Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015;372: DOI: /NEJMoa

2 SUPPLEMENTARY APPENDIX A Randomized Acute Endovascular Stroke Trial Within a Population-Based Registry T.G. Jovin, A. Chamorro, E. Cobo, M.A. de Miquel, C. A. Molina, A. Rovira, L. San Román, J. Serena, S. Abilleira, M. Ribó, M. Millán, X. Urra, P. Cardona, E. López-Cancio, A. Tomasello, C. Castaño, J. Blasco, L. Aja, L. Dorado, H. Quesada, M. Rubiera, M. Hernández-Pérez, M. Goyal, A.M. Demchuk, R. von Kummer, M. Gallofré, A. Dávalos for the REVASCAT Trial Investigators. Table of contents 1 List of sites, investigators and administrative staff. 2 2 SONIIA Registry. Supplementary Methods and Results Supplementary Methods of REVASCAT trial: 6 Medical therapy and specified intervention requirements. Details of imaging assessment. Changes in trial course and planned analysis due to external evidence 4 Supplementary Figure S1: Consort flow diagram. 7 5 Supplementary Figure S2: Network of acute public hospitals involved in the acute system of 8 stroke care of Catalonia, Spain 6 Supplementary Figure S3: Flow chart of all endovascular treatments performed throughout 9 the REVASCAT trial. 7 Supplementary Figure S4. Kaplan Meier survival curve Supplementary Figure S5: Treatment effect on modified Rankin Scale scores at 3 months by minimization factors and IV alteplase Supplementary Figure S6. Pre-specified analysis and sensitivity analyses of the Primary 17 Outcome in the first interim analysis (n=174) and in the final analysis of the included patients (n=206).. 10 Supplementary Table S1 Inclusion and exclusion criteria Supplementary Table S2 Timing of study procedures Supplementary Table S3 Chart review assessment of 67 patients who appeared eligible for REVASCAT based on registry data and received EVT at REVASCAT participating centres Supplementary Table S4 Additional baseline characteristics of the 206 patients Supplementary Table S5 Workflow metrics and angiographic variables in patients allocated to the intervention arm Supplementary Table S6 Other adjudicated serious adverse events by treatment groups Supplementary Table S7 Other adverse events reported by local investigators by treatment groups References DSMB Charter DSMB letter with stopping recommendations First Interim analysis focused on the first 174 patients evaluated by the DSMB

3 1. LIST OF SITES, INVESTIGATORS AND ADMINISTRATIVE STAFF Enrolling Clinical Centers (number recruited): Hospital Vall d Hebrón (76): M. Ribó (P.I.), E. Sanjuan, M. Rubiera, J. Pagola, A. Flores, M. Muchada, P. Meler, E. Huerga, S. Gelabert, P. Coscojuela, A. Tomasello, D. Rodriguez, E. Santamarina, O. Maisterra, S. Boned, L. Seró, A. Rovira, C.A. Molina. Hospital Germans Trias (47): M. Millán (P.I.), L. Muñoz, N. Pérez de la Ossa, M. Gomis, L. Dorado, E. López-Cancio, E. Palomeras, J. Munuera, P. García Bermejo, S. Remollo, C. Castaño, R. García-Sort, P. Cuadras, P. Puyalto, M. Hernández-Pérez, M. Jiménez, A. Martínez-Piñeiro, G. Lucente, A. Dávalos. Hospital Clínic (44): A. Chamorro (co-p.i.), X. Urra (co-p.i.), V. Obach, A. Cervera, S. Amaro, L. Llull, J. Codas, M. Balasa, J. Navarro, H. Ariño, A. Aceituno, S. Rudilosso, A. Renu, J. M. Macho, L. San Roman, J. Blasco, A. López, N. Macías. Hospital de Bellvitge (39): P. Cardona (P.I.), H. Quesada, F. Rubio, L. Cano, B. Lara, M. A. de Miquel, L. Aja. Steering Committee: A. Dávalos and T.G. Jovin (co-chairs), A. Chamorro, C. Molina, J. Serena, L. San Román, M.A. de Miquel, A. Rovira and E. Cobo (Statistician). Data and Safety Monitoring Board: G. Albers (chair), K. Lees, J. Arenillas, R. Roberts (Independent Statistician). Neuroimaging Corelab: M. Goyal, A. M. Demchuk, P Minhas, F Al-Ajlan, M Salluzzi, L Zimmel, S Patel, M Eesa Angiography Corelab: R. von Kummer. Critical Events Committee: J. Martí-Fàbregas, B. Jankowitz Contract Research Organization: Anagram-ESIC, Barcelona Data Management and Biostatistics: Bioclever, Barcelona Central blinded evaluation of Modified Rankin Scale: J. Serena, M. Salvat-Plana. Trial Coordination Center: E. López-Cancio, M. Hernandez-Pérez, Hospital Germans Trias I Pujol, Badalona, Barcelona 2

4 2. SONIIA Registry. Supplementary Methods and Results Since January 2011, all ischemic stroke patients treated with any reperfusion treatment modality (endovascular treatment (EVT) +/- iv t-pa) are being entered into the SONIIA registry, a populationbased, government-mandated, prospective database. 1 The registry is subject to annual external audits to ensure completeness. Undeclared cases are retrospectively included to eventually have a nonbiased view of the quality of reperfusion therapies performed in the territory defining this population of 7.5 million inhabitants. Hospitals with capacity to deliver reperfusion treatments for stroke within the stroke network of publicly financed centers in Catalonia include cases through a web-based tool. This network of stroke hospitals concentrates virtually all reperfusion therapies delivered for ischemic stroke after the government of Catalonia commissioned the Stroke Program to organize acute stroke care in 2006 to cover the entire Catalan population. Data from the health administration database that includes all acute hospitalizations in public and private centers show that between 2011 and 2014, private hospitals performed 4 (0.0001%) iv thrombolyses and 3 (0.002%) endovascular treatment out of 4266 iv thrombolyses and 1143 EVT recorded in public centers. Additionally, per Catalan health authorities mandated protocol, all stroke alerts with EMS involvement are transferred to the nearest public hospital with capacity to perform iv t-pa. Thus, the Catalan network of public stroke treating hospitals includes: community hospitals operating via telestroke, primary stroke centers and comprehensive stroke centers (Figure S2). The first 2 hospital categories contribute to SONIIA iv thrombolysis cases only while comprehensive stroke centers perform and report data on iv tpa and EVT. The registry is linked to the Health Insurance Population Registry of Catalonia which is universally available for all residents so that once the Health ID is entered the system automatically retrieves all socio-demographic data available for that person. Inclusion of non-insured (non-residents) people is also performed in every case. After having satisfied this initial step, stroke neurologists are required to enter a basic set of clinical, neuroimaging and outcome variables at baseline, hours and at 3 months. The SONIIA registry satisfies all legal requirements mandated by the local law regarding protection of personal data. All patients or their surrogate provided written informed consent before the endovascular procedure (whether experimental or routine) and data entry in the registry. Ascertainment of REVASCAT eligibility and failures of enrollment Throughout the REVASCAT trial, patients randomized to the active arm of the trial were also included in the SONIIA registry as were all patients treated with EVT under routine practice. The registry does not include any information that identifies patients as REVASCAT patients since their participation in the trial is fully masked. We used the registry as a data source for regularly monitoring the number of EVT patients who would satisfy basic REVASCAT entry criteria. By comparing that number to the number of patients randomized in the active arm (randomization ratio: 1:1), we obtained periodic estimates of the number of patients enrolled into the active arm versus potentially eligible but treated outside of the trial. Reasons for REVASCAT exclusion in patients treated with endovascular therapy outside the trial were prospectively defined and recorded. Centers defined by consensus, prior to initiation of the study, common additional criteria to treat patients outside the trial. These patients identified from the SONIIA registry as treated with EVT and potentially (by broad SONIIA based criteria) fulfilling REVASCAT criteria were then subjected to review of medical records at their respective sites periodically (approximately every 3 months) to determine whether they were truly REVASCAT eligible (ie did not have exclusion criteria not detected by the SONIIA registry such as for instance ASPECTS 3

