturer Jichi Medical University Shigeru Fujimoto Professor 0285-5-3111 Showa University Koto Toyosu hospital Yuki Kamiya Associate Professor 03-6204-6489 Tokyo Medical and Dental University Kazunori Miki Assistant Professor 03-3813-6111 Yokohamashintoshi Neurosurgical Hospital Masafumi Morimoto Director 045-911-2011 Mitsuhiro Iwasaki Chief Mihara Memorial Hospital Kazunori Akaji Chief 0270-24-3355 Akiyama Neurosurgical Hospital Yohei Takayama Chief 0458421838 Nagareyama Central Hospital Ryuzaburo Kanazawa Associate Professor 04-7154-5741 Tetsuhiro Higashida Chief New Tokyo Hospital Norihiro Ishii Chief 047-711-8700 Funabashi Municipal Medical Center Hiromichi Naito Chief 047-438-3321 Seisyo Hospital Masataka Takeuchi Chief 0465-35-5773 Dokkyo Medical School Koshigaya Hospital Tomoji Takigawa Professor 048-965-1111

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National Hospital Organization Disaster Keigo Shigeta Chief 042-536-5511 Medical Center Mito Medical Center Noriyuki Kato Chief 029-240-7711 National Center for Global Health and Masato Inoue Chief 03-3202-7181 Medicine Tokyo Medical University Takaaki Hashimoto Lecturer 03-3342-6111 Tokyo Medical University Hachioji Medical Junya Turukiri Lecturer 042-665-5611 Center NTT Medical Center Tokyo Seiji Okubo Chief 03-3448-6111 Chiba Emergency Medical Center Yorio Koguchi Chief 043-279-2111 Nippon Medical School Public Health Toshiaki Otsuka Asssociate Professor 03-3822-2131 3) Study Secretariat Department of Neurology, Nippon Medical School Kentaro Suzuki (representative), Naoko Akazawa, Yuko Ota Postal code: 113-8603 1-1-5, Sendagi, Bunkyo-ku, Tokyo Tel: 03-3822-2131 (extension 5838) 4) Protocol Manager Leader: Kazumi Kimura; Department of Neurology, Nippon Medical School Committee: Kentaro Suzuki; Department of Neurology, Nippon Medical School 5) Allocation Manager Kentaro Suzuki; Department of Neurology, Nippon Medical School 6) Data Manager Hiroshi Nagayama; Department of Neurology, Nippon Medical School 7) Data monitoring and safety board Akio Morita; Department of Neurosurgery, Nippon Medical School 8) Statistical Manager Toshiaki Otsuka; Department of Public Health, Nippon Medical School 9) Event evaluation committee Hiroyuki Yokota; Department of Critical Care Medicine, Nippon Medical School 10) Radiological Judgement committees Teruyuki Hirano; Department of Stroke Medicine, Kyorin University Shigeru Fujimoto; Department of Neurology, Jichi University

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2. Introduction and Rationale Recombinant tissue-plasminogen activator (rt-PA) was approved by the authority in 2005 in Japan and widely used as a standard treatment for patients with acute ischemic stroke. However, it is also known that rt-PA has limited effect for patients with large vessel occlusion (LVO); previous studies showed the recanalization rate was as low as 5.9% in patients with internal carotid artery (ICA) and 16.7% in those with proximal middle cerebral artery horizontal segment (MCA M1) occlusion.1, 2 As the progress in devises, the reperfusion therapy for patients with LVO with mechanical thrombectomy (MT) can dramatically improve the recanalization rate. Randomized controlled trials (RCTs) presented around 2015 showed that adding MT could improve recanalization rate and outcome, compared with rt-PA treatment.3-7 In these RCT, onset-to-reperfusion time played a critical role and shorter onset-reperfusion time lead better outcome.8 Indeed, 59% of the recanalized patients within 300 min achieved good functional outcome, it declined to 32% when recanalization was attained after 300 min from symptom onset. Shorter onset-to-groin puncture time was reported to be also associated with better outcome,9 so reducing onset-to-puncture and -reperfusion time is needed in managing acute stroke patients with LVO. Under the current guidelines, MT should be conducted in conjunction with rt-PA, when patients have indications for rt-PA. Therefore, there is no RCTs investigating the effectiveness of MT without rt-PA. One retrospective study revealed that MT without rt-PA, compared with MT plus rt-PA, reduced hemorrhagic complications and mortality.10 To skip rt-PA can reduce hemorrhagic complications and achieve better outcome. Therefore, we conduct prospective, multicentre RCT to elucidate the efficacy of MT without rt-PA for hyperacute ischemic stroke patients with LVO.

3. Purpose of the study The aims of the present study is to elucidate the difference in clinical outcome, hemorrhagic complications, onset-to-reperfusion time, and the rate of effective recanalization between MT with and without rt-PA in acute stroke patients with LVO.

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4. Study period From November 1st, 2016 through October 30th, 2019 (study entry ends July 31st, 2019).

5. Study site Department of Neurology, Nippon Medical School hospital

6. Sample size Poor outcome (modified Rankin scale [mRS] 5 or 6, 3 months after stroke onset) was assumed to be 47.5% in the MT without rt-PA group and 25% in the MT with rt-PA group, the required number of patients is calculated to be 67 patients in each group, for a total of 134 patients. Assuming a dropout rate, 200 patients (100 patients in each group) has been set.

7. Drugs and devices used in the study 1) Information about drugs and devices Drug: alteplace (Activacin [Kyowa Hakko Kirin] and Grtpa [Tanabe Mitsubishi Pharmacy]) Devices: Devices used for revascularization, such as: Penumbra (Medico’s Hirata), Trevo (Stryker), Solitaire (Medtronic), Revive (Johnson & Johnson), Gateway PTA Catheter, Wangspan stent, Precice, Carotid Wall stent, and PROTÉGÉ. 2) Expected adverse effect of the drugs or malfunction of the devices Hemorrhagic complications are known as adverse effects of these drugs and devices. When severe hemorrhagic complication occurs, every treatment is based on taking the highest priority on participants’ safety.

8. Patient population 1) Patient condition Ischemic stroke 2) Inclusion criteria Inclusion criteria

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1. Age ≥18 and <86 years at the time of informed consent 2. Clinical diagnosis of acute ischemic stroke with clinical symptoms 3. Modified Rankin scale score ≤2 4. ICA or M1 occlusion on MRA or CTA 5. Initial NIHSS ≥6 6. ASPECTS on initial DWI ≥5 or on initial CT ≥6 7.Onset to randomization within 4 h from onset. (Recomendation topuncture within 30 min from randomization) 8. Written informed consent by patient or next of kin.

Reasons for inclusion 1. Effectiveness of endovascular treatment for children has not been established, and in many elderly patients it is difficult to perform endovascular treatment due to meandering of blood vessels. 2. Since some cases show rapid improvement due to spontaneous recanalization, we targeted cases where the symptoms persisted. 3. To fairly assess outcomes 90 days after symptom onset. 4. The efficacy of endovascular therapy has been proven in patients with ICA or M1 occlusion. 5. The above items with sufficient evidence to benefit from reperfusion were targeted, based on past reports. 6. The above items with sufficient evidence to benefit from reperfusion were targeted, based on past reports. 7. When assigned to the EVT without rt-PA group but the EVT is difficult to perform (e.g., running of the blood vessel), there will be clear disadvantage to the patients allocated to the EVT without rt-PA group. To prevent this, we included it in the selection criteria so that intravenous rt-PA therapy could be performed in cases where EVT was difficult. 8. As in previous reports, we include patients with the consent.

3) Exclusion criteria Exclusion criteria

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1. Contraindication for contrast agent or endovascular therapy 2. Contraindication for IVT. 3. Presence of severe renal disorder (patients undergoing dialysis can be included) 4. Pregnancy or possibility of pregnancy 5. Unlikely to complete the study, such as due to progressive malignant tumor 6. Judged incompatible with the study by the investigators

Reason for exclusion 1. 2. 3. 4. Since it is considered that angiography is not recommended in such situation. In the present study, only cases where both rt-PA intravenous therapy and EVT can be performed are included. 5.In order to fairly evaluate the outcome 90 days after onset. 6.In order to ensure the safety of the study subjects and appropriately carry out the study.

9. Informed consent Before enrollment, physicians in charge must explain about this study with written and verbal explanation to all potential patients and/or their close relatives, using materials approved by institutional review board (IRB) in Nippon Medical School. Physicians guarantee potential patients and/or their close relatives chances to ask questions and sufficient time to decide whether they attend the study or not. Physicians in charge obtain informed consent from the potential patients after confirming their understanding and free will. When new information about efficacy and safety of rt-PA or MT, that may affect the participants’ attendance to this study, written materials must be revised after IRB approval, and re-consent is obtained from the patients or their close relatives. Because the potential patients for this study have stroke, consent from their close relatives is permitted due to difficulty in obtaining consent because of disturbance of consciousness, aphasia, or weakness. When the consent is obtained from patients’ relatives, the closest relative should be selected. Moreover, explanation to the patient must not be omitted even if the informed consent is obtained from relatives. We have prepared the written explanation with easy expression so as potential patients and their relatives can understand.

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10 Study design 1) The kind of the study and study design The kind of the study: interventional Study design: multicentre, randomized, open-label study 2) Outline of the study To elucidate the efficacy of MT without rt-PA, compared with MT with rt-PA, randomized controlled study is conducted. Medical history taking and examinations are performed just before the informed consent and physicians ascertain the eligibility. When cessation of participation is applied from the patients or their relatives, patients are immediately removed from the study.

[MT without rt-PA group] MT without rt-PA Rt-PA therapy will be performed when MT is difficult to perform. MT is regarded as difficult when time from groin puncture to guiding catheter placement exceeds 30 min. [MT with rt-PA] MT is performed after rt-PA therapy. 3) Rt-PA should be administered within 4.5 hours from symptom onset. The amount of 0.6mg/kg (maximum of 60 mg) is administered, 10% as bolus, and the rest of 90% as continuous infusion over one hour. 4) Concomitant treatment Below drugs must not concomitantly used within 24 hours after rt-PA therapy: warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban. 5) Management and delivery of the drugs and the devices

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The pharmaceutical and mechanical treatment performed in this study is approved as the treatment for stroke by the authority in Japan. Physicians use drugs or devices in the individual hospital. 6) Medication guidance Not applicable 7) Case enrolment and random allocation Physicians in charge should try to include all the patients who meet the inclusion criteria, and not to exclude from the study deliberately. Immediately after confirmation of LVO and obtaining consent from the patient, physicians allocated patients into specific group and avoiding treatment delay due to participation to this study. The allocation is conducted with web-based system. After entering institutional ID and password, and completion of checklist, the system presents the results of allocation: A) MT without rt-PA B) MT with rt-PA 8) Patients eligibility Physicians in charge must ascertain that the patients satisfy all the inclusion criteria and not correspond to none of the exclusion criteria (see p. 7-9). 9) Treatment after study participation In this study, standard medical treatment is provided after hyperacute management, so standard medical treatment is continued to be provided for patients belonging to both groups. 10) Biological samples from study participants In this study, biological sample from study participants is used only for study outcomes. All samples are discarded after anonymization. The storage period for case report forms ends the latter day of 5 years after announcement of study completion or 3 years after final result of the study is published.

