CHemical OptImization of Cerebral Embolectomy in Patients With Acute Stroke Treated With Mechanical Thrombectomy (CHOICE) Trial
Phase: PHASE2
Conditions: Stroke, Acute
Sponsor: Hospital Clinic of Barcelona

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CLINICAL STUDY PROTOCOL 
CHOICE 
 
 
CHemical OptImization of Cerebral Embolectomy in patients with acute stroke 
treated with mechanical thrombectomy (CHOICE TRIAL) 
 
 
 
Study Code: CHOICE 
Protocol Version 3.0: November 28, 2019  
EudraCT Number: 2018-002195-40 
SPONSOR: Fundació Clínic per la Recerca Biomèdica 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION THAT IS THE PROPERTY OF SPONSOR. 
NEITHER THIS DOCUMENT NOR THE INFORMATION HEREIN MAY BE REPRODUCED, USED, OR DISCLOSED TO ANY THIRD PARTY 
WITHOUT THE PRIOR WRITTEN CONSENT OF SPONSOR 

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SUMMARY OF THE TRIAL 
 
 
Title  
CHemical OptImization of Cerebral Embolectomy 
in 
patients 
with 
acute 
stroke 
treated 
with 
mechanical thrombectomy (CHOICE TRIAL) 
Study Design 
Multicenter, 
randomized, 
placebo-controlled, 
double blind, phase 2b trial of acute stroke patients 
treated with MT, in which two therapies are 
compared: rt-PA or placebo. Allocation at each 
center will account for 1 stratum: use of alteplase 
(yes vs. no) before MT. Subjects will be followed up 
to 90 days post-randomization 
Clinical Site Locations 
Catalonia Autonomous Community, Spain 
Study Centers 
Hospital Clínic de Barcelona (HC) 
Hospital Universitari de Bellvitge (HB) 
Hospital Vall d’Hebron (HVH) 
Hospital de la Santa Creu i Sant Pau (HSP) 
Hospital del Mar (HM) 
Hospital Germans Trias i Pujol (HGTP) 
Hospital Josep Trueta (HJT) 
Study Objective 
The study objective is to evaluate whether rt-PA is 
safe and efficient as an add-on to mechanical 
thrombectomy in patients with acute ischemic stroke 
and complete or near-complete recanalization of a 
proximal vessel occlusion and successful brain 
reperfusion on cerebral angiogram (corresponding to 
mTICI score 2b/3) 
Subject Population 
Patients with symptomatic large vessel occlusion 
(LVO) in the anterior circulation treated with MT 
resulting in a mTICI score 2b/3 on cerebral 
angiography  
Enrolment 
Patients will be enrolled in the angiosuit by 
interventionalists or neurologists once a mTICI 2b/3 
is confirmed on cerebral angiography. 
A sample size of 100 patients per treatment arm in 
a 1:1 allocation will have at least 80% statistical 
power for the primary outcome (mRS with 0-1 

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score values) assuming a rate of 40% in the control 
arm and a 21% benefit in the experimental arm 
(odds ratio (OR) of 2.33) for a 5% two-sided type I 
error. This sample size will also guarantee the 
study power for that relative treatment benefit even 
if the success rate in the control group rises up to 
≈56%. No study losses are accounted for since all 
randomised patients will be included in the 
analysis. 
 
Follow-up  
Each patient included will be followed up to 90 days 
from the stroke 
Inclusion Criteria 
1. Patients 
with 
symptomatic 
large 
vessel 
occlusion (LVO) in the anterior, middle or 
posterior cerebral arteries treated with MT 
resulting in a mTICI score 2b/3 at end of the 
procedure.  
Patients with an mTICI score 2b/3 on the 
diagnostic cerebral angiography before the 
onset of MT are also eligible for the study.  
2. Estimated delay to onset of rescue intraarterial 
rt-PA or placebo administration <24 hours from 
symptom onset, defined as the point in time the 
patient was last seen well 
3. No significant pre-stroke functional disability 
(modified Rankin scale 0-1), or mRS >1 that 
according to the investigator is not related to 
neurological 
disease 
(i.e. 
amputation, 
blindness) 
4. Age ≥18 
5. ASPECTS >6 on non-contrast CT (NCCT) scan 
or MRI if symptoms lasting <4.5 hours or 
ASPECTS > 6 on CT-Perfusion (CTP) or DWI-
MRI if symptoms >4.5 <24 hours.  
6. Informed consent obtained from patient or 
acceptable patient surrogate 
Exclusion Criteria 
1. NIHSS score on admission >25 

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2. Contraindication to IV t‐PA as per local national 
guidelines (except time to therapy) 
3. Use of carotid artery stents during the 
endovascular 
procedure 
requiring 
dual 
antiplatelet therapy during the first 24h  
4. Female who is pregnant or lactating or has a 
positive pregnancy test at time of admission 
5. Current participation in another investigation 
drug 
or 
device 
treatment 
study 
(except 
observational study i.e.: RACECAT or clinical 
trials not testing new medical devices or new 
drugs i.e.IMAGECAT) 
6. Known hereditary or acquired hemorrhagic 
diathesis, coagulation factor deficiency 
7. Known coagulopathy, INR >1.7 or use of novel 
anticoagulants <48h from symptom onset 
8. Platelets <50,000 
9. Renal Failure as defined by a serum creatinine 
>3.0 mg/dl (or 265.2 μmol/l) or glomerular 
Filtration Rate [GFR] <30 
10. Subject who requires hemodialysis or peritoneal 
dialysis, or who have a contraindication to an 
angiogram for whatever reason 
11. Any hemorrhage on CT/MRI 
12. Clinical presentation suggests a subarachnoid 
hemorrhage, even if initial CT or MRI scan is 
normal 
13. Suspicion of aortic dissection 
14. Subject currently uses or has a recent history of 
illicit drug(s) or abuses alcohol 
15. History of life threatening allergy (more than 
rash) to contrast medium 
16. SBP >185 mmHg or DBP >110 mmHg 
refractory to treatment 
17. Serious, 
advanced, 
terminal 
illness 
with 
anticipated life expectancy <6 months 
18. Pre-existing neurological or psychiatric disease 