5 scores < 6, as ASPECTS scores were not recorded In SONIIA). All cases treated outside of REVSSCAT (whether potentially eligible or not) were presented by local P.I.s at SC meetings to determine the degree of consecutive inclusion of eligible patients. The list of criteria for thrombectomy outside REVACAT were: 1) basilar artery occlusion; 2) pregnant woman meeting rest of REVASCAT criteria; 3) Anticoagulant treatment and INR>3; 4) Wake-up stroke and > 8 hours from the last time seen well if CTP or MR shows penumbra and negative FLAIR; 5) M2 occlusion and NIHSS score 10; 6) age > 80 yr and ASPECT score 9 or 10 if there is a terminus ICA or M1 occlusion; and 7) visiting patients not able to follow-up the study period. The registry coordinator attended the REVASCAT steering committee meetings regularly to give feedback on the proportion of EVT patients eligible for REVASCAT identified through the registry. Once the REVASCAT steering committee decided to terminate the trial based on the DSMB recommendation, we used registry data to identify all patients that underwent EVT within the REVASCAT period (24/Nov/ /Dec/2014) at the 6 hospitals performing EVT in Catalonia. We then applied REVASCAT inclusion criteria to the whole sample to identify all eligible patients both at REVASCAT participating hospitals (n= 4) and non-revascat centers. The REVASCAT inclusion criteria that were applicable to the registry data were: 1) age 18, 80; 2) prestroke modified Rankin scale score 0 or 1; 3) stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) before angiography 6; 4) intracranial ICA (distal ICA or T occlusions), M1 or tandem occlusions with a pre-treatment TICI score 0 or 1; and 5) time from last seen to groin puncture 8 hours. 4 Since the age criterion was amended in June 2014, we changed our search algorithm accordingly. Every 3 months throughout the trial, in preparation for the upcoming steering committee meeting, the list of cases retrieved by this search algorithm was identified using the anonymous registry ID number and forwarded to each REVASCAT hospital where local investigators reviewed each case in the list and sent back aggregated information about: number of REVASCAT-endovascular cases in the list and reasons for exclusion among the remaining REVASCAT eligible (non-randomized) patients. These anonymized cases were reviewed at each REVASCAT steering committee meeting to ensure compliance with enrollment. Importantly, we were aware that using registry data to detect REVASCAT eligible cases likely would overestimate the number of patients who met the entry criteria because some relevant clinical and neuroimaging features (e.g. lab deviations, pre-treatment ASPECTS score, etc.) are not recorded in the registry. 3. Supplementary Methods of REVASCAT Specified intervention requirements and medical therapy arm. Two independent contract research organizations were responsible for monitoring sites for accuracy and completeness of the data, data management and statistical programming. In order to avoid performance bias, patients in both arms were admitted at acute stroke units providing semi intensive care and continuous cardiovascular monitoring (or ICU if needed) and treated following the European Stroke Organization ESO guidelines 2. Most important aspects of the medical management include antiplatelet therapy (aspirin) after exclusion of intracerebral hemorrhage except in patients who have received iv t-pa in whom antithrombotic therapy can only be instituted after 24 hours. Blood pressure management generally not recommended in the first 24 hours until extremely high (220 mmhg systolic /120 mm Hg diastolic). In patients receiving iv t-pa these values are lower (185 mmhg and 110 mmhg respectively). Hemicraniectomy as a life preserving measure performed early in the course of brain swelling and in younger patients. Stroke unit care including early mobilization, DVT prophylaxis, aspiration prevention, and secondary stroke prevention according to stroke etiology. Stroke specific 4

6 rehabilitation. These guidelines were embraced by the Catalan Stroke Program in A group of 13 key evidence based performance measures of quality of in-hospital stroke care are prospectively on site monitored by technicians of the Stroke Program at regular intervals in participating centers. 3-6 Furthermore, Centers defined by consensus, prior to initiation of the study, common additional criteria and protocols to treat patients outside the trial. 1 Overall, the Catalan Program also monitors quality of reperfusion therapies. 7 Concomitant medications and non-pharmacological therapies were recorded during the trial. Endovascular protocol therapy was based on the following principles: 1) Only the Solitaire device (Solitaire-FR ) was allowed; 2) if the Solitaire device failed after a maximum of six passes per vessel, no pharmacological or other mechanical rescue therapies was allowed; 3) systemic anticoagulation was not allowed other than in the heparinized saline infusion as per local interventional procedure standards; 4) balloon angioplasty and/or stenting of extracranial ICA in cases with ICA/M1 tandem occlusions was allowed as per site specific protocols; 5) the use of general anesthesia or conscious sedation was left at the discretion of the neurointerventionalist. Intravenous alteplase was given within 4.5 hours in eligible patients treated at center that performed EVT or in patients initially treated at outside hospital and later transferred. CT or DWI and CTA or MRA was required at least 30 minutes after starting alteplase infusion to prove persistent arterial occlusion of the target arteries and the amount of infarct core before randomization. To reinforce achievement of fast reperfusion the metric of 60 minutes was chosen as recommended time from neuroimaging (first study) to treatment initiation (groin puncture). An ongoing quality improvement program monitored speed and quality of neurointerventional workflow. Ongoing efforts were made to ensure that the interventional team was activated as soon as a potentially eligible patient arrived to the treating center without waiting for completion of imaging studies or results of randomization Details of imaging assessment The timing of imaging studies is shown in table S2 of the supplementary appendix. In addition to the baseline non-contrasted CT, ASPECTS was also evaluated with the aid of CBV maps of CT Perfusion, CTA source imaging (CTA-SI) or DWI-MR in patients whose vascular occlusion study confirming qualifying occlusion was performed beyond 4.5 hours of last seen well. Follow-up non-contrast CT and CTA or DWI and MRA scans were performed at 24 (-2, +12h) hours for assessment of infarct volume, vessel revascularization and to rule out intracranial hemorrhage or malignant edema. Blinded core labs adjudicated all neuroimaging studies, including angiographic images. Infarct volumes at 24 hours on CT or MRI were adjudicated blinded to clinical data. In case both CT and MRI was available, for uniformity sake CT data was used. Volumes were calculated through software generated volumetric calculations (Quantomo 8 ) with manual adjustments when deemed necessary. In case of coexistence of hemorrhage and infarction, combined (infarction and hemorrhage) volumes were used. Given that in only two subjects follow-up scans were missing (in one patient who died before 24 hours a scan could not be performed due to clinical instability and in the other images were irretrievably lost) no imputations were made for missing values. Statistical analysis methods for infarct volume assessment were not pre- specified Primary outcome adjudication methodology 5