11. Study outcome Rationale for outcomes Primary efficacy endpoint Poor outcome defined as mRS score 5-6 at 90 days after stroke onset (superior) Secondary efficacy endpoints The mRS score at 90 days (shift analysis, non-inferior)

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Favorable outcome defined as mRS score 0-1 at 90 days after stroke onset Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset Favorable outcome defined as mRS score 0-3 at 90 days after stroke onset Favorable outcome defined as mRS score 0-1 at 90 days after stroke onset (non-inferior) Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset (non-inferior) Favorable outcome defined as mRS score 0-3 at 90 days after stroke onset (non-inferior) Improvement of mRS score as of 90 days after stroke onset Reperfusion of TICI score 2b or 3 at the end of EVT Recanalization of modified Mori grade 2 or 3 at 72 h after stroke onset Safety endpoints Any ICH on CT or MRI within 36 h after stroke onset. sICH as defined by NINDS and SITS-MOST criteria within 36 h after stroke onset. Major bleeding as defined by fatal bleeding, symptomatic bleeding in a critical area or organ, such as intraspinal, intraocular or bleeding causing a fall in hemoglobin ≥3 g/dL, or leading to transfusion of whole blood or red cells within 24 h after stroke onset

12. Observational items and examinations 1) Patients backgrounds Sex, Age, Height, Weight Vascular risk factors (Hypertension, Diabetes mellitus, Dyslipidemia, Atrial fiblliration, Chronic kidney disease, Heart failure, and smoking history) Past history of cerebrovascular diseases (Transient ischemic attack, Ischemic stroke, Intracerebral haemorrhage, and Subarachnoid haemorrhage) Past history of cardiovascular diseases (Myocardial infarction, Angina pectoris, peripheral artery disease) 2) Physical examinations, Imaging examinations Blood pressure and heart rate on admission NIHSS score: on admission, 24 h (±8 h) and 72 h (±8 h) after treatment, on discharge Premorbid mRS

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Imaging: ASPECTS on CT or DWI-ASPECTS on DWI (as positive include small lesions)before treatment Pre-treatment DWI and FLAIR more than 1 week after treatment T2* on admission (presence of microbleeds and SVS) Vascular imaging: Occluded vessel on CTA or MRA TICI score just after EVT treatment Presence of tandem lesion State of recanalization (using modified Mori grade) on MRA or CTA 48 h (± 24h) after treatment Time metrics: Onset-to-door, Door-to-groin puncture, Puncture-to-recanalization, Door-to-needle, and Door-to-randomization. 3) Treatment details Blood pressure before treatment IV rt-PA therapy: onset-to-needle time EVT: Onset-to-reperfusion time (or time from symptom onset to final angiogram when no reperfusion is achieved), number of pass, methods (mechanical thrombectomy, angioplasty, or local fibrinolysis), devices (Penumbra, Trevo, Solitaire, Revive, balloons, and intracranial stents), intra-arterial drug infusion (urokinase or rt-PA) Adverse events: Any intracerebral hemorrhage within 36 h and 7 days (±1 day) after treatment, Symptomatic intracerebral hemorrhage (SITS-MOST criteria and NINDS criteria), and other hemorrhagic complications. 4) Vital signs and laboratory data Blood pressure (on admission, before treatment), Heart rate, Body temperature Laboratory data: (WBC, Hemoglobin, Platelet count, Glucose, HbA1c, BNP, PT-INR, aPTT) Anticoagulant drugs, Antiplatelets, or Statins before admission 5) Follow-up mRS 90 days (±10 days) after onset (When mRS increase from pre-morbid mRS, denote whether the deterioration is due to stroke) a physician or clinical research coordinator who is blinded to treatment assignment assesses the mRS by telephone interview at 90 days. Etiology (TOAST criteria) Symptomatic recurrence during admission Surgical intervention

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6) Other adverse events Other adverse events are defined as all unfavorable events such as abnormal laboratory values and adverse reactions, regardless of causal relationship with drugs or treatments. Describe the details of adverse effects, timing of onset / recover, degree, treatment, outcome, severity assessment, and relevance with the study drug or treatment in the medical chart and case report form. Follow up if necessary. The severity of adverse events is defined as (1) mild: the state that study participation can be continued without treatment, (2) moderate: the state that study participation can be continued with treatment, and (3) severe: the state that study participation should be suspended.

13. Study discontinuation 1) Study discontinuation criteria for each participant Study participants who meet the below situation will be excluded from this study. i. Offer to decline participation or withdrawal of consent from the patient or their representatives. ii. Find out not to meet the inclusion criteria after study participation iii. The study terminates early iv. Difficult to study participation due to adverse events v. The participant should be excluded from the study for other reasons than the above, judged by the attending physician When the participant is excluded from this study, the date, reason, or situation of discontinuation will be recorded on their medical chart and case report form. Appropriate examinations will be performed on discontinuation to evaluate the efficacy and safety. When participants are excluded before treatment, patients will be informed about and treated with standard treatment. Physicians consider patients not to suffer disadvantages. 2) Study discontinuation criteria for this study Principal investigator consider study termination when: i. Obtaining serious information about safety or efficacy about the study ii. Predicted risks seem to overwhelm the expected benefit iii. Difficulty in recruiting participants and achieving the intended sample size iv. Purpose of the study is achieved before study completion v. Recommendation of termination is published from the institutional review board, or instructions to protocol change but difficult to accept the instruction

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When terminating the study, principal investigator report study termination and its reason to the director of the institution, with written documents.

14. Adverse events 1) Management of adverse events Investigators must conduct appropriate treatment immediately when participants show unfavourable medical conditions (adverse events) such as hemorrhagic complications, and describe the adverse events on medical chart and case report form. When adverse events are decided to be severe, follow the instructions below 2) management of severe adverse events. 2) Management of severe adverse events When severe adverse events occur, principal investigator conduct appropriate treatment immediately, and promptly reports it to the director of the institution and institutional IRB. Principal investigator also reports it to investigator in other institutions. Severe adverse events include not only adverse events occurred within the study period, but also severe adverse events occurred after study completion and suspected to be associated with the study. 3) Definition of severe adverse events i. Death, or events potentially lead death ii. Hospital admission or extension of hospital stay due to treatment iii. Disability or events potentially lead disability iv. Severe status according to above criteria 4) Matters to be included about severe adverse events i. Name of adverse event ii. Time of occurrence iii. Outcome (e.g., improve, unchanged, recovery, or death) iv. Time course v. Relevance to the study a. No relevance b. Probably no relevance c. Probably relevant d. Relevant

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When severe adverse events are assessed no/probably no relevance to the study, presumed cause of the adverse events should be reported.

15. Statistical Analysis Plan The primary study outcome measure was superiority of the poor outcome at 90 days. We first used unadjusted logistic regression to test whether direct MT therapy was superior to bridging therapy. The secondary efficacy analyses included the comparison of ordinal scores on the modified Rankin scale to test for the noninferiority of the direct MT vs bridging therapy with ordinal logistic regression (shift analysis), where the OR is calculated for each cut-point across the mRS (for example, 0 versus 1–6, then 0–1 versus 2–6, and so on), and then a summary OR is calculated from the individual ORs, under the assumption that the individual ORs are the same. We also performed secondary analyses of the primary outcome with adjustment for minimization and key prognostic covariates, as well as secondary analyses in the per-protocol population. Next, clinical characteristics, recanalization success rate, hemorrhagic event rate (Any ICH, symptomatic ICH and other hemorrhagic complication), and other MT parameters were compared between the two groups. For ease of interpretation, all reported P-values are multiplied by 2, so that an alpha of 0.05 can be used in analyses. The other P-values are two-sided. All P-values were pre-specified not to be adjusted. JMP version 11 software (SAS Institute, Cari, NC) was used the analysis.

16. Privacy policy 1) When treating raw data or consent forms, consider participants’ privacy. 2) Identifying code is used in forms submitted to outside hospital, instead of names. 3) Correspondence table between participants’ name and identifying code is strictly kept in the department of neurology. 4) When the results of the study are reported, no identifiable information is included. 5) Acquired data in the study is exclusively used for the study.

17. Consideration for safety or disadvantage When adverse events are occurred, appropriate examination and treatment are performed promptly. Hemorrhagic complication can be occurred as a serious complication in this study. Prompt action is required for each sites and declared in this protocol (see Section 14. Adverse events).

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18. Publish policy about the results of the study Measurements or examinations required in this study is frequently tested in acute stroke management, and the results of examinations are reported to the patients or relatives. The results of this study is published promptly after completion of the study (see Section 24. Registration of research plan and publication of research results)

19. Cost burden for participants Medical check-ups, measurements, examinations, and treatment in this study is totally under the public health insurance. No drugs or procedures beyond public health insurance is used or performed in this study. So, additional fee for participation to this study are not expected.

20. Compensation for health hazards All treatments and examinations are conducted under the public health insurance. Health hazards attributable to this study are also treated under the public health insurance. Organisation, institutions, or individuals such as physician in charge involved in this study will not compensate the participants’ self-pay burden, leave compensation, and additional hospital charge associated with extension of admission. Physicians in charge manage in- hospital resources to treat participants’ health damage promptly and appropriately. This study has clinical trial insurance for health hazards potentially attributable to this study. All the stuffs involved in this study are insured, and clinical trial insurance covers health damage (including death) to study participants from start of this study through one year after study completion. Clinical trial insurance covers: (1) Economic burden of the insureds’ legal liability for study participants (except from medical procedures). (2) Economic burden of the insureds’ liability for health hazards for study participants that is not clearly shown to have no relation to this study. This compensation is based on health damage compensation standard*, which is written in informed consent forms. *Health damage compensation standard In the event that death or physical disability corresponding to the first or second class of the sequelae according to the separate table of the Enforcement Order of the

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Pharmaceuticals and Medical Devices Agency, The compensation will be paid with reference to the payment of the health damage relief business (hereinafter referred to as the “side effect damage relief system”) due to side effects or infection with biological products. Investigators are mandatory required to purchase doctor liability insurance in preparation for liability. If a remedy for adverse drug reaction is available, investigators explain it to the study participants and work to ensure smooth claiming of benefits.

21. Monitoring and auditing Described separately.

22. Response to ethical guidelines and the Declaration of Helsinki This study will be conducted in compliance with the ethical guidelines for medical research on human health (Ministry of Health, Labor and Welfare, Japan, Dec. 2014) and the Helsinki Declaration.

23. Storage and disposal of samples and information Samples and information related to this study (including copy of application documents, notification form, copy of various application forms and reports, study participants identification code list, consent form, copy of case report, and other data necessary to guarantee the reliability for data) are securely stored in Department of Neurology, Nippon Medical School, for a period of 5 years after the end of the study was reported, or 3 years from the date of reporting the final publication of the results of the study, whichever is later, and that information is not available outside this study. After the storage period, discard the samples and information in an unidentified (anonymized) state.

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24. Registration of research plan and publication of research results The research plan of this study is registered in the University hospital Medical Information Network (UMIN). For assignment and data registration, use those created by ShibaSho Co., Ltd. Regardless of the outcome, the results of this study will be submitted to the journal by the principal investigator or collaborator as soon as possible after the end of the study. The results obtained in this study will be jointly announced by the participating facilities.

25. Information on research funding sources and conflicts of interest All the medical treatments in this study are performed under public health insurance. Insurance fee and miscellaneous expenses will be covered by research expenses from the Department of Neurology, Nippon Medical School. There are no conflicts of interest to report for this study.

26. Attribution of intellectual property rights If intellectual property rights such as patent rights are found from the results of this study, they belong to the research institution or the researcher that conducts this study.

27. Content and method of reporting to the director of the institution The principal investigator shall report the progress of the study to the director of the hospital and the IRB every year after the approval. In addition, reports will be made each time the study is stopped or completed. The principal investigator shall promptly report to the director of the hospital and the IRB, when principal investigator acknowledges the occurrence of a serious adverse event, protocol deviation, needs to change or revise the protocol, and the protcol does not meet the current guidelines.