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that would confound evaluation 
19. Presumed vasculitis or septic embolization 
20. Unlikely to be available for 90-day follow-up 
(e.g. no fixed home address, visitor from 
overseas) 
Primary Outcome 
Proportion of patients with a mRS 0 to 1 at 90 days.  
Analysis  
The statistical analysis will be carried out in 
accordance with the principles specified in the 
International Conference on Harmonization (ICH) 
Topic E9 (CPMP / ICH / 363/96) 
Safety endpoints 
1. Mortality at 90 days 
2. sICH rates at 24 hours 
Study Timeline 
Recruitment period estimated in 24 months 
F-up per patient: 3 months 
Primary Analysis 
The primary outcome will be estimated using a log-
binomial 
regression 
model 
including 
the 
stratification variables, except centre. In the 
unexpected event that the model does not fit, the 
Poisson regression model with long-link and robust 
variance estimator will be used instead. 
Steering Committee 
Ángel Chamorro (Chair) 
Sergio Amaro 
Pere Cardona 
Antonio Dávalos 
Juan Macho 
Joan Martí-Fábregas 
Laura Oleaga 
Jaume Roquer 
Ferrán Torres (Biostatistician) 
Xabier Urra 
Joaquín Serena 
Neuroimaging Core 
Lab 
Luis San Román (Chair) 
Antonio López 
Carlos Laredo 
Neurointerventionalism 
Harmonization 
Jordi Blasco (Chair) 
Alejandro Tomasello 
Leopoldo Guimaraens 

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Roger Barranco 
Carlos Castaño 
Patient’s recruitment 
Board 
Mónica Millán (Chair) 
Elisa Cuadrado 
Pol Camps 
Clinical Study 
Management 
ANAGRAM-ESIC 
Data Safety Monitoring 
Board (DSMB) 
Dr. Tudor Jovin (Chair). University of Pittsburgh 
Dr. Enrique Leira. University of Iowa 
Dr. José Ríos (Biostatistician) Autonomous 
University of Barcelona 
Data 
Management 
- 
eCRF - Statistics 
 
IDIBAPS - Hospital Clínic Barcelona 
 
Sponsor  
Fundació Clínic per la Recerca Biomèdica 
 
 
 

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TABLE OF CONTENTS 
SUMARY OF THE TRIAL. ................................................................................................ 2 
TABLE OF CONTENTS ................................................................................................... 7 
PROTOCOL SIGNATURE PAGE SPONSOR AND CHAIRMAN ..................................... 9 
PROTOCOL SIGNATURE PAGE PRINCIPAL INVESTIGATOR ................................... 10 
1. ADMINISTRATIVE INFORMATION............................................................................ 11 
2. INTRODUCTION ........................................................................................................ 13 
 
2.1 Background and rationale ................................................................................. 13 
 
   2.1.1 Overview of reperfusion therapy in acute ischemic stroke ....................... 13 
 
   2.1.2 Maximizing brain reperfusion: a target for treatment improvement ......... 17 
 
   2.1.3 Justification of CHOICE ............................................................................... 17 
 
2.2 OBJECTIVES ...................................................................................................... 19 
 
2.3 TRIAL DESIGN .................................................................................................... 19 
3. METHODS .................................................................................................................. 19 
 
3.1STUDY SETTING .................................................................................................. 19 
 
3.2 ELEGIBILITY CRITERIA ..................................................................................... 19 
 
   3.2.1 Inclusion Criteria .......................................................................................... 19 
 
   3.2.2 Exclusion Criteria ......................................................................................... 20 
 
   3.2.3  Brain Imaging. ............................................................................................. 21 
 
3.3 INTERVENTIONS ................................................................................................ 21 
 
   3.3.1 Blinding. ........................................................................................................ 23 
 
   3.3.2 Concomitant care and interventions prohibited during the trial. .............. 23 
 
3.4  ASSIGNMENT OF INTERVETION. ALLOCATIONS AND SEQUENCE 
                   GENERATION. ............................................................................................ 23 
  3.5 OUTCOMES. ....................................................................................................... 23 
 
   3.5.1 Primary outcome .......................................................................................... 25 
 
   3.5.2 Secondary outcomes ................................................................................... 25
 
   3.5.3 Tertiary outcomes ........................................................................................ 25 
 
   3.5.4 Pre-specified subgroup analysis ................................................................. 25 
 
   3.5.5 Safety outcomes ........................................................................................... 26 
 
   3.5.6 Adverse events (AEs) and Serious Adverse Events (SAEs) ...................... 26 
 
      3.5.6.1 Definitions and Classification ................................................................ 26 
 
      3.5.6.2 Recording of AEs and SAEs .................................................................. 27 
 
      3.5.6.3 Prompt Reporting of SAEs ..................................................................... 28 
 
      3.5.6.4 Evaluating AEs and SAEs ...................................................................... 28 
 
         3.5.6.4.1 Assessment of Intensity ................................................................... 28 
           3.5.6.4.2 Assessment of Causality ................................................................. 29 