7 Locally, each site designated one or more mrs-certified independent neurologist, not involved in patient management to record the mrs score in a face-to-face visit as evaluated following a structured interview 9. In order to safeguard blinding, during the first half of the study an external mrs-certified nurse centrally evaluated mrs scores by telephone call, recording the interview by audio-tape. In case of discrepancy between local investigator and audio based external evaluator a single, blinded neurologist (ELC) made a final evaluation based upon audio tape review. After a protocol update in the second half of the study, the face-to-face structured interviews at 90 days and 12 months were video recorded and evaluated by one single external, blinded mrs -certified neurologist (JS). Primary analysis is based on central evaluator through video recording (106 evaluations). In case these were unavailable, outcome determined in person by masked local investigators were used as default (65 evaluations). The total number of evaluations excluding deaths before 90 days was External evidence changed trial course and planned analysis. Data Safety Monitoring Board (DSMB) recommended, and masked Steering Committee (SC) agreed, to stop recruitment because emerging results showed that equipoise was lost. That is, the trial was stopped because the primary hypothesis was no longer an open question, not because the first REVASCAT interim look reached pre-defined boundaries for declaring superiority of endovascular treatment. In view of pending outcomes in the overrunning 32 patients already randomized, SC asked to remain blinded to the interim results and decided to accept the DSMB recommendation based on their ethical suggestions, but unaware that this specific situation was not a pre-planned decision scheduled on the study protocol. Once the SC had access to the full dataset it became apparent that: (1) the final reason to stop recruitment was due to external information, not statistical significance at the first interim look; (2) this early stopping due to external reasons was planned neither in the study protocol nor in the statistical analysis plan (SAP); (3) the original objective of our study to provide independent evidence for rejecting the null hypothesis of no effect did no longer apply, and (3) as the decision to stop the trial did not rely on REVASCAT sequential protocol, but on external evidence, the need to adjust alpha level for several looks was no longer self-evident; and (4) future analyses of REVASCAT data in metaanalyses will employ the standard 95% level. Unfortunately neither the protocol nor the SAP had considered how the analysis should be performed in case the trial would be stopped because of external evidence. After thoughtful discussions around the previous considerations, the SC decided to be consistent with similar trials, which report nominal 95%CI and with future meta-analysis that will also employ nominal 95%CI. 6

8 4. Figure S1. Consort flow diagram * TICI 3 (n=3) and TICI 2b (n=2) Four cases in the medical arm and one case in the intervention arm were evaluated by telephone interview due to poor clinical conditions (mrs=4 or 5) 7

9 5. Figure S2.- Network of acute public hospitals involved in the acute system of stroke care of Catalonia, Spain Type of center CSC PSC 8 8 CH-TS CH without TS Total The figure shows distribution of acute-care public hospitals by hospital categories. All these hospitals are part of the acute system of stroke care (so called, the Stroke Code) that covers the whole territory and population (7.5 M). Private hospitals do exist but are not part of the network. Private hospitals do not provide endovascular therapies for stroke patients even though within , 3 EVT were detected at such hospitals. CSC denotes comprehensive stroke center, PSC primary stroke center, CH-TS community hospital with telestroke facilities. Figures refer to the number of centers during the two years of the REVASCAT trial. 8

10 6. Figure S3. Flow chart of all endovascular treatments performed throughout the REVASCAT trial. Colored boxes depict the REVASCAT population. See text on page 4 in the Supplementary Appendix for explanation. * Age cutoff of 80 years was amended to 85 years by June

11 7. Figure S4. Kaplan Meier survival curve. Adjusted mortality hazard ratio by minimization factors and IV alteplase is 1.18 (95%CI, 0.60, 2.32) 10

12 8. Figure S5. Treatment effect on modified Rankin Scale scores at 3 months by minimization factors, IV alteplase and ASPECTS score. Stratified by Age (p for interaction, 0.19). 11

13 Stratified by NIHSS (p for interaction, 0.34) 12

14 Stratified by time from stroke onset to randomization (p for interaction, 0.09). 13

15 Stratified by treatment arterial occlusion site (p for interaction, 0.81). 14

16 Stratified by treatment with IV alteplase (p for interaction, 0.75). 15

17 Stratified by ASPECT Score (p for interaction,

18 9. Figure S6. Pre-specified analysis and sensitivity analyses of the Primary Outcome in the first interim analysis (n=174) used by the DSMB to take the decision to stop the trial and in the final analysis of the included patients (n=206). Distribution of the modified Rankin Scale scores at 90 days in the intention-to-treat population in S6-1) First interim analysis according to A) Central evaluation through video recording (77 evaluations) or local investigators as default (65 evaluations); B) Blinded local investigator evaluation (n=142) and to C) Central blinded evaluation, either by video (n=77) or telephone interview (n=65); thirty-two patients died before 90 days; and in S6-2) Final analysis according to A) Central evaluation through video recording (106 evaluations) or local investigators as default (65 evaluations); B) Blinded local investigator evaluation (n=165) and to C) Central blinded evaluation, either by video (n=106) or telephone interview (n=65). Thirty-five patients died before 90 days. S6-3. Triangular model boundaries with upper (u) and (λ) lower stopping limits and statistics (Z value) for the first interim analysis (first dot, n=174) and final analysis (second dot, n=206) according to A) Central evaluation through video recording (106 evaluations) or local investigators as default (65 evaluations); B) Blinded local investigator evaluation (n=165) and to C) Central blinded evaluation, either by video (n=106) or telephone interview (n=65). S6-1) First interim analysis (n=174) A) Adjusted OR, 1.93 (95%CI, 1.13, 3.31) 17

19 B) Adjusted OR, 2.06 (95%CI, 1.21, 3.50) C) Adjusted OR, 2.13 (95%CI, 1.24, 3.66) 18

20 S6-2) Final analysis (n=206) Adjusted OR, 1.71 (95%CI, 1.05, 2.81) Adjusted OR, 1.93 (95%CI, 1.18, 3.17) 19

21 Adjusted OR, 1.83 (95%CI, 1.12, 3.00) S6-3. Triangular model boundaries and statistics for the first interim analysis (n=174) and final analysis (n=206) A) State of the sequential plot (ITT population) Summary of the test statistics and upper (u) and ( ) lower stopping limits (ITT population) B) Analysis n Z V u 1st Interim Final

22 State of the sequential plot (ITT population) Summary of the test statistics and upper (u) and ( ) lower stopping limits (ITT population) Analysis n Z V u 1st Interim Final C) State of the sequential plot (ITT population) Summary of the test statistics and upper (u) and ( ) lower stopping limits (ITT population) Analysis n Z V u 1st Interim Final