28. References and materials References

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1. Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S, Akhtar N, Orouk FO, Salam A, Shuaib A, Alexandrov AV, Investigators C. Site of arterial occlusion identified by transcranial doppler predicts the response to intravenous thrombolysis for stroke. Stroke. 2007;38:948-954 2. Hirano T, Sasaki M, Mori E, Minematsu K, Nakagawara J, Yamaguchi T, Japan Alteplase Clinical Trial IIG. Residual vessel length on magnetic resonance angiography identifies poor responders to alteplase in acute middle cerebral artery occlusion patients: Exploratory analysis of the japan alteplase clinical trial ii. Stroke. 2010;41:2828-2833 3. Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, Albers GW, Cognard C, Cohen DJ, Hacke W, Jansen O, Jovin TG, Mattle HP, Nogueira RG, Siddiqui AH, Yavagal DR, Baxter BW, Devlin TG, Lopes DK, Reddy VK, du Mesnil de Rochemont R, Singer OC, Jahan R, Investigators SP. Stent-retriever thrombectomy after intravenous t-pa vs. T-pa alone in stroke. N Engl J Med. 2015;372:2285-2295 4. Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, San Roman L, Serena J, Abilleira S, Ribo M, Millan M, Urra X, Cardona P, Lopez-Cancio E, Tomasello A, Castano C, Blasco J, Aja L, Dorado L, Quesada H, Rubiera M, Hernandez-Perez M, Goyal M, Demchuk AM, von Kummer R, Gallofre M, Davalos A, Investigators RT. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372:2296-2306 5. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, Roy D, Jovin TG, Willinsky RA, Sapkota BL, Dowlatshahi D, Frei DF, Kamal NR, Montanera WJ, Poppe AY, Ryckborst KJ, Silver FL, Shuaib A, Tampieri D, Williams D, Bang OY, Baxter BW, Burns PA, Choe H, Heo JH, Holmstedt CA, Jankowitz B, Kelly M, Linares G, Mandzia JL, Shankar J, Sohn SI, Swartz RH, Barber PA, Coutts SB, Smith EE, Morrish WF, Weill A, Subramaniam S, Mitha AP, Wong JH, Lowerison MW, Sajobi TT, Hill MD, Investigators ET. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019-1030 6. Campbell BC, Mitchell PJ, Investigators E-I. Endovascular therapy for ischemic stroke. N Engl J Med. 2015;372:2365-2366 7. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, van Walderveen MA, Staals J, Hofmeijer J, van Oostayen JA, Lycklama a Nijeholt GJ, Boiten J, Brouwer PA, Emmer BJ, de Bruijn SF, van Dijk LC, Kappelle LJ, Lo RH, van Dijk EJ, de Vries J, de Kort PL, van Rooij WJ, van den Berg JS, van Hasselt BA, Aerden LA, Dallinga RJ, Visser MC, Bot JC, Vroomen PC, Eshghi O, Schreuder TH, Heijboer RJ, Keizer K, Tielbeek AV, den Hertog

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HM, Gerrits DG, van den Berg-Vos RM, Karas GB, Steyerberg EW, Flach HZ, Marquering HA, Sprengers ME, Jenniskens SF, Beenen LF, van den Berg R, Koudstaal PJ, van Zwam WH, Roos YB, van der Lugt A, van Oostenbrugge RJ, Majoie CB, Dippel DW, Investigators MC. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:11-20 8. Hwang YH, Kang DH, Kim YW, Kim YS, Park SP, Liebeskind DS. Impact of time-to- reperfusion on outcome in patients with poor collaterals. AJNR Am J Neuroradiol. 2015;36:495-500 9. Prabhakaran S, Ruff I, Bernstein RA. Intervention for acute stroke--reply. JAMA. 2015;314:626-627 10. Broeg-Morvay A, Mordasini P, Bernasconi C, Buhlmann M, Pult F, Arnold M, Schroth G, Jung S, Mattle HP, Gralla J, Fischer U. Direct mechanical intervention versus combined intravenous and mechanical intervention in large artery anterior circulation stroke: A matched-pairs analysis. Stroke. 2016;47:1037-1044

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Final protocol

Direct mechanical thrombectomy in acute LVO stroke (SKIP study): a randomized controlled trial

Research Plan UMIN 000021488

Principal Investigator: Kazumi Kimura, Department of Neurology, Nippon Medical School

113-8603 1-1-5, Sendagi, Bunkyo-ku, Tokyo Tel: 03-3822-2131 (extension 4050) Fax: 03-3822-4865 E-mail: [email protected]

Planned Study period: From November 1st, 2016 to October 30th, 2019 This research plan has created May 2nd, 2016 This research plan has accepted November 1st, 2016 This research plan has revised June 8th, 2018

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1. Study Organization 1) Principal investigator Kazumi Kimura, Department of Neurology, Nippon Medical School Yuji Matsumaru, Department of Neurosurgery, Tsukuba University 2) Study site and investigators in charge Study site Investigator Title Contact Nippon Medical School Kazumi Kimura Professor 03-3822-2131 Kentaro Suzuki Assistant Professor Junya Aoki Lecturer Yasuhiro Nishiyama Asssociate Professor Tranomon Hospital Wataro Tsuruta Chief 03-3588-1111 Tokyo Metropolitan Tama Medical Center Takahiro Ota Chief 042-323-5111 Masayuki Ueda Chief The Jikei University Yasuyuki Iguchi Professor 03-3433-1111 Toshihiro Ishibashi Asssociate Professor Kyorin University Teruyuki Hirano Professor 0422-47-5511 Tatsuo Amano Assistant Professor Tsukuba University Yuji Matsumaru Professor 029-893-3900 Mikito Hayakawa Lecturer Jichi Medical University Shigeru Fujimoto Professor 0285-5-3111 Showa University Koto Toyosu hospital Yuki Kamiya Associate Professor 03-6204-6489 Tokyo Medical and Dental University Kazunori Miki Assistant Professor 03-3813-6111 Yokohamashintoshi Neurosurgical Hospital Masafumi Morimoto Director 045-911-2011 Mitsuhiro Iwasaki Chief Mihara Memorial Hospital Kazunori Akaji Chief 0270-24-3355 Akiyama Neurosurgical Hospital Yohei Takayama Chief 0458421838 Nagareyama Central Hospital Ryuzaburo Kanazawa Associate Professor 04-7154-5741 Tetsuhiro Higashida Chief New Tokyo Hospital Norihiro Ishii Chief 047-711-8700 Funabashi Municipal Medical Center Hiromichi Naito Chief 047-438-3321 Seisyo Hospital Masataka Takeuchi Chief 0465-35-5773 Dokkyo Medical School Koshigaya Hospital Tomoji Takigawa Professor 048-965-1111

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National Hospital Organization Disaster Keigo Shigeta Chief 042-536-5511 Medical Center Mito Medical Center Noriyuki Kato Chief 029-240-7711 National Center for Global Health and Masato Inoue Chief 03-3202-7181 Medicine Tokyo Medical University Takaaki Hashimoto Lecturer 03-3342-6111 Tokyo Medical University Hachioji Medical Junya Turukiri Lecturer 042-665-5611 Center St. Marianna University Toyoko Hospital Toshihiro Ueda Vice Director 044-977-8111 NTT Medical Center Tokyo Seiji Okubo Chief 03-3448-6111 Chiba Emergency Medical Center Yorio Koguchi Chief 043-279-2111 Nippon Medical School Public Health Toshiaki Otsuka Asssociate Professor 03-3822-2131 3) Study Secretariat Department of Neurology, Nippon Medical School Kentaro Suzuki (representative), Naoko Akazawa, Yuko Ota Postal code: 113-8603 1-1-5, Sendagi, Bunkyo-ku, Tokyo Tel: 03-3822-2131 (extension 5838) 4) Protocol Manager Leader: Kazumi Kimura; Department of Neurology, Nippon Medical School Committee: Kentaro Suzuki; Department of Neurology, Nippon Medical School 5) Allocation Manager Kentaro Suzuki; Department of Neurology, Nippon Medical School 6) Data Manager Hiroshi Nagayama; Department of Neurology, Nippon Medical School 7) Data monitoring and safety board Akio Morita; Department of Neurosurgery, Nippon Medical School 8) Statistical Manager Toshiaki Otsuka; Department of Public Health, Nippon Medical School 9) Event evaluation committee Hiroyuki Yokota; Department of Critical Care Medicine, Nippon Medical School 10) Radiological Judgement committees Teruyuki Hirano; Department of Stroke Medicine, Kyorin University

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Shigeru Fujimoto; Department of Neurology, Jichi University

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4. Study period From November 1st, 2016 through October 30th, 2019 (study entry ends July 31st, 2019).

5. Study site Department of Neurology, Nippon Medical School hospital

6. Sample size Favorable outcome (modified Rankin scale [mRS] 0-2, 3 months after stroke onset) was assumed to be 48.6% in the MT without rt-PA group and 35.2% in the MT with rt-PA group,11 the required number of patients is calculated to be 89 patients in each group, for a total of 178 patients. Assuming a dropout rate of 10%, 200 patients (100 patients in each group) has been set.

7. Drugs and devices used in the study 3) Information about drugs and devices Drug: alteplace (Activacin [Kyowa Hakko Kirin] and Grtpa [Tanabe Mitsubishi Pharmacy]) Devices: Devices used for revascularization, such as: Penumbra (Medico’s Hirata), Trevo (Stryker), Solitaire (Medtronic), Revive (Johnson & Johnson), Gateway PTA Catheter, Wangspan stent, Precice, Carotid Wall stent, and PROTÉGÉ. 4) Expected adverse effect of the drugs or malfunction of the devices Hemorrhagic complications are known as adverse effects of these drugs and devices. When severe hemorrhagic complication occurs, every treatment is based on taking the highest priority on participants’ safety.

8. Patient population 4) Patient condition Ischemic stroke 5) Inclusion criteria

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Inclusion criteria 1. Age ≥18 and <86 years at the time of informed consent 2. Clinical diagnosis of acute ischemic stroke with clinical symptoms 3. Modified Rankin scale score ≤2 4. ICA or M1 occlusion on MRA or CTA 5. Initial NIHSS ≥6 6. ASPECTS on initial DWI ≥5 or on initial CT ≥6 7.Onset to randomization within 4 h from onset. (Recomendation topuncture within 30 min from randomization) 8. Written informed consent by patient or next of kin.

6) Exclusion criteria Exclusion criteria

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10 Study design 11) The kind of the study and study design The kind of the study: interventional Study design: multicentre, randomized, open-label study 12) Outline of the study To elucidate the efficacy of MT without rt-PA, compared with MT with rt-PA, randomized controlled study is conducted. Medical history taking and examinations are performed just before the informed consent and physicians ascertain the eligibility. When cessation of participation is applied from the patients or their relatives, patients are immediately removed from the study.

[MT without rt-PA group] MT without rt-PA Rt-PA therapy will be performed when MT is difficult to perform. MT is regarded as difficult when time from groin puncture to guiding catheter placement exceeds 30 min. [MT with rt-PA] MT is performed after rt-PA therapy. 13) Rt-PA should be administered within 4.5 hours from symptom onset. The amount of 0.6mg/kg (maximum of 60 mg) is administered, 10% as bolus, and the rest of 90% as continuous infusion over one hour. 14) Concomitant treatment Below drugs must not concomitantly used within 24 hours after rt-PA therapy: warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban. 15) Management and delivery of the drugs and the devices

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The pharmaceutical and mechanical treatment performed in this study is approved as the treatment for stroke by the authority in Japan. Physicians use drugs or devices in the individual hospital. 16) Medication guidance Not applicable 17) Case enrolment and random allocation Physicians in charge should try to include all the patients who meet the inclusion criteria, and not to exclude from the study deliberately. Immediately after confirmation of LVO and obtaining consent from the patient, physicians allocated patients into specific group and avoiding treatment delay due to participation to this study. The allocation is conducted with web-based system. After entering institutional ID and password, and completion of checklist, the system presents the results of allocation: A) MT without rt-PA B) MT with rt-PA 18) Patients eligibility Physicians in charge must ascertain that the patients satisfy all the inclusion criteria and not correspond to none of the exclusion criteria (see p. 7-9). 19) Treatment after study participation In this study, standard medical treatment is provided after hyperacute management, so standard medical treatment is continued to be provided for patients belonging to both groups. 20) Biological samples from study participants In this study, biological sample from study participants is used only for study outcomes. All samples are discarded after anonymization. The storage period for case report forms ends the latter day of 5 years after announcement of study completion or 3 years after final result of the study is published.