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        3.5.6.4.3 Assessment of Expectedness .......................................................... 28 
 
       3.5.6.4.4 Follow-up of AEs and SAEs ............................................................... 28 
 
3.6 STATISTICAL METHODS. .................................................................................. 28 
 
   3.6.1 General Remarks .......................................................................................... 28 
 
   3.6.2 Sample size calculation ............................................................................... 29 
 
   3.6.3 Data Blind Review (DBR) ............................................................................. 31 
 
   3.6.4 Analysis populations ................................................................................... 31 
 
   3.6.5 Randomisation Procedure ........................................................................... 31 
 
   3.6.6 Inferential Analysis  ...................................................................................... 30 
         3.6.6.1 Primary endpoint ........................................................................................... 30 
         3.6.6.2 Secondary endpoints and safety outcomes .......................................... 32 
         3.6.6.3 General strategy for the rest of variables ............................................... 33 
 
   3.6.7 Multiplicity adjustments and interim analysis ............................................ 33 
 
   3.6.8 Handling of missing data ............................................................................. 33 
 
   3.6.9 Subgroup analysis ....................................................................................... 34 
 
3.7 STUDY FEASIBILITY. ......................................................................................... 33 
4. DATA MANAGEMENT/MONITORING AND QUALITY CONTROL. ........................... 34 
 
4.1 Data collection methods .................................................................................... 34 
 
4.2 Data management .............................................................................................. 34 
 
4.3 Data monitoring .................................................................................................. 35 
 
4.4 Screening log...................................................................................................... 35 
 
4.5 Data auditing ...................................................................................................... 36 
 
4.6 Independent committees ................................................................................... 36 
 
4.7 Training of investigators and site personnel .................................................... 36 
5. ETHICS AND DISSEMINATION. ................................................................................ 37 
 
5.1 Research Ethics approval .................................................................................. 37 
 
5.2 Consent ............................................................................................................... 37 
 
5.3 Confidentiality .................................................................................................... 38 
 
5.4 Record Retention and Codi Ictus Catalonia (CICAT) ....................................... 38 
 
5.5 Dissemination policy .......................................................................................... 39 
6. APPENDIXES. ............................................................................................................ 40 
 
6.1 Abbreviations and Acronyms ............................................................................ 40 
 
6.2 Informed consent. .............................................................................................. 42 
 
6.3 Modified Rankin scale (structured phone-based interview) ............................ 43 
 
6.4 Angiographic assessment: The mTICI score ................................................... 45 
 
6.5 Study Assessments ........................................................................................... 48 
 
6.6 Bibliography ....................................................................................................... 49 

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PROTOCOL SIGNATURE PAGE SPONSOR  
 
STUDY CODE: CHOICE  
 
Study titled: A phase 2b trial comparing the administration of alteplase or placebo for 
Reperfusion Injury Control in acute stroke patients secondary to large vessel occlusion 
treated with mechanical thrombectomy 
 
The signatures on this page indicate review and approval of the final version of the 
protocol. 
 
By signing this document we confirm that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not 
limited to, the International Conference on Harmonization Guideline for Good Clinical 
Practice (GCP) and the ethical principles that have their origins in the Declaration of 
Helsinki. 
 
 
 
 
 
_______________________  
 
 
 
_________________  
Dr. Ángel Chamorro   
 
 
 
 
   Date of signature 
Chairman/ Sponsor’s Representative Name  
 
 
 

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PROTOCOL SIGNATURE PAGE PRINCIPAL INVESTIGATOR  
 
STUDY CODE: CHOICE   
 
Study titled: CHemical Optimization of Intraarterial Cerebral Embolectomy in acute stroke 
patients treated with mechanical thrombectomy 
The signatures on this page indicate review and approval of the final version of the 
protocol. 
 
By signing this document we confirm that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not 
limited to, the International Conference on Harmonization Guideline for Good Clinical 
Practice (GCP) and the ethical principles that have their origins in the Declaration of 
Helsinki. 
 
 
 
 
 
 
_________________________  
Principal Investigator’s Name 
 
 
 
 
________________                            
 
________________ 
 Signature  
 
 
 
 
 
Date of signature 
 
 
 

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1. 
ADMINISTRATIVE INFORMATION 
 
Title:  CHemical OptImization of Cerebral Embolectomy in patients with acute stroke 
treated with mechanical thrombectomy (CHOICE TRIAL) 
 
Protocol version:  Version 3, November 28, 2019 
 
Funding:  Marató de TV3 
 
Study Steering Committee 
Ángel Chamorro. Neurologist (Chair), Hospital Clínic, Barcelona 
Sergio Amaro. Neurologist, Hospital Clínic, Barcelona 
Pere Cardona. Neurologist, Service of Neurology, Hospital de Bellvitge, Barcelona 
Antonio Dávalos. Neurologist, Hospital Germans Trias I Pujol, Badalona 
Juan Macho. Neurointerventionalist, Hospital Clínic Barcelona 
Joan Martí-Fábregas, Neurologist, Hospital Sant Pau, Barcelona 
 