23 10. Table S1- Inclusion and exclusion criteria and Summary of protocol amendments. Inclusion Criteria Exclusion Criteria 1. Acute ischemic stroke where patient is ineligible for IV thrombolytic treatment or the treatment is contraindicated (e.g., subject presents beyond recommended time from symptom onset), or where patient has received IV thrombolytic therapy without recanalization after a minimum of 30 min from start of iv tpa infusion 2. No significant pre-stroke functional disability (mrs 1) 3. Baseline NIHSS score obtained prior to randomization must be equal or higher than 6 points 4. Age 18 and Occlusion (TICI 0-1) of the intracranial ICA (distal ICA or T occlusions), MCA-M1 segment or tandem proximal ICA/MCA-M1 suitable for endovascular treatment, as evidenced by CTA, MRA or angiogram, with or without concomitant cervical carotid occlusion or stenosis 6. Patient treatable within eight hours of symptom onset. Symptoms onset is defined as point in time the patient was last seen well (at baseline). Treatment start is defined as groin puncture. 7. Informed consent obtained from patient or acceptable patient surrogate Clinical criteria 1. Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR > Baseline platelet count < /µL 3. Baseline blood glucose of < 50mg/dL or >400mg/dl 4. Severe, sustained hypertension (SBP > 185 mm Hg or DBP > 110 mm Hg) NOTE: If the blood pressure can be successfully reduced and maintained at the acceptable level using ESO guidelines recommended medication (including iv antihypertensive drips), the patient can be enrolled. 5. Patients in coma (NIHSS item of consciousness >1) (Intubated patients for transfer could be randomized only in case an NIHSS is obtained by a neurologist prior transportation). 6. Seizures at stroke onset which would preclude obtaining a baseline NIHSS 7. Serious, advanced, or terminal illness with anticipated life expectancy of less than one year. 8. History of life threatening allergy (more than rash) to contrast medium 9. Subjects who have received iv t-pa treatment beyond 4,5 hours from the beginning of the symptoms 10. Patients with acute stroke within the first 48 hours after percutaneous cardiac or cerebrovascular interventions and major surgery (beyond 48h they should be randomized in REVASCAT or excluded for EVT if poor medical conditions) 11. Renal insufficiency with creatinine 3 mg/dl 12. Woman of childbearing potential who is known to be pregnant or lactating or who has a positive pregnancy test on admission. 13. Subject participating in a study involving an investigational drug or device that would impact this study. 22

24 Summary of protocol amendments 14. Cerebral vasculitis 15. Patients with a pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, mrs score at baseline must be 1. This excludes patients who are severely demented, require constant assistance in a nursing home type setting or who live at home but are not fully independent in activities of daily living (toileting, dressing, eating, cooking and preparing meals, etc.) 16. Unlikely to be available for one year follow-up (e.g. no fixed home address, visitor from overseas). Neuroimaging criteria 17. Hypodensity on CT or restricted diffusion amounting to an ASPECTS score of <7 on non-contrast CT, or <6 on DWI MRI. Patients 81 to 85 years old with ASPECTS score on non-contrast CT or DWI MRI <9 must be excluded. ASPECTS must be also evaluated by CBV maps of CT Perfusion, CTA source imaging (CTA-SI) or DWI-MR in patients whose vascular occlusion study (CTA/MR) confirming qualifying occlusion, is performed beyond 4.5 hours of last seen well. 18. CT or MR evidence of hemorrhage (the presence of microbleeds is allowed). 19. Significant mass effect with midline shift. 20. Evidence of ipsilateral carotid occlusion, high grade stenosis or arterial dissection in the extracranial or petrous segment of the internal carotid artery that cannot be treated or will prevent access to the intracranial clot or excessive tortuosity of cervical vessels precluding device delivery/deployment 21. Subjects with occlusions in multiple vascular territories (e.g., bilateral anterior circulation, or anterior/posterior circulation) 22. Evidence of intracranial tumor (except small meningioma). Protocol version number and date Protocol Final Version 1.0 dated on 20Jun2012 Version 2.0 dated on 15Apr2013 Notes regarding the new version Initial version approved by ECs involved and by the Spanish Authorities. Change to sequential design with consequent change in sample size. The maximum sample population is changed to 690 patients, with interim looks at 174, 346, 518. New definition of principal variable: from dichotomy mrs 0-2 to shift distribution of the scale collapsing 5 and 6 in one single worst value) Change in some eligibility criteria. Clarification in accreditation of interventionists & patient s required care (CONSORT recommendations) Addition of telephonic informed consent. Change in the publication policy. Changes made in the version of CIP. Version 3.0 dated Addition of video recording of the structured interview Rankin at 3 and 12 months to be evaluated by an independent observer blinded to treatment 23

25 on 30Sep2013 Version 4.0 dated on 11Apr2014 group according to randomization. Changes made in the version of the CIP and PIS&IC Allowed use of any kind of Solitaire (includes change of CIP title) Clarification on blood sampling. Change of PI in one participating site. Addition of a new participating site (Pittsburgh) Change in eligibility criteria (up to 85 years old and consequent change in exclusion criteria # 17) Changes made in the version of the CIP and PIS&IC 24

26 10. Table S2- Timing of study procedures Assessments / Actions: Baseline Consent Randomization Demographics Medical History X X X X Procedure* 24 (-2/+12) hours post random. Blood labs X X Baseline meds X 5±2 days postrandom, or discharge X only in case of relevant differences between baseline and 24h blood lab 90 ± 14 Days 6 Months ± 14 Days 12 Months ± 14 Days mrs X 1 3 NIHSS assessment X Stroke etiology X Admission Details X CTA or MRA X X CTP, CT-SI or MRI X 2 Angiogram X Procedure Details X Thrombus Location / TICI X Hospital Stay 4 X Barthel/ Trail Making Test A-B EuroQol EQ-5D/ 3 Relevant Meds & AE/SAEs..on an ongoing basis.. *As per randomization 1 This mrs score should be based on subject s score prior to the stroke symptom onset. 2 CTP, CT-SI or DWI-MRI should be used at baseline for ASPECTS evaluation and patient selection if time from onset >4.5 hours. 3 mrs and EuroQol 6 months evaluation can be done by telephone interview 4 Overall stay: should include all hospitalization days since random to discharge (i.e. home, rehab facilities) including stay at referral hospitals. To be done by a blinded local evaluator To be done by a blinded independent evaluator 25

27 12. Table S3. Chart review assessment of 67 patients who appeared eligible for REVASCAT based on registry data and received EVT at REVASCAT participating centers Fulfilled all REVASCAT entry criteria but escaped randomization no. (%) 8 (11.9%) Did not meet eligibility criteria for following reasons no. (%): Occlusion site (ipsilateral carotid occlusion/ high-grade stenosis/ arterial dissection in the extracranial or petrous segment of the ICA that cannot be treated or thought to prevent access to the intracranial clot, excessive tortuosity of cervical vessels precluding device deployment, multiple vessel occlusion) 19 (28.3) Comorbidity not recorded in the registry (cancer, renal insufficiency, HIV+HCV) 12 (17.9) Foreigners and/or unlikely to be available for 3-month follow-up 7 (10.4) Unavailable informed consent due to absence of an acceptable patient s surrogate 6 (9.0) Wake-up strokes with last time seen undetermined or not well established 6 (9.0) Other clinical conditions (sustained hypertension, coma, pregnancy) 4 (6.0) ASPECTS score (non contrast CT scan <7 or <6 on DWI MRI) 3 (4.5) Coronary angioplasty within previous 48 hours 2 (3.0) Total 67 (100) 26