11. Study outcome Primary efficacy endpoint Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset (non- inferior)(intention to treat analysis) Secondary efficacy endpoints The mRS score at 90 days (shift analysis, non-inferior)

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Poor outcome defined as mRS score 5-6 at 90 days after stroke onset Poor outcome defined as mortality at 90 days after stroke onset Favorable outcome defined as mRS score 0-1 at 90 days after stroke onset Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset Favorable outcome defined as mRS score 0-3 at 90 days after stroke onset Favorable outcome defined as mRS score 0-1 at 90 days after stroke onset (non-inferior) Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset (non-inferior)(per protocol analysis) Favorable outcome defined as mRS score 0-3 at 90 days after stroke onset (non-inferior) Improvement of mRS score as of 90 days after stroke onset Reperfusion of TICI score 2b or 3 at the end of EVT Recanalization of modified Mori grade 2 or 3 at 72 h after stroke onset Safety endpoints Any ICH on CT or MRI within 36 h after stroke onset. sICH as defined by NINDS and SITS-MOST criteria within 36 h after stroke onset. Major bleeding as defined by fatal bleeding, symptomatic bleeding in a critical area or organ, such as intraspinal, intraocular or bleeding causing a fall in hemoglobin ≥3 g/dL, or leading to transfusion of whole blood or red cells within 24 h after stroke onset

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NIHSS score: on admission, 24 h (±8 h) and 72 h (±8 h) after treatment, on discharge Premorbid mRS Imaging: ASPECTS on CT or DWI-ASPECTS on DWI (as positive include small lesions) before treatment Pre-treatment DWI and FLAIR more than 1 week after treatment T2* on admission (presence of microbleeds and SVS) Vascular imaging: Occluded vessel on CTA or MRA TICI score just after EVT treatment Presence of tandem lesion State of recanalization (using modified Mori grade) on MRA or CTA 48 (± 24h) after treatment Time metrics: Onset-to-door, Door-to-groin puncture, Puncture-to-recanalization, Door-to-needle, and Door-to-randomization. 3) Treatment details Blood pressure before treatment IV rt-PA therapy: onset-to-needle time EVT: Onset-to-reperfusion time (or time from symptom onset to final angiogram when no reperfusion is achieved), number of pass, methods (mechanical thrombectomy, angioplasty, or local fibrinolysis), devices (Penumbra, Trevo, Solitaire, Revive, balloons, and intracranial stents), intra-arterial drug infusion (urokinase or rt-PA) Adverse events: Any Intracerebral hemorrhage within 36 h and 7 days (±1 day) after treatment, Symptomatic intracerebral hemorrhage (SITS-MOST criteria and NINDS criteria), and other hemorrhagic complications. 4) Vital signs and laboratory data Blood pressure (on admission, before treatment), Heart rate, Body temperature Laboratory data: (WBC, Hemoglobin, Platelet count, Glucose, HbA1c, BNP, PT-INR, aPTT) Anticoagulant drugs, Antiplatelets, or Statins before admission 5) Follow-up mRS 90 days (±10 days) after onset (When mRS increase from pre-morbid mRS, denote whether the deterioration is due to stroke) the mRS was assessed by physical examination or telephone interview at 90 days after onset by a third independent observer, who was also blinded. Etiology (TOAST criteria)

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Symptomatic recurrence during admission Surgical intervention 6) Other adverse events Other adverse events are defined as all unfavorable events such as abnormal laboratory values and adverse reactions, regardless of causal relationship with drugs or treatments. Describe the details of adverse effects, timing of onset / recover, degree, treatment, outcome, severity assessment, and relevance with the study drug or treatment in the medical chart and case report form. Follow up if necessary. The severity of adverse events is defined as (1) mild: the state that study participation can be continued without treatment, (2) moderate: the state that study participation can be continued with treatment, and (3) severe: the state that study participation should be suspended.

13. Study discontinuation 3) Study discontinuation criteria for each participant Study participants who meet the below situation will be excluded from this study. vi. Offer to decline participation or withdrawal of consent from the patient or their representatives. vii. Find out not to meet the inclusion criteria after study participation viii. The study terminates early ix. Difficult to study participation due to adverse events x. The participant should be excluded from the study for other reasons than the above, judged by the attending physician When the participant is excluded from this study, the date, reason, or situation of discontinuation will be recorded on their medical chart and case report form. Appropriate examinations will be performed on discontinuation to evaluate the efficacy and safety. When participants are excluded before treatment, patients will be informed about and treated with standard treatment. Physicians consider patients not to suffer disadvantages. 4) Study discontinuation criteria for this study Principal investigator consider study termination when: vi. Obtaining serious information about safety or efficacy about the study vii. Predicted risks seem to overwhelm the expected benefit viii. Difficulty in recruiting participants and achieving the intended sample size ix. Purpose of the study is achieved before study completion

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x. Recommendation of termination is published from the institutional review board, or instructions to protocol change but difficult to accept the instruction When terminating the study, principal investigator report study termination and its reason to the director of the institution, with written documents.

14. Adverse events 5) Management of adverse events Investigators must conduct appropriate treatment immediately when participants show unfavourable medical conditions (adverse events) such as hemorrhagic complications, and describe the adverse events on medical chart and case report form. When adverse events are decided to be severe, follow the instructions below 2) management of severe adverse events. 6) Management of severe adverse events When severe adverse events occur, principal investigator conduct appropriate treatment immediately, and promptly reports it to the director of the institution and institutional IRB. Principal investigator also reports it to investigator in other institutions. Severe adverse events include not only adverse events occurred within the study period, but also severe adverse events occurred after study completion and suspected to be associated with the study. 7) Definition of severe adverse events v. Death, or events potentially lead death vi. Hospital admission or extension of hospital stay due to treatment vii. Disability or events potentially lead disability viii. Severe status according to above criteria 8) Matters to be included about severe adverse events vi. Name of adverse event vii. Time of occurrence viii. Outcome (e.g., improve, unchanged, recovery, or death) ix. Time course x. Relevance to the study a. No relevance b. Probably no relevance c. Probably relevant

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d. Relevant When severe adverse events are assessed no/probably no relevance to the study, presumed cause of the adverse events should be reported.

15. Statistical Analysis Plan The primary study outcome measure was noninferiority of the favorable outcome at 90 days. We first used unadjusted logistic regression to test whether direct MT therapy was noninferior to bridging therapy. To satisfy the noninferiority hypothesis, the lower bound of the one-sided 97.5% confidence interval for the odds ratio (OR) of the primary outcome of the Direct MT group compared with the Bridging group needed to exceed 0.74. This noninferiority margin was derived from a previous meta-analysis of bridging therapy compared with the best medical treatment,12 with the margin defined according to the upper bound of the 95% confidence interval for the OR of the primary outcome with standard medical care versus the combination of medical care and MT. The margin of 0.74 represents the midpoint between the upper bound of the 95% confidence interval of the estimated effect of the standard medical care and 1.0 (using bridging therapy with medical care and MT as a reference). The secondary efficacy analyses included the comparison of ordinal scores on the modified Rankin scale to test for the noninferiority of the direct MT vs bridging therapy with ordinal logistic regression (shift analysis), where the OR is calculated for each cut-point across the mRS (for example, 0 versus 1–6, then 0–1 versus 2–6, and so on), and then a summary OR is calculated from the individual ORs, under the assumption that the individual ORs are the same. We also performed secondary analyses of the primary outcome with adjustment for minimization and key prognostic covariates, as well as secondary analyses in the per-protocol population. Next, clinical characteristics, recanalization success rate, hemorrhagic event rate (Any ICH, symptomatic ICH and other hemorrhagic complication), mortality and other MT parameters were compared between the two groups. For ease of interpretation, all reported P-values for noninferiority are multiplied by 2, so that an alpha of 0.05 can be used in analyses. The other P-values are two-sided. All P-values were pre-specified not to be adjusted. JMP version 11 software (SAS Institute, Cari, NC) was used the analysis.

16. Privacy policy 1) When treating raw data or consent forms, consider participants’ privacy. 2) Identifying code is used in forms submitted to outside hospital, instead of names.

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3) Correspondence table between participants’ name and identifying code is strictly kept in the department of neurology. 4) When the results of the study are reported, no identifiable information is included. 5) Acquired data in the study is exclusively used for the study.

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This study has clinical trial insurance for health hazards potentially attributable to this study. All the stuffs involved in this study are insured, and clinical trial insurance covers health damage (including death) to study participants from start of this study through one year after study completion. Clinical trial insurance covers: (3) Economic burden of the insureds’ legal liability for study participants (except from medical procedures). (4) Economic burden of the insureds’ liability for health hazards for study participants that is not clearly shown to have no relation to this study. This compensation is based on health damage compensation standard*, which is written in informed consent forms. *Health damage compensation standard In the event that death or physical disability corresponding to the first or second class of the sequelae according to the separate table of the Enforcement Order of the Pharmaceuticals and Medical Devices Agency, The compensation will be paid with reference to the payment of the health damage relief business (hereinafter referred to as the “side effect damage relief system”) due to side effects or infection with biological products. Investigators are mandatory required to purchase doctor liability insurance in preparation for liability. If a remedy for adverse drug reaction is available, investigators explain it to the study participants and work to ensure smooth claiming of benefits.

21. Monitoring and auditing Described separately.

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identification code list, consent form, copy of case report, and other data necessary to guarantee the reliability for data) are securely stored in Department of Neurology, Nippon Medical School, for a period of 5 years after the end of the study was reported, or 3 years from the date of reporting the final publication of the results of the study, whichever is later, and that information is not available outside this study. After the storage period, discard the samples and information in an unidentified (anonymized) state.

39 Supplement 1

The principal investigator shall promptly report to the director of the hospital and the IRB, when principal investigator acknowledges the occurrence of a serious adverse event, protocol deviation, needs to change or revise the protocol, and the protcol does not meet the current guidelines.

28. References and materials References 1. Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S, Akhtar N, Orouk FO, Salam A, Shuaib A, Alexandrov AV, Investigators C. Site of arterial occlusion identified by transcranial doppler predicts the response to intravenous thrombolysis for stroke. Stroke. 2007;38:948-954 2. Hirano T, Sasaki M, Mori E, Minematsu K, Nakagawara J, Yamaguchi T, Japan Alteplase Clinical Trial IIG. Residual vessel length on magnetic resonance angiography identifies poor responders to alteplase in acute middle cerebral artery occlusion patients: Exploratory analysis of the japan alteplase clinical trial ii. Stroke. 2010;41:2828-2833 3. Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, Albers GW, Cognard C, Cohen DJ, Hacke W, Jansen O, Jovin TG, Mattle HP, Nogueira RG, Siddiqui AH, Yavagal DR, Baxter BW, Devlin TG, Lopes DK, Reddy VK, du Mesnil de Rochemont R, Singer OC, Jahan R, Investigators SP. Stent-retriever thrombectomy after intravenous t-pa vs. T-pa alone in stroke. N Engl J Med. 2015;372:2285-2295 4. Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, San Roman L, Serena J, Abilleira S, Ribo M, Millan M, Urra X, Cardona P, Lopez-Cancio E, Tomasello A, Castano C, Blasco J, Aja L, Dorado L, Quesada H, Rubiera M, Hernandez-Perez M, Goyal M, Demchuk AM, von Kummer R, Gallofre M, Davalos A, Investigators RT. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372:2296-2306 5. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, Roy D, Jovin TG, Willinsky RA, Sapkota BL, Dowlatshahi D, Frei DF, Kamal NR, Montanera WJ, Poppe AY, Ryckborst KJ, Silver FL, Shuaib A, Tampieri D, Williams D, Bang OY, Baxter BW, Burns PA, Choe H, Heo JH, Holmstedt CA, Jankowitz B, Kelly M, Linares G, Mandzia JL, Shankar J, Sohn SI, Swartz RH, Barber PA, Coutts SB, Smith EE, Morrish WF, Weill A, Subramaniam S, Mitha AP, Wong JH, Lowerison MW, Sajobi TT, Hill MD, Investigators ET. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019-1030 6. Campbell BC, Mitchell PJ, Investigators E-I. Endovascular therapy for ischemic stroke. N Engl J Med. 2015;372:2365-2366 7. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, van Walderveen MA, Staals J, Hofmeijer J, van Oostayen JA, Lycklama a Nijeholt GJ, Boiten J, Brouwer PA, Emmer BJ, de Bruijn SF, van Dijk LC, Kappelle LJ, Lo RH, van Dijk EJ, de Vries J, de Kort PL, van Rooij WJ, van den Berg JS, van Hasselt BA, Aerden LA, Dallinga RJ, Visser MC, Bot JC, Vroomen PC, Eshghi O, Schreuder TH, Heijboer RJ, Keizer K, Tielbeek AV, den Hertog HM, Gerrits DG, van den Berg-Vos RM, Karas GB, Steyerberg EW, Flach HZ, Marquering HA, Sprengers ME, Jenniskens SF, Beenen LF, van den Berg R, Koudstaal PJ, van Zwam WH, Roos YB, van der Lugt A, van Oostenbrugge RJ,