Laura Oleaga. Neuroradiologist, Hospital Clínic, Barcelona 
Jaume Roquer. Neurologist, Service of Neurology, Hospital del Mar, Barcelona 
Joaquín Serena. Neurologist, Service of Neurology, Hospital Josep Trueta, GironaFerran 
Torres.  Biostatistician, Hospital Clínic, Barcelona 
Xabier Urra. Neurologist, Hospital Clínic, Barcelona 
 
Sponsor 
Fundació Clínic per a la Recerca Biomèdica 
Roselló, 149-153 
otri@clinic.cat  
 
Data and Safety Monitoring Board (DSMB) 
Tudor Jovin (Chair). Neurointerventionalist, University of Pittsburgh 
Enrique Leira. Neurologist. University of Iowa 
José Ríos, Biostatististics Unit. Autonomous University of Barcelona 
 
Neuroimaging Core Lab 
Luis San Román (Chair). Neurointerventionalist, Hospital Clínic, Barcelona 
Antonio López. Neurointerventionalist, Hospital Clínic, Barcelona 
Carlos Laredo, Physicist, Hospital Clínic, Barcelona 
 

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Neurointerventionalism Harmonisation 
Jordi Blasco (Chair). Neurointerventionalist, Hospital Clínic, Barcelona 
Alejandro Tomasello. Neurointerventionalist, Hospital Vall de Hebrón, Barcelona 
Leopoldo Guimaraens. Hospital del Mar, Barcelona 
Roger Barranco. Hospital de Bellvitge, Barcelona 
Carlos Castaño, Neurointerventionalist, Hospital Germans Trias i Pujol, Badalona 
 
Patient’s recruitment Board 
Mónica Millán (Chair), Neurologist, Hospital Germans Trias i Pujol, Badalona   
Elisa Cuadrado, Neurologist, Hospital del Mar, Barcelona 
Pol Camps, Neurologist, Hospital Sant Pau, Barcelona 
 
Funder and Sponsor of the CHOICE trial will have no influence on the study design, 
collection, management, analysis and interpretation of data, writing of the report and 
decision to submit the report for publication. Chairs and members of the Executive 
Committee will perform all these activities. 
 
 

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2. 
INTRODUCTION 
 
Stroke represents the second single most frequent cause of death for people older than 60 
years, the most frequent cause of permanent disability, and the second most common 
cause of dementia, and uses approximately 3–7% of the total health-care expenditure in 
high-income countries. By 2050, more than 1.5 billion people in the world will be aged 65 
years or older and the global burden of stroke will keep increasing in parallel with the 
ageing population.1 Although a remarkable progress has been made in the management of 
patients with acute ischemic stroke during the past 10 years, with the widespread 
implementation of specialist stroke units, evidence of the efficacy of intravenous (IV) 
thrombolytic treatment, and reporting of randomized controlled trials (RCTs) establishing 
the value of endovascular thrombectomy, 2  stroke still represents the first cause of 
permanent disability in adult people. In consequence, there is a pressing need to continue 
investigating new treatments for this devastating disease. 
 
2.1 Background and rationale 
  
2.1.1 Overview of reperfusion therapy in acute ischemic stroke 
 
Intravascular thrombosis remains a leading cause of death and disability for which 
thrombolysis is the only pharmacological remedy. The thrombolytic, rt-PA, has become 
essentially synonymous with thrombolysis but its use, or that of one of its longer half-life 
derivates, has been declining due to its inadequate efficacy in AMI, incompatibility with 
PCI, limited efficacy and risk of ICH in ischemic stroke, and too high a bleeding risk for 
most patients with venous thromboembolism. Instead, intra-arterial devices have become 
the treatment of choice in AMI are becoming more frequently used in ischemic stroke as 
well. The resort to these time-consuming methods to treat very time-sensitive conditions is 
a reflection on the inadequacy of current thrombolysis.  
 
The main aim of acute ischemic stroke treatment is to salvage the penumbra or volume of 
hypo-perfused, non-functional, yet still viable tissue surrounding the infarcted core, and 
several reperfusion therapies have shown positive clinical results. A meta-analysis of 
individual patient data from nine randomized trials comparing intravenous alteplase with 
placebo or open control showed that alteplase increased the odds of a good stroke 
outcome (i.e., a modified Rankin scale score of zero or one at 3–6 months), with earlier 
treatment associated with bigger proportional benefit.3 Accordingly, rapid administration of 
IV recombinant tissue-type plasminogen activator (rt-PA) to appropriate patients remains 
the mainstay of early treatment of acute ischemic stroke.4 However, IV rt-PA induces 
recanalization in only 40% of the cases,5 and this rate is even lower in occlusions of the 

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M1 segment of the middle cerebral artery or the intracranial internal carotid artery, where 
the rate of recanalization is approximately 20% and 10%,6,7 respectively. 
 