28 13. Table S4. Additional baseline characteristics of the 206 patients Characteristic Intervention (n=103) Control (n=103) Age, yr, median [IQR] 67 (58, 76) 69 (62, 75) Ischemic cardiopathy no. (%) 17 (16.5) 9 (8.7) Hyperlipidemia no. (%) 54 (52.4) 62 (60.2) Current smoking no. (%) 26 (25.2) 23 (22.5) Peripheral vascular diseases no. (%) 5 (4.9) 5 (4.9) Systolic blood pressure mm Hg (SD) 142 (19.6) 141 (22.5) Diastolic blood pressure mm Hg (SD) 78.0 (12.2) 79.7 (13.8) Serum glucose mg/dl, mean (SD) 7.1 (1.8) 7.3 (2.0) Current antiplatelet drugs use no. (%) 26 (25.2) 31 (30.1) Current oral anticoagulants use no. (%) 23 (22.3) 16 (15.5) Current statins or lipid lowering drugs use no. (%) 42 (40.8) 48 (46.6) Contraindication for IV t-pa therapy no. (%) 33 (32.0) 23 (22.3) Time from stroke onset > 4.5 h Oral anticoagulants and INR >1.7 or new oral anticoagulants 12 5 Recent surgery 5 - Recent ischemic stroke 1 3 Coagulation disorders or treatment with full anticoagulant dose of heparin 2 2 Recent gastrointestinal or endometrial bleeding 2 1 Aortic aneurysm 1-27

29 14. Table S5. Workflow metrics and angiographic variables in patients allocated to the intervention arm Intervention Variable (n=103) Time from stroke onset to groin puncture min. Median [IQR] 269 [201, 340] Time from hospital arrival to groin puncture min. Median [IQR] 109 [85, 163] Time from imaging to groin puncture min. Median [IQR] 67 [47, 84] Time from stroke onset to revascularization min. Median [IQR] 355 [269,430] Time from groin puncture to revascularization min. Median [IQR] (n=92) 59 [36, 95] Time from groin puncture to end of the procedure min. Median [IQR] (n=92) 75 [50, 114] Number of Solitaire passes median [IQR] 2.0 [1.0, 4.0] General anesthesia and intubation no. (%) 7 (6.8) Not allowed devices or IA drugs use no. (%)* 2 (1.9) Balloon guide catheter use no. (%) 62 (60.2) Ipsilateral carotid stenting no. (%) 9 (8.7) Thrombectomy not performed no. (%) 5 (4.8) Occlusion site not reached no. (%) 0 No occlusion in a target artery at time of the 5 (4.8) procedure no. (%) Occlusion site no. (%) (Corelab evaluation) Intracranial ICA MCA- M1 segment M2 M3 Ipsilateral extracranial carotid occlusion Ipsilateral carotid stenosis >50% No occlusion Non assessable TICI classification no. (%) (Local investigator evaluation) 0 (no reperfusion) 1 (antegrade flow past the initial occlusion, but limited distal branch filling with little or slow distal reperfusion) 2a (antegrade reperfusion of less than 2/3 of the previously ischemic territory) 2b (antegrade reperfusion of more than 2/3 of the previously ischemic territory) 3 (complete antegrade reperfusion of the Baseline (n=103) 93 (90.3) 3 (2.9) 1 (1.0) 3 (2.9) 3 (2.9) 25 (24.5) 65 (63.7) 7 (6.8) 1 (1.0) 16 (15.7) 12 (11.8) 3 (2.9) 1 (1.0) Post treatment (n=103) 5 (4.9) 1 (1.0) 15 (14.6) 37 (35.9) 45 (43.7) 28

30 previously ischemic territory, with absence of visualized occlusion in all distal branches) * One patient was treated with intracranial stenting and one patient received intraarterial alteplase Corelab assessments were pre-specified as the primary assessment of reperfusion and are shown in Table 2 of main paper. The Corelab used modified TICI, according to its charter, and investigators used TICI. Modified TICI classifies 2b as >50% reperfusion and TICI classifies 2b as >2/3 reperfusion. 29

31 15. Table S6. Other adjudicated serious adverse events by treatment groups Events no. (%) Intervention (n=103) Acute pulmonary edema 1 (1.0) Control (n=103) Aspiration pneumonia 15 (14.6) 9 (8.7) Cardiogenic shock due to thrombosis of prosthetic valve 1 (1.0) Extracranial hemorrhage 5 (4.9) Heart failure 1 (1.0) Metastatic cancer 1 (1.0) 1 (1.0) Pulmonary embolism 2 (1.9) Seizures 7 (6.8) 3 (2.9) Shock 1 (1.0) Stent thrombosis 1 (1.0) 30

32 15. Table S7. Other adverse events reported by local investigators by treatment groups* Adverse Event - n Intervention (n=103) Control (n=103) Nervous System Disorders Headache Convulsion or sezures 10 6 Agitation 5 4 Subarachnoid Haemorrhage 4 0 Carotid Artery Stenosis 3 0 Syncope 3 6 Carotid Artery Dissection 2 0 Motor Dysfunction 2 1 Brain Oedema 1 0 Cerebral Artery Embolism 1 0 Depressed Level Of Consciousness 1 0 Epilepsy 1 0 Mononeuritis 1 0 Muscle Spasticity 1 1 Myoclonus 1 0 Neuralgia 1 2 Presyncope 1 0 Psychomotor Hyperactivity 1 0 Diziness 1 1 Cognitive dysfunction 1 2 Transient Ischaemic Attack 1 1 Infections And Infestations Urinary Tract Infection Respiratory Tract Infection 16 9 Pneumonia 4 5 Septic Shock 3 1 Tracheobronchitis 4 5 Abdominal Abscess 2 0 Celulitis 0 1 Clostridium Difficile Colitis

33 Gastrointestinal Infection 1 1 Gingivitis 1 1 Herpes Zoster 1 0 Vascular Disorders Vasospasm 14 0 Hypertension Hypotension 10 5 Phlebitis 6 7 Artery Dissection 3 1 Haematoma 2 2 Arterial Thrombosis 1 1 Arteriosclerosis 1 0 Deep Vein Thrombosis 1 6 Hypertensive Crisis 1 4 Iliac Vein Occlusion 1 0 Peripheral Arterial Occlusive Disease 2 0 Hypovolemic shock 0 1 Peripheral embolism 0 4 Cardiac Disorders Atrial Fibrillation Bradycardia 7 7 Cardiac Failure 5 3 Tachycardia 5 6 Atrial Flutter 2 1 Acute Myocardial Infarction 1 1 Aortic Valve Disease Mixed 1 1 Cardiogenic Shock 1 0 Endocarditis Noninfective 1 0 Mitral Valve Incompetence 1 0 Stress Cardiomyopathy 1 0 Taquiarrithmia 2 0 Ventricular Fibrillation 1 1 Cardiac arrest 0 3 Intracardiac thrombus 0 1 Angina