40 Supplement 1

Majoie CB, Dippel DW, Investigators MC. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:11-20 8. Hwang YH, Kang DH, Kim YW, Kim YS, Park SP, Liebeskind DS. Impact of time-to-reperfusion on outcome in patients with poor collaterals. AJNR Am J Neuroradiol. 2015;36:495-500 9. Prabhakaran S, Ruff I, Bernstein RA. Intervention for acute stroke--reply. JAMA. 2015;314:626-627 10. Broeg-Morvay A, Mordasini P, Bernasconi C, Buhlmann M, Pult F, Arnold M, Schroth G, Jung S, Mattle HP, Gralla J, Fischer U. Direct mechanical intervention versus combined intravenous and mechanical intervention in large artery anterior circulation stroke: A matched-pairs analysis. Stroke. 2016;47:1037-1044 11. Weber R, Nordmeyer H, Hadisurya J, Heddier M, Stauder M, Stracke P, Berger K, Chapot R. Comparison of outcome and interventional complication rate in patients with acute stroke treated with mechanical thrombectomy with and without bridging thrombolysis. J Neurointerv Surg. 2017;9:229-233 12. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, Davalos A, Majoie CB, van der Lugt A, de Miquel MA, Donnan GA, Roos YB, Bonafe A, Jahan R, Diener HC, van den Berg LA, Levy EI, Berkhemer OA, Pereira VM, Rempel J, Millan M, Davis SM, Roy D, Thornton J, Roman LS, Ribo M, Beumer D, Stouch B, Brown S, Campbell BC, van Oostenbrugge RJ, Saver JL, Hill MD, Jovin TG. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387:1723-1731

41 Supplement 1

A summary of all protocol changes

Dates of the change Pre change Post change 6/8/2018 1.Study organization Nippon Medical School: Add new member Yasuhiro Nishiyama

St. Marianna University Toyoko Hospital: Toshihiro Ueda Change the hospital name

6/8/2018 6.Sample size 6.Sample size Poor outcome (modified Rankin scale Favorable outcome (modified Rankin [mRS] 5 or 6, 3 months after stroke scale [mRS] 0-2, 3 months after onset) was assumed to be 47.5% in the stroke onset) was assumed to be MT without rt-PA group and 25% in 48.6% in the MT without rt-PA group the MT with rt-PA group, the required and 35.2% in the MT with rt-PA number of patients is calculated to be group,11 the required number of 67 patients in each group, for a total of patients is calculated to be 89 patients 134 patients. Assuming a dropout rate, in each group, for a total of 178 200 patients (100 patients in each patients. Assuming a dropout rate of group) has been set. 10%, 200 patients (100 patients in each group) has been set.

6/8/2018 11. Study outcomes 11. Study outcomes Primary efficacy endpoint: Primary efficacy endpoint: superiority of the rate of poor outcome noninferiority of the rate of favorable defined as mRS 5,6 outcome defined as mRS 0-2 11. Study outcomes 11. Study outcomes Secondary efficacy endpoint: Secondary efficacy endpoint: The mRS score at 90 days The mRS score at 90 days (shift noninferiority of the rate of favorable analysis, non-inferior) outcome defined as mRS 0-2 Poor outcome defined as mRS score 5-6 at 90 days after stroke onset Poor outcome defined as mortality at 90 days after stroke onset 6/8/2018 12.Observational items and 12.Observational items and examinations examinations a physician or clinical research the mRS was assessed by physical coordinator who is blinded to treatment examination or telephone interview at assignment assesses the mRS by 90 days after onset by a third telephone interview at 90 days. independent observer, who was also blinded. 6/8/2018 15.Statistical analysis plan 15.Statistical analysis plan The primary study outcome measure The primary study outcome measure was was superiority of the poor outcome at noninferiority of the favorable outcome at 90 days. We first used unadjusted 90 days. We first used unadjusted logistic logistic regression to test whether direct regression to test whether direct MT therapy was noninferior to bridging MT therapy was superior to bridging therapy. To satisfy the noninferiority therapy. hypothesis, the lower bound of the one- sided 97.5% confidence interval for the odds ratio (OR) of the primary outcome of the Direct MT group compared with the Bridging group needed to exceed 0.74. This noninferiority margin was derived from a previous meta-analysis of bridging therapy compared with the best medical treatment,12 with the margin defined according to the upper bound of the 95% confidence interval for the OR of the primary outcome with standard medical care versus the combination of medical care and MT. The margin of 0.74 represents the midpoint between the upper

42 Supplement 1

bound of the 95% confidence interval of the estimated effect of the standard medical care and 1.0 (using bridging therapy with medical care and MT as a reference). 6/8/2018 References: None References 11.Weber R, Nordmeyer H, Hadisurya J, Heddier M, Stauder M, Stracke P, Berger K, Chapot R. Comparison of outcome and interventional complication rate in patients with acute stroke treated with mechanical thrombectomy with and without bridging thrombolysis. J Neurointerv Surg. 2017;9:229-233 12.Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, Davalos A, Majoie CB, van der Lugt A, de Miquel MA, Donnan GA, Roos YB, Bonafe A, Jahan R, Diener HC, van den Berg LA, Levy EI, Berkhemer OA, Pereira VM, Rempel J, Millan M, Davis SM, Roy D, Thornton J, Roman LS, Ribo M, Beumer D, Stouch B, Brown S, Campbell BC, van Oostenbrugge RJ, Saver JL, Hill MD, Jovin TG. Endovascular thrombectomy after large- vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387:1723- 1731

43 Supplement 2

1 Supplement 2 2

3 Initial SAP

4 Direct mechanical thrombectomy

5 in acute LVO stroke (SKIP study):

6 a randomized controlled trial

7 Version 1.0

8 May 2nd, 2016

9 Statistical Analysis plan

10 UMIN 000021488

12 Principal Investigator: Kazumi Kimura, Department of Neurology,

13 Nippon Medical School

15 113-8603

16 1-1-5, Sendagi, Bunkyo-ku, Tokyo

17 Tel: 03-3822-2131 (extension 4050)

18 Fax: 03-3822-4865

19 E-mail: [email protected]

21 22

Supplement 2

23 The table of contents

24 Initial SAP

25 Statistical analysis committee ...... 4

26 Methods ...... 5

27 Patient population ...... 5

28 Randomization ...... 5 29 Clinical assessments at 90 days ...... 5

30 Outcome measures ...... 6

31 Sample size calculation ...... 6

32 Statistical analysis ...... 7

33 Study organization ...... 8

34 Supplementary Tables...... 9

35 References ...... 12 36

37 Final SAP

38 Statistical analysis committee ...... 14

39 Methods ...... 15

40 Patient population ...... 15

41 Clinical assessments at 90 days ...... 15

42 Randomization ...... 15

43 Outcome measures ...... 16

44 Sample size calculation ...... 17

45 Definition of analysis sets ...... 18

Supplement 2

46 Statistical analysis ...... 19

47 Study organization ...... 21

48 Supplementary Tables...... 22

49 References ...... 27 50

51 A summary of All SAP changes ...... 28

52 53

Supplement 2

55 Statistical analysis committee

57 Toshiaki Otsuka, M.D., Ph.D., Department of Hygiene and Public Health, Nippon

58 Medical School, Tokyo, Japan

Supplement 2

61 Methods

62 Patient population

63 Intravenous tissue plasminogen activator-eligible acute ischemic stroke patients

64 with occlusion of the internal cerebral artery or horizontal part of the middle

65 cerebral artery were enrolled into the SKIP study. The occluded vessel was

66 evaluated by magnetic resonance angiography (MRA) or computed tomographic

67 angiography (CTA). Inclusion and exclusion criteria are listed in Table 1.

69 Randomization

70 Patients were randomly assigned in a 1:1 ratio to one of two treatment groups

71 using a web-based data management system: the direct MT group or the

72 bridging therapy group. Using a minimization algorithm, we balanced the number

73 of patients into the two treatment groups of each hospital.

75 Clinical assessments at 90 days

76 A physician or clinical research coordinator who is blinded to treatment

77 assignment assesses modified Rankin Scale (mRS) at 90 days after onset by

78 telephone interview at 90 days.

Supplement 2

80 Outcome measures

81 Efficacy and safety end-points in the initial protocol are listed in

82 Supplemental Table 2.

83 The primary outcome measure is the rate of poor outcome defined as

84 mRS 5,6 at 90 days. The secondary outcome measures are shift analysis of the

85 mRS at 90 days after onset, per protocol (PP) analysis of mRS 5,6 at 90 days,

86 and recanalization rate of the occluded arteries. Successful recanalization is

87 defined as an extended modified Thrombolysis in Cerebral Infarction (eTICI)

88 score1 ≥ 2b according to angiographic findings after MT therapy. The safety

89 outcomes are symptomatic ICH defined by the National Institute of Neurological

90 Disorders and Stroke (NINDS) 2 and Safe Implementation of Thrombolysis in

91 Stroke-Monitoring Study (SIT-MOST3) criteria at 36 hours from onset and any

92 ICH, including asymptomatic and symptomatic ICH.

94 Sample size calculation

95 A previous observational study4 showed that poor outcome at 90 days

96 for ischemic stroke was observed in 25% and 47.5% of patients who had

Supplement 2

97 received direct MT and bridging therapy,respectively. According to those results,

98 we estimated that 134 patients (67 patients in either group) would need to be

99 enrolled to detect the superiority of direct MT to the combination of IVT and MT,

100 based on a 2-sided level of 0.05 and a power of 0.80. Accounting for possible

101 treatment failures, protocol violations, and dropouts, we decided to enroll 200

102 patients.

103

104 Statistical analysis

105 The primary study outcome measure is superiority of the favorable

106 outcome at 90 days. We will first use unadjusted logistic regression to test

107 whether direct MT therapy will be superior to bridging therapy.

108 The secondary efficacy analyses include the comparison of ordinal

109 scores on the modified Rankin scale to test for the superiority of the direct MT vs

110 bridging therapy with ordinal logistic regression (shift analysis), where the OR is

111 calculated for each cut-point across the mRS (for example, 0 versus 1–6, then

112 0–1 versus 2–6, and so on), and then a summary OR is calculated from the

113 individual ORs, under the assumption that the individual ORs are the same. We

114 also performed secondary analyses of the primary outcome with adjustment for

Supplement 2

115 minimization and key prognostic covariates, as well as secondary analyses in

116 the per-protocol population. Next, clinical characteristics, recanalization success

117 rate, hemorrhagic event rate, and other MT parameters were compared between

118 the two groups using unadjusted logistic regression analysis. The P-values are

119 two-sided. JMP version 11 software (SAS Institute, Cari, NC) was used the

120 analysis.

121

122 Study organization

123 The SKIP study was organized by a central coordinating center located

124 at Nippon Medical School, and conducted in approximately 22 centers in Japan.

125 The SKIP study receives no funding support.

126

Supplement 2

127 Supplementary Tables.

128 Table 1. Inclusion and exclusion criteria of the SKIP study

Inclusion criteria

Age ≥18 and <86 years at the time of informed consent

Clinical diagnosis of acute ischemic stroke with clinical symptoms

Modified Rankin scale score ≤2

ICA or M1 occlusion on MRA or CTA

Initial NIHSS ≥6

ASPECTS on initial DWI ≥5 or on initial CT ≥6

Onset to randomization within 4 h from onset.

Written informed consent by patient or next of kin.

Exclusion criteria

Contraindication for contrast agent or endovascular therapy

Contraindication for IVT

Presence of severe renal disorder (patients undergoing dialysis can be included)

Pregnancy or possibility of pregnancy

Unlikely to complete the study, such as due to progressive malignant tumor

Judged incompatible with the study by the investigators

129 ICA, internal carotid artery; ASPECTS: Alberta Stroke Program Early CT Score; M1,

130 first segment of middle cerebral artery; MRA, magnetic resonance angiography; CTA,

131 computed tomographic angiography; DWI, diffusion-weighted imaging; IVT, intravenous

132 thrombolysis

Supplement 2

133 Table 2. Efficacy and safety assessment in the initial protocol

Primary efficacy endpoint

Poor outcome defined as mRS score 5-6 at 90 days after stroke onset

Secondary efficacy endpoints

The mRS score at 90 days (shift analysis)

Favorable outcome defined as mRS score 0-1 at 90 days after stroke onset

Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset

Favorable outcome defined as mRS score 0-3 at 90 days after stroke onset

Favorable outcome defined as mRS score 0-1 at 90 days after stroke onset

(non-inferior)

Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset

(non-inferior)

Favorable outcome defined as mRS score 0-3 at 90 days after stroke onset

(non-inferior)

Improvement of mRS score as of 90 days after stroke onset

Recanalization of TICI score 2b or 3 at the end of EVT

Recanalization of modified Mori grade 2 or 3 at 72 h after stroke onset

Safety endpoints

ICH on CT or MRI within 36 h after stroke onset.

sICH as defined by an increase in NIHSS score of ≥4 from baseline on CT or MRI

within 36 h after stroke onset.