IA thrombolysis involves administration of high concentrations of thrombolytic agents near 
the thrombus, utilizing lower doses than systemic administration, which may result in lower 
systemic complications, and less local neurotoxic effects of thrombolytic agents. The 
disadvantages of the IA modality include the potential delay required to obtain initial 
cerebral angiography and position of the micro-catheter for administration of the 
thrombolytic agent. IA thrombolysis also allows the simultaneous use of mechanical 
devices to facilitate thrombolysis, 8  and combining the IA delivery with mechanical 
thrombectomy (MT) increases the surface area exposed to the thrombolytic agents. The 
concern of delaying treatment onset using the IA route alone led to the initiative of 
delivering the IA thrombolysis following IV thrombolysis. Thus, the Emergency 
Management of Stroke (EMS) bridging trial, which had a randomized, double-blind, 
placebo control design, demonstrated higher  recanalization rates (53%) in the combined 
IV/IA alteplase treatment group than in the IA alteplase group (28%).9 In this study, 35 
patients were treated within 3 hours of symptom onset and received IV rt-PA (0.6 mg/kg, 
60 mg maximum, 10% of the dose as a bolus over 1 minute and the remainder over 30 
minutes) or placebo. This was followed by immediate cerebral angiography and local IA 
administration of rt-PA through the catheter if a clot in the appropriate arterial distribution 
was identified. A maximum local IA dose of 20 mg was given and the infusion was 
continued for a maximum of 2 hours. In EMS, there was no difference in clinical outcomes 
between the 2 groups and no significant difference in the rate of symptomatic ICH. Indeed, 
there were no parenchymal hematomas in the trial; symptomatic ICH within 24 hours 
occurred in 1 placebo/IA patient only; beyond 24 hours, symptomatic ICH occurred in 2 
IV/IA patients only. 
 
The Interventional Management of Stroke Trial III (IMS III) was a PROBE, 2-arm, 
superiority trial that enrolled 656 patients with a major ischemic stroke who received IV rt-
PA within 3 hours of stroke onset. 10 Patients were randomly allocated 1:2 to standard dose 
IV rt-PA (0.9 mg/kg) or to IV rt-PA 0.6 mg/kg followed by endovascular therapy with a 
device and/or IA rt-PA, if occlusion persisted and if the endovascular intervention could be 
begun within 5 hours and completed within 7 hours of onset. For subjects who the study 
neurointerventionalist elected to treat with the standard micro-catheter infusion of rt-PA, as 
in the IMS I Pilot Trial, the rt-PA concentration for IA administration was 0.5 mg/1 ml 
solution (50 mg/100 cc - reconstituted with 50 cc of sterile water without preservatives and 
diluted to 100 cc total with 50 cc normal saline). A maximum IA dose of 22 mg was 
administered over two hours of infusion. The trial was stopped early for futility after 656 of 

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projected 900 subjects were enrolled. There was no significant difference in outcome 
between the IV rt-PA only group and the endovascular group for the primary end point of 
the percentage of patients with a good outcome as measured by modified Rankin Scale 
(mRS) score of 0 to 2 or for death at 90 days. Findings in the endovascular-therapy and 
intravenous rt-PA groups were similar for mortality at 90 days (19.1% and 21.6%, 
respectively; P = 0.52) and the proportion of patients with symptomatic intracerebral 
hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P = 
0.83).Yet, the IMS III trial showed that the proportion of patients who obtained a mRS 
score of 2 or less at 90 days of the therapy (primary outcome of the study) increased in 
parallel with the magnitude of reperfusion measured using the Thrombolysis In Cerebral 
Infarction (TICI) grade.11 Thus, the primary outcome occurred in 12.7% of the 55 patients 
with a TICI score of 0, in 27.6% of the 29 patients with a TICI score of 1, in 34.3% of the 
108 patients with a TICI score of 2a, in 47.9% of the 119 patients with a TICI score of 2b, 
and in 71.4% of the 7 patients with a TICI score of 3 (P<0.001). These results highlight the 
importance of obtaining complete brain reperfusion to maximize the benefits of mechanical 
thrombectomy. 
 
Prior small case series have demonstrated that IA therapy with thrombolytic agents,12 ,13 
Mechanical Clot Disruption (MCD),14 or a combination of IA thrombolytic agents with MCD 
15,16 are safe and effective with and without prior full-dose IVT in restoring flow in acute 
large artery occlusions. Nine IA thrombolytic agents, when used in low doses, have been 
found to be safe in conjunction with MCD. A series of 8 patients suggested that an IA rt-PA 
dose up to 40 mg is safe,17 but these patients did not receive prior IVT. The overall efficacy 
and safety of IA versus IV thrombolysis in patients with acute ischemic stroke was updated 
in a recent meta-analysis18 that showed that IA thrombolysis in patients was significantly 
more likely to result in a favourable outcome than was IVT. However, other meta-analyses 
using different study selection criteria found no significant benefit of IA over IV. 19 
Altogether, IA thrombolysis initiated within 6 h of stroke onset might be considered in 
carefully selected patients who have contraindications to the use of IV alteplase, although 
alteplase does not have US Food and Drug Administration approval for intra-arterial use, 
and the adverse effects associated with this administration route have yet to be 
established.20 Unfortunately, there are no published reports of observational or randomized 
studies of IA thrombolysis performed after MT to attempt improving the perfusion rate of 
territories distal to the proximal arterial occlusion. 
 