34 Injury, Poisoning And Procedural Complications Post Procedural Haematoma 11 0 Arterial Rupture 3 0 Head Injury 2 0 Post Procedural Haemorrhage 2 0 Subcutaneous Haematoma 2 3 Contusion 1 6 Craniocerebral Injury 1 1 Overdose 1 1 Procedural Haemorrhage 1 0 Procedural Pain 1 0 Spinal Column Injury 1 1 Vascular Pseudoaneurysm 1 0 Hip or femur fracture 0 3 Rib, upper limb or wrist fracture 0 3 Respiratory, Thoracic And Mediastinal Disorders Pneumonia Aspiration Bronchospasm 4 0 Pulmonary Embolism 4 1 Acute Pulmonary Oedema 3 1 Hiccups 2 2 Respiratory Failure 2 2 Dyspnoea 1 1 Pneumothorax 1 1 Respiratory Arrest 1 0 Sleep Apnoea Syndrome 1 0 Pleural effusion 0 2 Gastrointestinal Disorders Vomiting Nausea 4 1 Constipation 3 4 Abdominal Pain 2 0 Diarrhoea 2 5 Rectal Haemorrhage 2 2 Abdominal Pain Upper

35 Colitis 1 1 Colitis Ischaemic 1 0 Upper Gastrointestinal Haemorrhage 1 General Disorders And Administration Site Conditions Pyrexia Chest Pain 4 4 Extravasation 3 0 Oedema Peripheral 2 1 Thrombosis In Device 1 0 Blood And Lymphatic System Disorders Anaemia Anaemia Vitamin B12 Deficiency 1 0 Coagulopathy 1 0 Febrile Neutropenia 1 0 Leukocytosis 1 2 Splenic Infarction 1 0 Thrombocytopenia 1 0 Psychiatric Disorders Depression Confusional State 3 2 Agitation 1 1 Anxiety 1 2 Apathy 1 0 Insomnia 1 0 Hallucinations 0 2 Completed Suicide 0 1 Metabolism And Nutrition Disorders Hyperglycaemia 9 12 Diabetes Mellitus 2 2 Hyponatraemia 2 2 Dehydration 1 1 Dyslipidaemia 1 1 Gout 1 1 Hyperlipidaemia 1 1 Hypertriglyceridaemia

36 Iron Deficiency 1 0 Vitamin D Deficiency 1 0 Musculoskeletal And Connective Tissue Disorders Back Pain 6 3 Arthritis 3 3 Arthralgia 2 2 Groin Pain 1 3 Synovial Cyst 1 0 Tendonitis 1 0 Renal And Urinary Disorders Haematuria 6 7 Urinary Retention 6 6 Renal Failure 3 2 Urinary Tract Obstruction 1 0 Neoplasms Benign, Malignant And Unspecified (Incl Cysts And 6 Polyps) 5 Breast Cancer 1 0 Metastasis 1 1 Metastatic Neoplasm 1 1 Neoplasm Malignant 1 0 Rectal Cancer 1 2 Thyroid Neoplasm 1 0 Renal cancer 0 1 Mielodisplasic syndrome 0 1 Skin And Subcutaneous Tissue Disorders 5 6 Rash 2 3 Dermatitis 1 1 Dermatosis 1 0 Erythema 1 1 Ear And Labyrinth Disorders 3 2 Ear Haemorrhage 1 0 Ear Pain 1 1 Vertigo 1 1 Endocrine Disorders 3 2 Hyperthyroidism

37 Hypothyroidism 1 0 Thyroiditis 1 0 Eye Disorders 3 1 Eyelid Oedema 1 0 Optic Atrophy 1 0 Retinal Artery Occlusion 1 0 Blindness 0 1 Investigations 3 1 Activated Partial Thromboplastin Time Prolonged 1 0 Blood Potassium Increased 1 0 Haematocrit Decreased 1 0 Transaminases increase 1 Surgical And Medical Procedures 3 4 Tracheostomy 3 3 Endarterectomy 0 1 Hepatobiliary Disorders 1 2 Cholecystitis 1 1 Total * Adverse events are classified following the MedDRA medical terminology dictionary 36

38 16. References 1. Abilleira S, Cardona P, Ribo M, et al. Outcomes of a Contemporary Cohort of 536 Consecutive Patients With Acute Ischemic Stroke Treated With Endovascular Therapy. Stroke. 2014;45: European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee. Guidelines for management of ischemic stroke and transient ischemic attack 2008; Cerebrovasc Dis 2008;25: Abilleira S, Ribera A, Permanyer-Miralda G,et al. Noncompliance with certain quality indicators is associated with risk-adjusted mortality after stroke. Stroke. 2012;43: Abilleira S, Ribera A, Sánchez E, et al.t he Second Stroke Audit of Catalonia shows improvements in many, but not all quality indicators. Int J Stroke. 2012;7: Abilleira S, Dávalos A, Chamorro A, et al. Catalan Stroke Code and Thrombolysis Study Group. Outcomes of intravenous thrombolysis after dissemination of the stroke code and designation of new referral hospitals in Catalonia: the Catalan Stroke Code and Thrombolysis (Cat-SCT) Monitored Study. Stroke. 2011;42: Abilleira S, Gallofré M, Ribera A, et al.. Quality of in-hospital stroke care according to evidencebased performance measures: results from the first audit of stroke, Catalonia, Spain. Stroke. 2009;40: Abilleira S, Ribera A, Dávalos A, et al. Functional outcome after primary endovascular therapy or IV thrombolysis alone for stroke. An observational, comparative effectiveness study. Cerebrovasc Dis.2014;38: Kosior JC, Idris S, Dowlatshahi D et al. PREDICT/Sunnybrook CTA ICH study investigators. Quantomo: validation of a computer-assisted methodology for the volumetric analysis of intracerebral haemorrhage. Int J Stroke Aug;6(4): Kosior JC, Idris S, Dowlatshahi D, et al. Quantomo: validation of a computer-assisted methodology for the volumetric analysis of intracerebral haemorrhage. Int J Stroke Aug;6(4): Wilson JT, Hareendran A, Grant M, et al. Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the modified Rankin Scale. Stroke; a journal of cerebral circulation 2002;33:

39 18.- REVASCAT trial Data Safety Monitoring Board (DSMB) Charter I. Membership The Data Safety Monitoring Board (DSMB) is an independent board of 4 individuals who are not otherwise participating in any other role in the study: Dr. Greg Albers chair of committee, Dr. Ken Lees, Dr. Juan Francisco Arenillas, and Dr. Robin Roberts (statistician). All members will sign a consulting agreement with Fundació ICTUS Malaltia Vascular that provides for financial compensation as well as indemnification. II. Responsibilities The roles of the DSMB are to assist trial investigators; to ensure that the rights and welfare of trial subjects are protected; and to decide about study continuation on interim analyses: 1. Active participation in decisions made by the steering committee. 2. Regular partially masked monitoring of the study safety by review of occurrence rates of Significant Adverse Events (SAEs) as defined in the study protocol and provided by the CRO (Anagram) after adjudication by the Clinical Events Committee. Recommendations to halt the study prematurely will be based on a clinically unacceptable occurrence of Procedure and/or Device related SAEs or clinically important difference in the patient outcomes between the 2 arms that are sufficient to raise ethical concerns. 3. Formal open interim efficacy analysis according to prespecified stopping rules in order to recommend continuation, modification, or halting of the study. All recommendations will be made directly to the Co-chairmen of REVASCAT as delegates of the sponsor Fundació ICTUS Malaltia Vascular. The CRO (Anagram) and co-chairmen of REVASCAT will review significant adverse events that are collected during ongoing monitoring of the Study, and will ensure that any significant safety concerns are provided to the participating DSMB members in a timely manner. Bioclever will directly send interim efficacy statistical analyses to both the chair and the statistician of the DSMB. Formal open efficacy interim analyses have been scheduled after 174, 346, 518 and 690 patients reached the end of follow up. III. Meeting Frequency and Format DSMB pre-scheduled teleconferences will occur at regular intervals without participation from the Sponsor, co-chairmen nor Steering Committee. Safety monitoring will occur after every 50 enrolled subjects reach the first week of follow up. The data provided to the DSMB will be blinded (Group A and B). The meetings will routinely include review of data output tables from the trial for enrolled patients. If the DSMB determines that not enough information is available to make a fully informed determination about the safety profile of either arm of the study they may request additional information or analyses. 38