Major bleeding as defined by fatal bleeding, symptomatic bleeding in a critical

area or organ, such as intraspinal, intraocular or bleeding causing a fall in

hemoglobin ≥3 g/dL, or leading to transfusion of whole blood or red cells within 24 h

Supplement 2

after stroke onset

134

Supplement 2

135 References

136 1. Goyal M, Fargen KM, Turk AS, et al. 2C or not 2C: defining an improved

137 revascularization grading scale and the need for standardization of angiography

138 outcomes in stroke trials. J Neurointerv Surg 2014;6:83-6.

139 2. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med

140 1995;333:1581-7.

141 3. Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase for

142 acute ischaemic stroke in the Safe Implementation of Thrombolysis in

143 Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet

144 2007;369:275-82.

145 4. Broeg-Morvay A, Mordasini P, Bernasconi C, et al. Direct Mechanical

146 Intervention Versus Combined Intravenous and Mechanical Intervention in Large

147 Artery Anterior Circulation Stroke: A Matched-Pairs Analysis. Stroke

148 2016;47:1037-44.

149

150

151

Supplement 2

152 Final SAP

153

154 Direct mechanical thrombectomy

155 in acute LVO stroke (SKIP study):

156 a randomized controlled trial

157 Version 2.0 (final protocol)

158 August 2nd, 2018

159 Statistical Analysis plan

160 UMIN 000021488

161

162 Principal Investigator: Kazumi Kimura, Department of Neurology,

163 Nippon Medical School

164

165 113-8603

166 1-1-5, Sendagi, Bunkyo-ku, Tokyo

167 Tel: 03-3822-2131 (extension 4050)

168 Fax: 03-3822-4865

169 E-mail: [email protected]

170

171 172

Supplement 2

173 Statistical analysis committee

174

175 Toshiaki Otsuka, M.D., Ph.D., Department of Hygiene and Public Health, Nippon

176 Medical School, Tokyo, Japan

177

178

Supplement 2

179 Methods

180 Patient population

181 Intravenous tissue plasminogen activator-eligible acute ischemic stroke patients

182 with occlusion of the internal cerebral artery or horizontal part of the middle

183 cerebral artery are enrolled into the SKIP study. The occluded vessel is

184 evaluated by magnetic resonance angiography (MRA) or computed tomographic

185 angiography (CTA). Inclusion and exclusion criteria are listed in Table 1.

186

187 Clinical assessments at 90 days

188 The mRS is assessed by physical examination or telephone interview at 90 days

189 after onset by a third independent observer, who was also blinded.

190

191 Randomization

192 Patients were randomly assigned in a 1:1 ratio to one of two treatment groups

193 using a web-based data management system: the direct MT group or the

194 bridging therapy group. Using a minimization algorithm, we balanced the number

195 of patients into the two treatment groups of each hospital.

196

Supplement 2

197 Outcome measures

198 Efficacy and safety end-points in the initial protocol are listed in Supplemental

199 Table 2. We changed the primary efficacy endpoint from superiority of the rate of

200 poor outcome defined as mRS 5,6 to non-inferiority of the rate of favorable

201 outcome defined as mRS 0-2 on 1 August 2018, because we fit the primary

202 outcome to match other clinical trials of the same theme and change the theme

203 to be useful to clinical practice. the SKIP investigators always requested IRB to

204 use the mRS 0-2 for noninferiority as primary analysis. However the IRB

205 required SKIP investigators to change from mRS 0-2 for noninferiority to mRS

206 5-6 for superiority as primary analysis prior to study start, because there were no

207 confirm data to support the mRS 0-2 than mRS 5-6 approach. Then, when about

208 half the patients had been enrolled in the trial, a group in Germany published an

209 observational study that provided more data regarding the mRS 0-2 endpoint4.

210 Therefore, IRB accepted to use mRS 0-2 for noninferiority as primary

211 analysis.We show the end-points in the final protocol in Supplemental Table 3.

212 The primary outcome measure is the rate of favorable outcome defined as

213 modified Rankin scale score of 0-2 at 90 days (noninferiority). The secondary

214 outcome measures are a shift analysis of the modified Rankin scale score at 90

Supplement 2

215 days after onset, per protocol (PP) analysis of a modified Rankin scale score of

216 0-2 at 90 days, mortality at 90 days, and reperfusion rate of the occluded arteries.

217 Successful reperfusion is defined as an extended Thrombolysis in Cerebral

218 Infarction (eTICI) score 1 ≥2b (range, 0 [no reperfusion] to 3 [complete

219 reperfusion]) according to digital subtraction angiography findings after

220 mechanical thrombectomy therapy. The safety (adverse) events are

221 symptomatic intracerebral hemorrhage, as defined by the National Institute of

222 Neurological Disorders and Stroke (NINDS 2) and Safe Implementation of

223 Thrombolysis in Stroke-Monitoring Study (SIT-MOST 3) criteria, and any

224 intracerebral hemorrhage including asymptomatic and symptomatic intracerebral

225 hemorrhage at 36 hours from onset.

226

227 Sample size calculation

228 In the initial protocol, we estimated sample size of 134 patients (67

229 patients in either group) for the superiority analysis of poor outcome defined as

230 mRS 5,6 at 90 days. Then, we have changed the primary outcome and thus we

231 re-calculated sample size. A previous observational study4 showed that

232 favorable outcome at 90 days for ischemic stroke was observed in 48.6% and

Supplement 2

233 35.2% of patients who had received direct MT and bridging therapy, respectively.

234 According to those results, we estimated that 178 patients (89 patients in either

235 group) would need to be enrolled to detect the noninferiority of direct MT to the

236 combination of IVT and MT, based on a 1-sided level of 0.025 and a power of

237 0.80. Accounting for possible treatment failures, protocol violations, and

238 dropouts, we decided to enroll 200 patients.

239

240 Definition of analysis sets

241 All patients who have been randomised to either cotrol or intervention

242 arms will be included in the full analysis set irrespective of their protocol

243 adherence and continued participation in the study. All analyses will be

244 performed using the full analysis set. Noninderiority analyses of a modified

245 Rankin scale score of 0-2 at 90 days will also be perfomed using the PP analysis

246 set, which excludes patients whose modified Rankin scale at pre stroke is higher

247 than 2 and a large volume infarct (Alberta Stroke Program Early CT Score of 0-5

248 or DWI- Alberta Stroke Program Early CT Score of 0-4) from full analysis set.

249

250 Statistical analysis

Supplement 2

251 The primary study outcome measure is noninferiority of the favorable

252 outcome at 90 days. We will first use unadjusted logistic regression to test

253 whether direct MT therapy will be noninferior to bridging therapy. To satisfy the

254 noninferiority hypothesis, the lower bound of the one-sided 97.5% confidence

255 interval (CI) for the odds ratio (OR) of the primary outcome of the Direct MT

256 group compared with the Bridging group needs to exceed 0.74. This

257 noninferiority margin is derived from a previous meta-analysis of bridging

258 therapy compared with the best medical treatment,5 with the margin defined

259 according to the upper bound of the 95% CI for the OR of the primary outcome

260 with standard medical care versus the combination of medical care and MT. The

261 margin of 0.74 represents the midpoint between the upper bound of the 95% CI

262 of the estimated effect of the standard medical care and 1.0 (using bridging

263 therapy with medical care and MT as a reference).

264 In a secondary efficacy analysis, the modified Rankin scale ordinal scores will be

265 compared between groups to test for the non-inferiority of mechanical

266 thrombectomy compared with combined intravenous thrombolysis plus

267 mechanical thrombectomy, using ordinal logistic regression analysis (shift

268 analysis), where the OR will be calculated for each cut-point across the mRS

Supplement 2

269 scale score (for example, 0 versus 1–6, then 0–1 versus 2–6, and so on), and

270 then a summary OR will be calculated from the individual ORs, under the

271 assumption that the individual ORs are the same.. The proportional odds

272 assumption will be validated by a Brant test. We will also performe secondary

273 analyses of the primary outcome with adjustment for minimization and key

274 prognostic covariates, as well as secondary analyses in the PP population.

275 Thereafter, the clinical characteristics, successful reperfusion rate, hemorrhagic

276 events rate, and other mechanical thrombectomy parameters will be compared

277 between the two groups using unadjusted logistic regression analysis. As safety

278 (adverse) events, any and symptomatic intracerebral hemorrhage will be

279 assessed to superiority of mechanical thrombectomy alone compared with

280 combined intravenous thrombolysis plus mechanical thrombectomy.

281 Imputation for missing data will not be conducted becauase there were no

282 missing data at the time of prespecified, interim safety analysis.

283 Noninferiority analyses use a 1-sided 97.5% CI of the estimated effect whereas

284 other analyses use a 2-sided 95% CI of the estimated effect for judgement of

285 statistical significance. For point estimates, p<0.05 is considered statistically

286 significant. All data analyses are performed with JMP version 11 software (SAS

Supplement 2

287 Institute, Cari, NC) and Stata version 14 software (Stata Corp, College Station,

288 TX).

289

290 Study organization

291 In the final protocol, the SKIP study was conducted at 23 stroke centers

292 in Japan. And the SKIP study was funded by the Japanese Society for

293 Neuroendovascular Therapy (JSNET).

Supplement 2

294 Supplementary Tables.

295 Table 1. Inclusion and exclusion criteria of the SKIP study

Inclusion criteria

Age ≥18 and <86 years at the time of informed consent

Clinical diagnosis of acute ischemic stroke with clinical symptoms

Modified Rankin scale score ≤2

ICA or M1 occlusion on MRA or CTA

Initial NIHSS ≥6

ASPECTS on initial DWI ≥5 or on initial CT ≥6

Onset to randomization within 4 h from onset.

Written informed consent by patient or next of kin.

Exclusion criteria

Contraindication for contrast agent or endovascular therapy

Contraindication for IVT

Presence of severe renal disorder (patients undergoing dialysis can be included)

Pregnancy or possibility of pregnancy

Unlikely to complete the study, such as due to progressive malignant tumor

Judged incompatible with the study by the investigators

296 ICA, internal carotid artery; ASPECTS: Alberta Stroke Program Early CT Score; M1,

297 first segment of middle cerebral artery; MRA, magnetic resonance angiography; CTA,

298 computed tomographic angiography; DWI, diffusion-weighted imaging; IVT, intravenous

299 thrombolysis

Supplement 2

300 Table 2. Efficacy and safety assessment in the initial protocol

Primary efficacy endpoint

Poor outcome defined as mRS score 5-6 at 90 days after stroke onset

Secondary efficacy endpoints

The mRS score at 90 days (shift analysis)

Favorable outcome defined as mRS score 0-1 at 90 days after stroke onset

Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset

Favorable outcome defined as mRS score 0-3 at 90 days after stroke onset

Favorable outcome defined as mRS score 0-1 at 90 days after stroke onset

(non-inferior)

Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset

(non-inferior)

Favorable outcome defined as mRS score 0-3 at 90 days after stroke onset

(non-inferior)

Improvement of mRS score as of 90 days after stroke onset

Recanalization of TICI score 2b or 3 at the end of EVT

Recanalization of modified Mori grade 2 or 3 at 72 h after stroke onset

Safety endpoints

ICH on CT or MRI within 36 h after stroke onset.

sICH as defined by an increase in NIHSS score of ≥4 from baseline on CT or MRI

within 36 h after stroke onset.

Major bleeding as defined by fatal bleeding, symptomatic bleeding in a critical

area or organ, such as intraspinal, intraocular or bleeding causing a fall in

hemoglobin ≥3 g/dL, or leading to transfusion of whole blood or red cells within 24 h

Supplement 2

after stroke onset

301

Supplement 2

302 Table 3. Efficacy and safety assessment in the final protocol

Primary efficacy endpoint

Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset

(non-inferior)(intention to treat analysis)

Secondary efficacy endpoints

The mRS score at 90 days (shift analysis)

Poor outcome defined as mRS score 5-6 at 90 days after stroke onset

Poor outcome defined as mortality at 90 days after stroke onset

Favorable outcome defined as mRS score 0-1 at 90 days after stroke onset

Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset

Favorable outcome defined as mRS score 0-3 at 90 days after stroke onset

Favorable outcome defined as mRS score 0-1 at 90 days after stroke onset

(non-inferior)

Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset

(non-inferior)(per protocol analysis)

Favorable outcome defined as mRS score 0-3 at 90 days after stroke onset

(non-inferior)

Improvement of mRS score as of 90 days after stroke onset

Recanalization of TICI score 2b or 3 at the end of EVT

Recanalization of modified Mori grade 2 or 3 at 72 h after stroke onset

Safety endpoints

ICH on CT or MRI within 36 h after stroke onset.

sICH as defined by an increase in NIHSS score of ≥4 from baseline on CT or MRI

within 36 h after stroke onset.