In 2015, several RCTs showed that MT results in complete vessel recanalization in three 
of four treated patients, and this treatment was superior to IV alteplase in improving stroke 
outcomes in selected patients with large proximal artery occlusions. 21 , 22 , 23 , 24 , 25  A 

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comprehensive systematic review and meta-analysis of eight RCTs (totalling 2049 
patients) confirmed that MT was associated with an increased likelihood of good outcome 
(i.e., a modified Rankin scale score of zero to two at 90 days) compared with standard 
alteplase treatment. 26  Patients receiving alteplase before MT also had a significant 
improvement in outcome compared with patients who received only one of these treatment 
approaches (Yarbrough et al. 2015). MT in combination with IA pharmacologic 
thrombolysis has been associated with higher rates of recanalization. 27  In a recent 
individual patient data meta-analysis by the HERMES group of patients with large-vessel 
ischemic stroke, earlier treatment with MT + medical therapy compared with medical 
therapy alone was associated with lower degrees of disability at 3 months and the clinical 
benefit became non-significant after 7.3 hours. 28 More recently, the DAWN (Diffusion 
weighted imaging (DWI) or computerized tomography perfusion (CTP) assessment with 
clinical mismatch in the triage of wake up and late presenting strokes undergoing neuro-
intervention with Trevo) data was reported.29 Patients with wake-up and late-presenting 
stroke were screened and if they met the inclusion criteria (age ≥18 years, NIHSS ≥10, 
pre-mRS 0–1, time-last-seen-well to randomization 6–24 hours, excluding large infarcts 
and confirmation of large vessel occlusion on CTA or MRA) underwent imaging with the 
RAPID software, CTP or DWI. Qualifying patients had to meet the following clinical 
imaging mismatch criteria: patients’ ≥80 years old had to have NIHSS ≥10 with a core 
˂21cc; ˂80 year old patients had to have NIHSS ≥10 with a core of ˂31cc or NIHSS ≥20 
with a core of ˂51cc. The symptomatic intracerebral hemorrhage (sICH) rate was 4.8% in 
the treatment arm versus 3.2% in the control arm. A statistically significant difference was 
observed in neurological deterioration (defined as greater than 4 points worse on the 
NIHSS by five days) between the two groups with 10.5% in the treatment arm versus 
22.1% in the control arm (p˂0.01). In the weighted mRS based co-primary outcome, the 
mean mRS value in the treatment group was 5.5 versus 3.4 in the control group; a 2.1 
difference in the weighted mRS score, which is highly significant with a Bayesian 
probability of superiority of >0.9999 (which is similar to p˂0.0001). The co-primary 
endpoint of 90-day functional independence was 48.6% in the treatment group versus 
13.1% in the control group; a 35.5% actual difference, which is highly significant with a 
Bayesian probability of superiority of >0.9999. This translates to a number needed to treat 
of 2.8 to achieve functional independence. 
 
Despite the unquestionable value of current reperfusion therapies less than half of the 
patients that receive MT show permanent benefits. 15–19 A likely relevant reason to these 
insufficient clinical benefits is the lack of adequate brain reperfusion despite successful 
recanalization (futile recanalization). In the recent endovascular trials, “successful” brain 
reperfusion occurred in 75% of treated patients, including a group of 37% of patients who 

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obtained complete reperfusion (mTICI 3 score) and a group of 38% of patients who 
obtained only near complete reperfusion (mTICI 2b score) on cerebral angiography. 
Although several studies have shown a graded association between the amount of brain 
tissue re-perfused and the degree of clinical benefit,30 the most recent endovascular trials 
did not report individual stroke outcomes amongst patients with mTICI 2b or 3 scores. 
 
2.1.2 Maximizing brain reperfusion: a target for treatment improvement 
Structural and functional alterations in the microvasculature may be major barriers for 
adequate reperfusion of the ischemic brain regardless of complete recanalization and 
constitute the no-reflow phenomenon. 31 , 32  In experimental models, downstream 
microvascular thrombosis (DMT) may occur early during brain ischemia and before 
recanalization, and this mechanism may be a major contributing factor to incomplete 
reperfusion.33 It is possible that a similar mechanism may limit the therapeutic potential of 
MT in patients with acute stroke. Originally attributed to spasm or cellular swelling around 
the vessel wall, the no reflow phenomenon is currently ascribed to microvascular clogging 
triggered by neutrophils trapped within the microcirculation,34 clogging of the perivascular 
space, 35 distal micro-embolism, 36  and oxidative stress generated in pericytes, 37 , 38  or 
arteriolar smooth muscle cells.39 In experimental studies, this clogging was prevented or 
reversed using genetic or pharmacological manipulations of cell mediated inflammation,40 
but these measures were futile or harmful at the bedside.41 Considering the nature of these 
mechanisms, we believe that IA thrombolytic therapy is a pharmacological approach that 
deserves adequate testing is patients with incomplete reperfusion following MT. 
Mechanical embolus retrieval does recanalize the occluded larger arteries without 
considering the status of the distal smaller arteries. However, recanalization of the primary 
arterial occlusive lesion does not necessarily translate into reperfusion of ischemic tissue 
through the distal capillaries. IA pharmacologic therapy remains the only possible 
alternative in such situations to ensure complete angiographic reperfusion to the ischemic 
tissue. 
 