40 The DSMB members will make reasonable efforts to meet by phone conference within 2 weeks after each new data set or interim analyses report is received. If a request for an urgent meeting is made, the DSMB will make every effort to convene within hours. IV. Methods of Organizing the Data for Review Any event which is, or could potentially be, categorized as a Procedure or Device related SAE including all of the following will be identified and will be adjudicated by the Clinical Events Committee: Vessel perforation Intramural Arterial dissection ICH or death occurring within 24 (-6/+12) hours post-procedure Embolization to a previously uninvolved territory Access site complication requiring surgical repair or blood transfusion In vivo device failure (in vivo breakage) These events will be reported to the DSMB independently of the Group A vs. B data to allow blinding between groups. SAEs that do not increase the likelihood of unmasking will be included with the Group A vs. B demographic and outcome data. The DSMB may, at any time, request additional information or statistical analyses to be provided in order to conduct a thorough review of the data. The DSMB also reserves the right to request unblinding of the data (Group A vs. B treatment groups) if sufficient safety concerns arise regarding Procedure or Device related SAEs or clinically important differences in the patient outcomes between the 2 arms that raise ethical concerns V. Documentation of Meeting Minutes The DSMB Coordinator (Mary Wittig- wittigma@upmc.edu) will be responsible for communication with the DSMB members regarding scheduling of meetings. Meetings will be scheduled and facilitated by the DSMB Coordinator using . Every effort will be made to schedule meetings at a time that is mutually convenient for all 4 members of the committee. Input from all 4 members is required for DSMB decisions to be finalized. The DSMB Chair will document the results of the DSMB meeting discussions and determination, as well as any requests for follow up information and all action items and send this information by to the Principal Investigators with 24 hours after each meeting. VI. Confidentiality Statement By signing this charter, the DSMB members hereby certify that they are willing and able to maintain strict confidentiality of all analyses, DSMB meeting discussions, determinations, and minutes. VII. Post-study Roles and Responsibilities 39

41 At the conclusion of the study the results of the final statistical analyses will be shared with the DSMB members. The DSMB members contribution will be acknowledged in the primary publication. VIII. Statement of agreement with this Charter By signing and dating below I indicate my agreement with the content of this charter and willingness to serve on the DSMB. DSMB Chair Greg Albers 10 /_3 / 2012 DSMB Member Ken Lees / / DSMB Member Juan Francisco Arenillas / / DSMB Member Robin Roberts / / 40

42 19.- DSMB decision letter after the first interim analysis 41

43 REVASCAT STUDY RandomizEd trial of revascularization with Solitarire FR device versus best medical therapy in the treatment of Acute stroke due to anterior circulation large vessel occlusion presenting within 8 hours of symptom onset Study code: REVASCAT FIRST INTERIM ANALYSIS Prepared by: Sponsor: FUNDACIÓ ICTUS December 5, 2014 Version 2.0

44 Sponsor: Fundació Privada ICTUS Malaltia Vascular Protocol: REVASCAT Signature Page The undersigned hereby approve the first interim analysis. Author Date Signature Neus Cerdà Senior Statistician BioClever Barcelona Approval Erik Cobo Independent Statistician Universitat Politècnica de Catalunya Barcelona Antonio Dávalos Clinical Director Departament de Neurociències H. Universitari Germans Trias i Pujol Barcelona Tudor G. Jovin, MD Department of Neurological Surgery, UPMC Pittsburgh Gregory Albers DSMB Chairman Stanford Version: 2.0 (05DEC2014) First Interim Analysis Page 2 of 26

45 Sponsor: Fundació Privada ICTUS Malaltia Vascular Protocol: REVASCAT Table of contents SIGNATURE PAGE STUDY PATIENTS... 4 TABLE 1 PATIENT DISPOSITION ANALYSIS POPULATIONS... 4 TABLE 2 PATIENT DISCONTINUATION ITT POPULATION PRIMARY ENDPOINTS ANALYSES PRIMARY ENDPOINTS ANALYSES... 6 TABLE 3 MRS AT 90 DAYS BY THERAPY GROUP (ITT POPULATION)... 6 TABLE 4 SUMMARY OF THE TEST STATISTICS AND UPPER (U) AND (λ) LOWER STOPPING LIMITS (ITT POPULATION)... 6 FIGURE 1. STATE OF THE SEQUENTIAL PLOT (ITT POPULATION)... 7 TABLE 5 ODDS RATIO FOR PRIMARY ENDPOINT AT 90 DAYS (ITT POPULATION)... 7 FIGURE 2. DESCRIPTION OF THE MODIFIED RANKIN SCORE BY THERAPY GROUP (ITT POPULATION)... 8 TABLE 6 ODDS RATIO (UNADJUSTED) FOR PRIMARY ENDPOINT AT 90 DAYS (ITT POPULATION) SENSITIVITY ANALYSIS TABLE 7 MRS AT 90 DAYS BY THERAPY GROUP (ITT POPULATION)... 9 TABLE 8 SUMMARY OF THE TEST STATISTICS AND UPPER (U) AND (λ) LOWER STOPPING LIMITS (ITT POPULATION)... 9 FIGURE 3. STATE OF THE SEQUENTIAL PLOT (ITT POPULATION) TABLE 9 ODDS RATIO FOR PRIMARY ENDPOINT AT 90 DAYS (ITT POPULATION) FIGURE 4. DESCRIPTION OF THE MODIFIED RANKIN SCORE BY THERAPY GROUP (ITT POPULATION) TABLE 10 ODDS RATIO (UNADJUSTED) FOR PRIMARY ENDPOINT AT 90 DAYS (ITT POPULATION) SENSITIVITY ANALYSIS TABLE 11 MRS AT 90 DAYS BY THERAPY GROUP (ITT POPULATION) TABLE 12 SUMMARY OF THE TEST STATISTICS AND UPPER (U) AND (λ) LOWER STOPPING LIMITS (ITT POPULATION) FIGURE 5. STATE OF THE SEQUENTIAL PLOT (ITT POPULATION) TABLE 13 ODDS RATIO FOR PRIMARY ENDPOINT AT 90 DAYS (ITT POPULATION) FIGURE 6. DESCRIPTION OF THE MODIFIED RANKIN SCORE BY THERAPY GROUP (ITT POPULATION) TABLE 14 ODDS RATIO (UNADJUSTED) FOR PRIMARY ENDPOINT AT 90 DAYS (ITT POPULATION) DEMOGRAPHICS AND BASELINE CHARACTERISTICS TABLE 15 STRATIFICATION FACTORS (ITT POPULATION) ANNEXES Version: 2.0 (05DEC2014) First Interim Analysis Page 3 of 26