Supplement 2

Major bleeding as defined by fatal bleeding, symptomatic bleeding in a critical area or

organ, such as intraspinal, intraocular or bleeding causing a fall in hemoglobin ≥3 g/dL,

or leading to transfusion of whole blood or red cells within 24 h after stroke onset

303

304

305

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306 References

307 1. Goyal M, Fargen KM, Turk AS, et al. 2C or not 2C: defining an improved

308 revascularization grading scale and the need for standardization of angiography

309 outcomes in stroke trials. J Neurointerv Surg 2014;6:83-6.

310 2. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med

311 1995;333:1581-7.

312 3. Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase for

313 acute ischaemic stroke in the Safe Implementation of Thrombolysis in

314 Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet

315 2007;369:275-82.

316 4. Weber R, Nordmeyer H, Hadisurya J, et al. Comparison of outcome and

317 interventional complication rate in patients with acute stroke treated with

318 mechanical thrombectomy with and without bridging thrombolysis. J Neurointerv

319 Surg 2017;9:229-33.

320 5. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy

321 after large-vessel ischaemic stroke: a meta-analysis of individual patient data

322 from five randomised trials. Lancet 2016;387:1723-31.

323

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324 A summary of all SAP changes

325 Dates of the change Ver 1.0 change Ver 2.0 change 8/2/2018 Clinical assessments at 90 days A physician or clinical research The modified Rankin scale coordinator who is blinded to (mRS) is assessed by physical treatment assignment assesses examination or telephone modified Rankin Scale (mRS) at 90 interview at 90 days after onset days after onset by telephone by a third independent observer, interview at 90 days. who was also blinded.

8/2/2018 Primary and secondary outcome Primary and secondary outcome Efficacy and safety end-points in Efficacy and safety end-points in the initial protocol are listed in the initial protocol are listed in Supplemental eTable 2. Supplemental eTable 2. We The primary outcome measure is changed the primary efficacy the rate of poor outcome defined as endpoint from superiority of the mRS 5,6 at 90 days. The rate of poor outcome defined as secondary outcome measures are mRS 5,6 to non-inferiority of the shift analysis of the mRS at 90 rate of favorable outcome days after onset, per protocol (PP) defined as mRS 0-2 on 1 August analysis of mRS 5,6 at 90 days, 2018, because we fit the primary and recanalization rate of the outcome to match other clinical occluded arteries. Successful trials of the same theme and recanalization is defined as change the theme to be useful to extendedmodified Thrombolysis in clinical practice. We show the Cerebral Infarction (eTICI) score1 ≥ end-points in the final protocol in 2b according to angiographic Supplemental eTable 3. findings after MT therapy. The The primary outcome measure safety outcomes are symptomatic is the rate of favorable outcome ICH defined by the National defined as modified Rankin Institute of Neurological Disorders scale score of 0-2 at 90 days and Stroke (NINDS) 2 and Safe (noninferiority). The secondary Implementation of Thrombolysis in outcome measures are a shift Stroke-Monitoring Study analysis of the modified Rankin

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(SIT-MOST3) criteria at 36 hours scale score at 90 days after from onset and any ICH, including onset, per protocol (PP) analysis asymptomatic and symptomatic of a modified Rankin scale score ICH. of 0-2 at 90 days, mortality at 90 days, and reperfusion rate of the occluded arteries. Successful reperfusion is defined as an extended Thrombolysis in Cerebral Infarction (eTICI) score1 ≥2b (range, 0 [no reperfusion] to 3 [complete reperfusion]) according to digital subtraction angiography findings after mechanical thrombectomy therapy. The adverse events are symptomatic intracerebral hemorrhage, as defined by the National Institute of Neurological Disorders and Stroke (NINDS2) and Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SIT-MOST3) criteria, and any intracerebral hemorrhage including asymptomatic and symptomatic intracerebral hemorrhage at 36 hours from onset.

8/2/2018 Sample size calculation Sample size calculation A previous observational study4 In the initial protocol, we showed that poor outcome at 90 estimated sample size of 134 days for ischemic stroke was patients (67 patients in either observed in 25% and 47.5% of group) for the superiority patients who had received direct analysis of poor outcome MT and bridging defined as mRS 5,6 at 90 days.

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therapy,respectively. According to Then, we have changed the those results, we estimated that primary outcome and thus we 134 patients (67 patients in either re-calculated sample size. A group) would need to be enrolled to previous observational study4 detect the superiority of direct MT showed that favorable outcome to the combination of IVT and MT, at 90 days for ischemic stroke based on a 2-sided level of 0.05 was observed in 48.6% and and a power of 0.80. Accounting for 35.2% of patients who had possible treatment failures, received direct MT and bridging protocol violations, and dropouts, therapy, respectively. According we decided to enroll 200 patients. to those results, we estimated that 178 patients (89 patients in either group) would need to be enrolled to detect the noninferiority of direct MT to the combination of IVT and MT, based on a 1-sided level of 0.025 and a power of 0.80. Accounting for possible treatment failures, protocol violations, and dropouts, we decided to enroll 200 patients.

8/2/2018 Definition of analysis sets All patients who have been randomised to either cotrol or intervention arms will be included in the full analysis set irrespective of their protocol adherence and continued participation in the study. All analyses will be performed using the full analysis set. Noninderiority analyses of a modified Rankin scale score of 0-2 at 90 days will also be

Supplement 2

perfomed using the PP analysis set, which excludes patients whose modified Rankin scale at pre stroke is higher than 2 and a large volume infarct (Alberta Stroke Program Early CT Score of 0-5 or DWI- Alberta Stroke Program Early CT Score of 0-4) from full analysis set.

8/2/2018 Statistical analysis Statistical analysis The primary study outcome The primary study outcome measure is superiority of the measure is noninferiority of the favorable outcome at 90 days. We favorable outcome at 90 days. will first use unadjusted logistic We will first use unadjusted regression to test whether direct logistic regression to test MT therapy will be superior to whether direct MT therapy will bridging therapy. be noninferior to bridging The secondary efficacy analyses therapy. To satisfy the include the comparison of ordinal noninferiority hypothesis, the scores on the modified Rankin lower bound of the one-sided scale to test for the superiority of 97.5% confidence interval (CI) the direct MT vs bridging therapy for the odds ratio (OR) of the with ordinal logistic regression primary outcome of the Direct (shift analysis), where the OR is MT group compared with the calculated for each cut-point across Bridging group needs to exceed the mRS (for example, 0 versus 1– 0.74. This noninferiority margin 6, then 0–1 versus 2–6, and so on), is derived from a previous and then a summary OR is meta-analysis of bridging calculated from the individual ORs, therapy compared with the best under the assumption that the medical treatment,5 with the individual Ors are the same. We margin defined according to the also performed secondary upper bound of the 95% CI for analyses of the primary outcome the OR of the primary outcome with adjustment for minimization with standard medical care and key prognostic covariates, as versus the combination of

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well as secondary analyses in the medical care and MT. The per-protocol population. Next, margin of 0.74 represents the clinical characteristics, midpoint between the upper recanalization success rate, bound of the 95% CI of the hemorrhagic event rate, and other estimated effect of the standard MT parameters were compared medical care and 1.0 (using between the two groups using bridging therapy with medical unadjusted logistic regression care and MT as a reference). analysis. The P-values are In a secondary efficacy analysis, two-sided. JMP version 11 the modified Rankin scale software (SAS Institute, Cari, NC) ordinal scores will be compared was used the analysis. between groups to test for the non-inferiority of mechanical thrombectomy compared with combined intravenous thrombolysis plus mechanical thrombectomy, using ordinal logistic regression analysis (shift analysis), where the OR will be calculated for each cut-point across the mRS scale score (for example, 0 versus 1–6, then 0–1 versus 2–6, and so on), and then a summary OR will be calculated from the individual ORs, under the assumption that the individual ORs are the same.. The proportional odds assumption will be validated by a Brant test. We will also performe secondary analyses of the primary outcome with adjustment for minimization and key prognostic covariates, as well as secondary analyses in the PP population. Thereafter,

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the clinical characteristics, successful reperfusion rate, hemorrhagic events rate, and other mechanical thrombectomy parameters will be compared between the two groups using unadjusted logistic regression analysis. As safety (adverse) events, any and symptomatic intracerebral hemorrhage will be assessed to superiority of mechanical thrombectomy alone compared with combined intravenous thrombolysis plus mechanical thrombectomy. Imputation for missing data will not be conducted becauase there were no missing data at the time of prespecified, interim safety analysis. Noninferiority analyses use a 1-sided 97.5% CI of the estimated effect whereas other analyses use a 2-sided 95% CI of the estimated effect for judgement of statistical significance. For point estimates, p<0.05 is considered statistically significant. All data analyses are performed with JMP version 11 software (SAS Institute, Cari, NC) and Stata version 14 software (Stata Corp, College Station, TX).

8/2/2018 Study organization Study organization

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The SKIP study was organized by In the final protocol, the SKIP a central coordinating center study was conducted at 23 located at Nippon Medical School, stroke centers in Japan. And the and conducted in approximately 22 SKIP study was funded by the centers in Japan. The SKIP study Japanese Society for receives no funding support. Neuroendovascular Therapy (JSNET). 8/2/2018 References References 1.Goyal M, Fargen KM, Turk AS, et 1.Goyal M, Fargen KM, Turk AS, al. 2C or not 2C: defining an et al. 2C or not 2C: defining an improved revascularization grading improved revascularization scale and the need for grading scale and the need for standardization of angiography standardization of angiography outcomes in stroke trials. J outcomes in stroke trials. J Neurointerv Surg 2014;6:83-6. Neurointerv Surg 2014;6:83-6. 2.Tissue plasminogen activator for 2.Tissue plasminogen activator acute ischemic stroke. N Engl J for acute ischemic stroke. N Med 1995;333:1581-7. Engl J Med 1995;333:1581-7. 3.Wahlgren N, Ahmed N, Davalos 3.Wahlgren N, Ahmed N, A, et al. Thrombolysis with Davalos A, et al. Thrombolysis alteplase for acute ischaemic with alteplase for acute stroke in the Safe Implementation ischaemic stroke in the Safe of Thrombolysis in Implementation of Thrombolysis Stroke-Monitoring Study in Stroke-Monitoring Study (SITS-MOST): an observational (SITS-MOST): an observational study. Lancet 2007;369:275-82. study. Lancet 2007;369:275-82. 4.Broeg-Morvay A, Mordasini P, 4.Weber R, Nordmeyer H, Bernasconi C, et al. Direct Hadisurya J, et al. Comparison Mechanical Intervention Versus of outcome and interventional Combined Intravenous and complication rate in patients with Mechanical Intervention in Large acute stroke treated with Artery Anterior Circulation Stroke: mechanical thrombectomy with A Matched-Pairs Analysis. Stroke and without bridging 2016;47:1037-44. thrombolysis. J Neurointerv Surg 2017;9:229-33. 5.Goyal M, Menon BK, van

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Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016;387:1723-31. 326

327

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Supplemental Online Content

Suzuki K, Matsumaru Y, Takeuchi M; SKIP Study Investigators. Effect of mechanical thrombectomy without vs with intravenous thrombolysis on functional outcome among patients with acute ischemic stroke: the SKIP randomized clinical trial. JAMA. doi:10.1001/jama.2020.23522

eBox 1. Inclusion and Exclusion Criteria of the SKIP Study eBox 2. Prespecified Outcome Measures in the SKIP Study eTable. Primary and Secondary Efficacy Endpoints and Adverse Events eAppendix. SKIP study investigators

This supplemental material has been provided by the authors to give readers additional information about their work.

eBox 1. Inclusion and Exclusion Criteria of the SKIP Study

Inclusion criteria

Age ≥18 and <86 years at the time of informed consent

Clinical diagnosis of acute ischemic stroke with clinical symptoms

Modified Rankin scale score ≤2

ICA or M1 occlusion on MRA or CTA

Initial NIHSS ≥6

ASPECTS on initial DWI ≥5 or on initial CT ≥6

Onset to randomization within 4 h from onset.