2.1.3 Justification of CHOICE 
While previous studies of improving brain reperfusion using IA thrombolytic therapy were 
done before the recanalization of a proximal LVO, in this project we intend to administer IA 
thrombolysis after the successful recanalization of a LVO. Indeed, this temporal approach 
might prove to be crucial to facilitate a greater access of the drug to the distal vascular bed 
and thus allow a more effective lytic effect on microcirculatory thrombi. 
The current guideline for healthcare professionals from the American Heart 
Association/American Stroke Association (AHA/ASA) states that the use of salvage 
technical adjuncts including IA fibrinolysis may be reasonable to achieve a satisfactory 

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angiographic result in patients treated with MT (Class IIb recommendation).[20] Yet, the 
usefulness, and effectiveness of salvage IA thrombolysis are not well established. The 
AHA/ASA also recommends that the angiographic technical goal of MT is to achieve a 
mTICI 2b or 3 scores.[20] Yet, growing evidence shows that combining these two mTICI 
scores into a single category of angiographic results may be misleading because they may 
show significant differences in clinical and radiologic outcomes. [11,42,43] To better address 
this issue, we reviewed recently our own experience, and compared the clinical and 
radiologic outcomes of patients with a mTICI 3 or a mTICI 2b score at the end of MT.44 All 
these patients received stent-retrievers and pretreatment IV alteplase was administered to 
approximately one third of the patients. The outcomes were evaluated in multivariate 
models following the HERMES Collaborators criteria, [28] and the covariates assessed in 
the models included age, sex, baseline stroke severity, target occlusion location, 
ASPECTS, pre-treatment IV alteplase, time to recanalization and the collateral score. 
Between March 2010 and May 2016, 125 of 347 (36%) patients treated with MT at 
Hospital Clínic of Barcelona met the entry criteria of the study. Contrarily, 222 patients 
were excluded for (1) a posterior circulation stroke (n = 31); (2) lost to follow-up due to 
transfer to a referral Primary Stroke Center after MT (n = 113); (3) unavailability of 
multimodal brain imaging (n = 37); or (4) mTICI 2a/1/0 score at the end of MT (n = 41). 
Recanalization of the local occlusion occurred within a median (IQR) of 285 (210–369) 
minutes of symptom onset; 51 (41%) patients achieved an mTICI 2b score and 74 (59%) 
patients a mTICI 3 score. Patients with final mTICI 2b or 3 scores did not show significant 
differences in demographics, risk factors, target occlusion location, use of bridging 
intravenous alteplase before MT, or size of infarct core calculated either with the 
ASPECTS on NCCT or on CTP (Table 1). Expectedly, a mTICI 3 score was associated 
with shorter time to recanalization from stroke onset, and less number of device passes. A 
final mTICI score 3 was more frequent in patients with good leptomeningeal collateral 
scores, and this association was highly significant in a multivariate model adjusted for the 
predefined covariates of the study, (odds ratio 2.765 95% CI 1.248–6.123). The primary 
outcome measure of the study showed that more patients with mTICI 3 were in a better 
score category on the mRS at 90 days than were patients with mTICI 2b, and this 
difference was statistically significant in ordinal regression analysis adjusted for 
confounders (odds ratio 2.018, 95% CI 1.033–3.945). 
Excellent outcome at 90 days was reported in 18 (35%) of 51 patients achieving an mTICI 
2b score and in 41 (55%) of 74 patients achieving an mTICI 3 score, (adjusted odds ratio 
2.739, 95% CI 1.124–6.182). Early dramatic recovery at 24 hours was diagnosed in 25 
(49%) patients with mTICI 2b and in 54 (73%) patients with mTICI 3, (adjusted odds ratio 
3.078, 95% CI 1.384–6.849). Finally, the mortality and the rate of symptomatic 
intracerebral hemorrhage did not differ between patients with mTICI 3 or 2b scores. 

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Collectively, this study demonstrated the relevance of achieving an mTICI 3 score at the 
end of MT to maximize the functional benefits of brain reperfusion. Compared with patients 
with an mTICI 2b score, patients who achieved a mTICI 3 had better overall health 
transitions in the full range of the mRS, increased proportions of excellent outcome and 
early dramatic recovery, less infarct growth and smaller final infarcts. Altogether, these 
results justify the search of more effective reperfusion therapies and call for a change of 
current practice recommendations in patients treated with MT indicating that only an mTICI 
3 angiographic score should be considered success after MT. 
 
2.2 OBJECTIVES 
The study objective is to evaluate whether rt-PA is safe and efficient as an add-on to 
mechanical thrombectomy in patients with acute ischemic stroke and complete or near-
complete recanalization of a proximal vessel occlusion and successful brain reperfusion on 
cerebral angiogram (corresponding to mTICI score 2b/3). 
 
2.3 TRIAL DESIGN 
Multicenter, randomized, placebo-controlled, double blind, phase 2b trial of acute stroke 
patients treated with MT, in which two therapies are compared: rt-PA or placebo. Allocation 
at each center will account for 1 stratum: use of alteplase (yes vs. no) before MT. Subjects 
will be followed up to 90 days post-randomization. 
 
3. 
METHODS 
3.1 
STUDY SETTING 
The CHOICE trial will be performed in Catalonia Autonomous Community, and it will 
include seven Endovascular Stroke Centers located in Barcelona,  Badalona and Girona: 
 
1. Hospital Clínic de Barcelona (HC) 
2. Hospital Universitari de Bellvitge (HB) 
3. Hospital Vall d’Hebron (HVH) 
4. Hospital de la Santa Creu i Sant Pau (HSP) 
5. Hospital del Mar (HM) 
6. Hospital Germans Trias i Pujol (HGTP) 
7. Hospital Josep Trueta (HJT) 
 
 
3.2 
ELIGIBILITY CRITERIA 
3.2.1   Inclusion Criteria 
1. Patients with symptomatic large vessel occlusion (LVO) in the anterior, middle or 
posterior cerebral artery treated with MT resulting in an mTICI score 2b/3 at end of 