46 Sponsor: Fundació Privada ICTUS Malaltia Vascular Protocol: REVASCAT 1 Study patients Table 1 Patient disposition Analysis populations SOLITAIRE DEVICE BEST MEDICAL THERAPY Number of patients with Informed Consent n (%) 88 (100.0%) 86 (100.0%) Number of patients in the SAFETY sample n (%) 88 (100.0%) 86 (100.0%) Number of patients excluded from the SAFETY sample (a) n (%) 0 ( 0.0%) 0 ( 0.0%) Number of patients in the ITT sample n (%) 88 (100.0%) 86 (100.0%) Number of patients excluded from the ITT sample (b) n (%) 0 ( 0.0%) 0 ( 0.0%) Number of patients in the PP sample n (%) 83 ( 94.3%) 81 ( 94.2%) Number of patients excluded from the PP sample n (%) 5 ( 5.7%) 5 ( 5.8%) Reasons for exclusion from PP sample 90 days FU visit done by telephone with a neurologist n (%) 1 ( 20.0%) 90 days FU visit done by telephone with a relative n (%) 1 ( 20.0%) 3 ( 60.0%) Administration of IA TPA during procedure n (%) 1 ( 20.0%) Fibrinolysis treatment administered one hour after randomization n (%) 1 ( 20.0%) Intracranial treatment used not allowed in the Revascat study n (%) 1 ( 20.0%) More than 90 min between the baseline CT and groin puncture (185 n (%) 1 ( 20.0%) min later) Patient does not meet study criteria (Rankin 2) n (%) 1 ( 20.0%) Number of patients who died during the study (before visit 90 days) n (%) 18 ( 20.5%) 14 ( 16.3%) Cause of death for patients who died Related with stroke n (%) 11 ( 61.1%) 7 ( 50.0%) Myocardial infarction n (%) 1 ( 7.1%) Other cardiovascular causes n (%) 1 ( 7.1%) Infectious disease (respiratory etiology not included) n (%) 1 ( 5.6%) Respiratory infection n (%) 1 ( 5.6%) 1 ( 7.1%) Pulmonary embolism n (%) 1 ( 5.6%) Gastro-intestinal haemorrhage n (%) 1 ( 7.1%) Others n (%) 4 ( 22.2%) 3 ( 21.4%) [\IA1_Table_1.sas] run Thursday, December 4, 2014 at 16:41:02 Note(s) Percentages are based on the number of patients included. ITT population includes all patients who were randomized and followed up, irrespective of whether they received intervention with Solitaire device or best medical therapy. Safety population includes all patients having received intervention with Solitaire device or best medical therapy. PP population includes all patients without the following major protocol deviations. (a) Since REVASCAT is testing an endovascular procedure, there are not reasons for exclusion from the SAFETY population. (b) Patient with not available informed consent and not randomized was the reason for exclusion from the ITT population. Version: 2.0 (05DEC2014) First Interim Analysis Page 4 of 26

47 Sponsor: Fundació Privada ICTUS Malaltia Vascular Protocol: REVASCAT Table 2 Patient discontinuation ITT population 24-2/+12hr post random SOLITAIRE DEVICE BEST MEDICAL THERAPY 5 ± 2 days post-random, or discharge SOLITAIRE DEVICE BEST MEDICAL THERAPY SOLITAIRE DEVICE 90 ± 14 days BEST MEDICAL THERAPY Number of patients n (%) 86 ( 97.7%) 86 (100.0%) 82 ( 95.3%) 82 ( 95.3%) 70 ( 85.4%) 72 ( 87.8%) Reason of withdrawal /Early termination a n (%) 2 ( 2.3%) 0 ( 0.0%) 4 ( 4.7%) 4 ( 4.7%) 12 ( 14.6%) 10 ( 12.2%) Withdrew consent n (%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Loss of follow-up n (%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Death n (%) 2 (100.0%) 0 ( 0.0%) 4 (100.0%) 4 (100.0%) 12 (100.0%) 10 (100.0%) Other reasons n (%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) [\IA1_Table_2.sas] run Thursday, December 4, 2014 at 16:41:02 Note(s) Percentages are based on the number of ITT patients by group evaluated in each visit a Reason by page End of Study Form Version: 2.0 (05DEC2014) First Interim Analysis Page 5 of 26

48 Sponsor: Fundació Privada ICTUS Malaltia Vascular Protocol: REVASCAT 2 Primary endpoints analyses 2.1. Primary endpoints analyses mrs at 90 days: video (central independent blinded) in part II (77 patients) and local evaluator in part I (65 patients) ( 32 patients who died before visit 90 days). Table 3 mrs at 90 days by therapy group (ITT population) mrs SOLITAIRE DEVICE BEST MEDICAL THERAPY n=88 n=86 0 n (%) 6 ( 6.8%) 3 ( 3.5%) 1 n (%) 16 ( 18.2%) 6 ( 7.0%) 2 n (%) 18 ( 20.5%) 13 ( 15.1%) 3 n (%) 16 ( 18.2%) 16 ( 18.6%) 4 n (%) 7 ( 8.0%) 15 ( 17.4%) 5/6 n (%) 25 ( 28.4%) 33 ( 38.4%) [\IA1_Table_3.sas] run Thursday, December 4, 2014 at 16:41:02 Note(s) Percentages are based on the number of ITT patients by group Table 4 Summary of the test statistics and upper (u) and (λ) lower stopping limits (ITT population) Interim n Z V u λ [\IA1_Table_4.sas] run Friday, December 5, 2014 at 16:11:23 Version: 2.0 (05DEC2014) First Interim Analysis Page 6 of 26

49 Sponsor: Fundació Privada ICTUS Malaltia Vascular Protocol: REVASCAT Figure 1. State of the sequential plot (ITT population) Table 5 Odds ratio for primary endpoint at 90 days (ITT population) Interim n OR 1, 95% CI (1.126, 3.308) OR adjusted for the sequential design and minimization factor, IV tpa use and centre [\IA1_Table_5.sas] run Thursday, December 4, 2014 at 16:41:02 Version: 2.0 (05DEC2014) First Interim Analysis Page 7 of 26

50 Sponsor: Fundació Privada ICTUS Malaltia Vascular Protocol: REVASCAT Figure 2. Description of the modified Rankin Score by therapy group (ITT population) Table 6 Odds ratio (unadjusted) for primary endpoint at 90 days (ITT population) Interim n OR 1, 95% CI (1.215, 3.499) OR for the sequential design and unadjusted for minimization factor, IV tpa use and centre [\IA1_Table_6.sas] run Thursday, December 4, 2014 at 16:41:02 Version: 2.0 (05DEC2014) First Interim Analysis Page 8 of 26