Written informed consent by patient or next of kin.

Exclusion criteria

Contraindication for contrast agent or endovascular therapy

Contraindication for IVT

Presence of severe renal disorder (patients undergoing dialysis can be included)

Pregnancy or possibility of pregnancy

Unlikely to complete the study, such as due to progressive malignant tumor

Judged incompatible with the study by the investigators

ICA, internal carotid artery; ASPECTS: Alberta Stroke Program Early CT Score; M1, first segment of middle cerebral artery; MRA, magnetic resonance angiography; CTA, computed tomographic angiography; DWI, diffusion-weighted imaging; IVT, intravenous thrombolysis

eBox 2. Prespecified Outcome Measures in the SKIP Study

Primary efficacy endpoint

Favorable outcome defined as mRS score 0-2 at 90 days after stroke onset

Secondary efficacy endpoints

The mRS score at 90 days (shift analysis)

Poor outcome defined as mRS score 5-6 at 90 days after stroke onset

Poor outcome defined as mortality at 90 days after stroke onset

Favorable outcome defined as mRS score 0-1 at 90 days after stroke onset

Favorable outcome defined as mRS score 0-3 at 90 days after stroke onset

Recanalization of TICI score 2b or 3 at the end of MT

Recanalization of modified Mori grade 2 or 3 at 72 h after stroke onset

Adverse events

Any ICH on CT or MRI within 36 h after stroke onset.

symptomatic ICH on CT or MRI within 36 h after stroke onset as defined by the

NINDS and SIT-MOST criteria.

Other major bleeding as defined by fatal bleeding, symptomatic bleeding in a

critical area or organ, such as intraspinal, intraocular or bleeding causing a fall in

hemoglobin ≥3 g/dL, or leading to transfusion of whole blood or red cells within 24 h

after stroke onset

eTable. Primary and Secondary Efficacy Endpoints and Adverse Events

MT IVT + Noninferiority analysis Superiority analysis

alone MT

n=101 n=103 Estimate of Odds Ratio P Estimate of Odds Ratio P

Difference (97.5% (97.5% 1-sided CI)a valueb Difference (95% CI) valueb

1-sided CI) (95% CI)

Primary outcome

Modified Rankin Scale 0-2 at 90 days, 60 59 2.1% (11.4% to 1.09 (0.63 to ∞) 0.18

no. (%) (59.4%) (57.3%) ∞)

Secondary outcomes

Modified Rankin Scale reduction (shift 0.97 (0.60 to ∞) 0.27

analysis)

Mortality at 90 days, no. (%) 8 (7.9%) 9 0.8% (9.5% to 0.90 (0.33 to 2.43) 1.00

(8.7%) 7.8%)

TICI gradec ≥ 2B, no. (%) 91 96 3.1% (11.8% to 0.66 (0.24 to 1.82) 0.46

(90.1%) (93.2%) 5.6%)

Modified Rankin Scale 0-1 at 90 daysd, 41 46 -4.1% (-18.6 % to 0.85 (0.49 to ∞) 0.62 0.56

no. (%) (40.6) (44.7) ∞)

Modified Rankin Scale 0-3 at 90 daysd, 74 73 2.4% (-11.7% to 1.13 (0.61 to ∞) 0.18 0.70

no. (%) (73.3%) (70.9%) ∞)

Modified Rankin Scale 5-6 at 90 daysd, 16 17 -0.7% (-12.2% to 0.95 (0.45 to 2.01) 0.90

no. (%) (15.8%) (16.5%) 10.9%)

Modified MORI grade 2-3 at 72 hoursd,e, 87/92 97/101 -2.4% (-9.0% to 0.54 (0.12 to 2.32) 0.41

no. (%) (94.6%) (96.0%) 4.1%)

Adverse events outcomes

Any ICH at 36 h from onset, no. (%) 34 52 16.8% (32.1% to 0.50 (0.28 to 0.88) 0.02

(33.7%) (50.5%) 1.6%)

Symptomatic ICH (NINDS criteria) at 36 8 (7.9%) 12 3.7% (13.0% to 0.65 (0.25 to 1.67) 0.48

h from onsetf, no. (%) (11.7%) 5.6%)

Symptomatic ICH (SIT-MOST criteria) 6 (5.9%) 8 1.8% (9.7% to 0.75 (0.25 to 2.24) 0.78

at 36 h from onsetg, no. (%) (7.8%) 6.1%)

Other hemorrhagic eventsd,h, no. (%) 1 (1.0%) 4 -2.9% (-7.7% to 0.25 (0.03 to 2.25) 0.22

(3.9%) 1.9%)

All analyses were conducted using the primary analysis set.

MT alone, mechanical thrombectomy alone; IVT + MT, intravenous thrombolysis plus mechanical thrombectomy; CI, confidence interval; TICI, Thrombolysis in Cerebral

Infarction; ICH, intracerebral hemorrhage; NINDS, National Institute of Neurological Diseases and Stroke; SITS-MOST, Safe Implementation of Thrombolysis in Stroke-Monitoring

Study; NIHSS, National Institutes of Health Stroke Scale; PP, per protocol

aThe non-inferiority margin was the odds ratio of 0.74

bP values refer to the comparison between MT alone and IVT + MT

cThe TICI grading system was based on the angiographic appearances of the treated occluded vessel and the distal branches: Scores on the TICI grade range from 0 to 3, with 0

indicating no perfusion, 1 indicating penetration with minimal perfusion, 2A indicating only partial filling (<50%) of the entire vascular territory, 2B indicating partial filling (≥50%), 2C

indicating near complete perfusion with the exception of slow flow or a few distal cortical emboli, 3 indicating complete perfusion

dAdditional data from text

e12 (5.8%) data for modified Mori grade were missing. We analyzed the recanalization rate of modified Mori grade except for missing data

fSymptomatic ICH was also assessed according to NINDS trial criteria: any intracerebral hemorrhage with neurologic deterioration from baseline (increase of ≥1 in the NIHSS score)

from baseline or death within 36 hours.

gThe main definition of symptomatic intracerebral hemorrhage was the definition from the SIT-MOST: a large local or remote parenchymal intracerebral hemorrhage (>30% of the

infarcted area affected by hemorrhage with a mass effect or extension outside the infarct) in combination with neurologic deterioration from baseline (increase of ≥4 in the NIHSS

score) or death within 36 hours

hFive patients had other hemorrhagic events. One bleeding from fracture occurred in the mechanical thrombectomy alone group, whereas one gastrointestinal bleeding and three

puncture site bleeding occurred in the combined group, respectively.

SKIP study investigators

: Kazumi Kimura, MD, PhD, Kentaro Suzuki, MD, PhD, Yasuhiro Nishiyama, MD, PhD, Junya

Aoki, MD, PhD, Chikako Nito, MD, PhD, Noriko Matsumoto, MD, PhD, Takuya Kanamaru, MD, PhD, Yuki

Sakamoto, MD, PhD, Toshiaki Otsuka, MD, PhD, Akio Morita, MD, PhD, Hiroyuki Yokota, MD, PhD;

: Yuji Matsumaru, MD, PhD, Mikito Hayakawa, MD, Aiki Marushima, MD, PhD, Yoshiro Ito, MD,

PhD, Masayuki Sato, MD, PhD, Shinya Minamimoto, MD, Tenyu Hino, MD, Taisuke Akimoto, MD, PhD; Seishou

: Masataka Takeuchi, MD; : Masafumi Morimoto, MD, PhD,

Mitsuhiro Iwasaki, MD, Chiyoe Hikita, MD, Yasufumi Inaka, MD, Hidekazu Yamazaki, MD, Shinya Fukuta, MD,

Hiroaki Sato, MD; : Ryuzaburo Kanazawa, MD, PhD, Tetsuhiro Higashida, MD, PhD,

Takanori Uchida, MD, Yuichi Takahashi, MD, PhD, Tomoyuki Yoshihara, MD, PhD, Hidenori Ohbuchi, MD, PhD,

Naoyuki Arai, MD; : Yohei Takayama, MD, Takekazu Akiyama, MD, Takahito

Yazaki, MD, PhD; : Yuki Kamiya, MD, PhD, Ayako Kuriki, MD, PhD,

Yoshifumi Miyauchi, MD, Keita Mizuma, MD, PhD, Hiroyasu Komuro, MD, Saori Fukuda, MD, Takashi Fujii MD,

Yuta Kato, MD, Takahide Wada, MD; : Keigo Shigeta, MD,

PhD, Hiroshi Yatsushige, MD, PhD, Masaya Enomoto MD, PhD, Kyoko Sumiyoshi, MD, PhD, Jiro Aoyama, MD,

Tomoyuki Nakano, MD, Yukika Arai, MD; : Seiji Okubo, MD, PhD, Tomonari Saito, MD,

PhD, Takehiro Katano, MD, Arata Abe, MD, PhD, Akihito Kutsuna, MD, Kazutaka Sawada, MD, Yuji Nishi, MD,

Yuho Takeshi, MD; : Norihiro Ishii, MD, PhD, Yoshinobu Sekihara MD, Yoshiyuki Takata, MD,

PhD, Yuzo Saito, MD; : Yorio Koguchi, MD, PhD, Tosihiro Yamauchi, MD, PhD, Koji

Suzuki, MD, PhD, Iichiro Matsuura, MD, Mitsuhiro Aikawa, MD;

: Kensuke Suzuki, MD, PhD, Akio Hyodo, MD, PhD, Tomoji Takigawa, MD, PhD, Yosuke Kawamura, MD,

Ryotaro Suzuki, MD, Ryuta Nakae, MD, PhD; : Masato Inoue, MD,

PhD, Yuta Tamai, MD, Tetsuo Hara, MD, PhD; : Hiromichi Naito, MD, Kazumi

Hatayama, MD, PhD, Takuya Moriwaki, MD, PhD, Fumio Nemoto, MD, Jun Niimi, MD, Atsushi Tsuruoka, MD, PhD,

Kenichiro Suyama, MD, Kenta Tasaka, MD, Kotaro Ueda, MD; Takahiro

Ota, MD, PhD, Masayuki Ueda, MD, PhD; Teruyuki Hirano, MD, PhD, Tatsuo Amano,

MD, Hiroyuki Kawano, MD, PhD, Yoshiko Unno, MD, PhD, Yuko Honda, MD, PhD;

: Noriyuki Kato, MD, PhD, Tomosato Yamazaki, MD, PhD, MD, Koji Hirata, MD;

: Toshihiro Ueda, MD, PhD, Tatsuro Takada, MD, Noriko Usuki, MD, Satoshi Takaishi, MD, PhD,

Tomohide Yoshie, MD, PhD, Kentaro Tatsuno, MD; : Yasuyuki Iguchi, MD, PhD,

Kenichiro Sakai, MD, PhD, Hiroki Takatsu, MD, Takahiro Maku, MD, Maki Takahashi, MD, Yuichi Murayama, MD,

PhD, Toshihiro Ishibashi, MD, PhD, Shota Kakizaki, MD, Tatsuya Hirotsu, MD, Kazufumi Horiuchi, MD;

: Kazunori Akaji, MD, PhD, Hiroaki Kimura, MD, Yoshio Tanizaki, MD, PhD, Satoka Shidoh, MD,

PhD, Ban Mihara, MD, PhD, Takao Kanzawa, MD, PhD, Youichi Mochizuki, MD; : Wataro

Tsuruta, MD, PhD, Yoshikazu Uesaka, MD, PhD, Takayuki Hara, MD, PhD, Hisayuki Hosoo, MD, PhD, Masahiro

Katsumata, MD, PhD; ; Kazunori Miki, MD, PhD, Kazutaka Sumita, MD, PhD,

Shigeru Nemoto, MD, PhD; : Shigeru Fujimoto, MD, PhD, Ryota Tanaka, MD, PhD.

Data Data available: Yes Data types: Deidentified participant data How to access data: [email protected] When available: With publication

Supporting Documents Document types: None

Additional Information Who can access the data: researchers whose proposed use of the data has been approved Types of analyses: for any purpose Mechanisms of data availability: after approval of a proposal