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the procedure.. Patients with an mTICI score 2b/3 on the diagnostic cerebral 
angiography before the onset of MT are also eligible for the study.   
2. Estimated delay to onset of rescue intraarterial rt-PA administration <24 hours from 
symptom onset, defined as the point in time the patient was last seen well 
3. No significant pre-stroke functional disability (modified Rankin scale 0-1), or mRS 
>1 that according to the investigator is not related to neurological disease (i.e. 
amputation, blindness) 
4. Age ≥18 
5. ASPECTS >6 on non-contrast CT (NCCT) scan or MRI if symptoms lasting <4.5 
hours or ASPECTS >6 on CT-Perfusion (CTP) or DWI-MRI if symptoms >4.5 <24 
hours.  
6. Informed consent obtained from patient or acceptable patient surrogate 
 
3.2.2 Exclusion Criteria 
1. 
NIHSS score on admission >25 
2. 
Contraindication to IV t‐PA as per local national guidelines (except time to therapy) 
3. 
Use of carotid artery stents during the endovascular procedure requiring dual 
antiplatelet therapy during the first 24h 
4. Female who is pregnant or lactating or has a positive pregnancy test at time of 
admission 
5. Current participation in another investigation drug or device treatment study (except 
observational study i.e.: RACECAT or clinical trials not testing new medical devices 
or new drugs i.e.IMAGECAT) 
6. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency 
7. Known coagulopathy, INR > 1.7 or use of novel anticoagulants < 48h from symptom 
onset 
8. Platelets < 50,000 
9. Renal Failure as defined by a serum creatinine > 3.0 mg/dl (or 265.2 μmol/l) or 
glomerular Filtration Rate [GFR] < 30 
10. Subject who requires hemodialysis or peritoneal dialysis, or who have a 
contraindication to an angiogram for whatever reason 
11. Any hemorrhage on CT/MRI 
12. Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT or MRI 
scan is normal 
13. Suspicion of aortic dissection 
14. Subject currently uses or has a recent history of illicit drug(s) or abuses alcohol 
15. History of life threatening allergy (more than rash) to contrast medium 
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17. Serious, advanced, terminal illness with anticipated life expectancy < 6 months 
18. Pre-existing neurological or psychiatric disease that would confound evaluation 
19. Presumed vasculitis or septic embolization 
20. Unlikely to be available for 90-day follow-up (e.g. no fixed home address, visitor 
from overseas) 
 
3.2.3 Brain Imaging 
Patients will have a non-contrast CT scan (NCCT) or brain MRI at hospital admission to 
rule out the presence of blood and estimate the Alberta stroke program early CT score 
(ASPECTS) that will be used to select into the trial only patients with ASPECTS > 6. 
Concomitantly, a whole brain CT-Perfusion (CTP) or DWI-MRI will be performed before 
transfer of the patient to the angio suite. The protocol for CTP acquisition will be 
harmonized by the Neuroimaging Core Lab as described in the Appendix. Patients will 
then receive MT according to the general methods described below. At 10 minutes of 
completion of the experimental therapy the angiographic results will be recorded on 
anterior-posterior and lateral projections for central scoring according to the modified 
Treatment of Cerebral Ischemia (mTICI) grading score (See below section 3.3 for further 
clarification). At 24 +12 hours of randomization, a NCCT (or MRI) will be performed to 
assess the presence of early bleeding complications following ECASS3 criteria (Appendix). 
At 48+24 hours of randomization, a brain MRI with DWI and T2* sequences will be 
performed to measure the volume of the infarction, estimate the growth of the infarction 
and assess the presence of late bleeding complications (Appendix). If a brain MRI cannot 
be performed for contraindications, intolerance or unavailability, a NCCT will be indicated. 
The admission NCCT (or MRI), admission CTP (or DWI-MRI), post-MT angiography, 24h 
NCCT and 48h brain MRI or NCCT will be transferred to the Central Imaging Core Lab 
(CICL) for storage and reading within 72 hours of image acquisition (Appendix). 
 
Other study visits and study assessments are specified in Appendix 6.5. 
 
3.3 
Interventions 
Patients with confirmed large vessel occlusion (LVO) of the anterior, middle or posterior 
cerebral artery and treated with MT will receive alteplase (Actylise®) or placebo if the 
mTICI score on cerebral angiography is 2b/3. Patients displaying an mTICI score 2b/3 on 
cerebral angiography before a first pass with an endovascular device could still be eligible 
for randomization into the study because we define the onset of mechanical thrombectomy 
as the time of groin puncture. 
Endovascular treatment will be carried out according to the usual practice of each center. 
Once the intracranial occlusion is confirmed, thrombectomy will be performed using any of 

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the techniques currently used, provided that the devices used are CE marked. The use of 
balloon catheter will be at the discretion of the interventionalist, as well as the 
thrombectomy system, which may be by aspiration, by means of stent-retriever devices or 
combination of both techniques. On the contrary, patients treated with devices under study 
will not be included in CHOICE. 
Likewise, the type of anesthesia will be decided by the team that performs the procedure, 
and none of the options, local anesthesia, sedation or general anesthesia, are grounds for 
exclusion. 
Once the thrombectomy procedure is finished, the cases that meet the inclusion criteria 
from the point of view of final reperfusion, that is, those with a mTICI 2b/3 will be 
randomized. The maximum will be six passes or six aspirations for the patient to meet the 
criteria for inclusion in CHOICE. The thrombectomy procedure will be considered complete 
once the neurointerventionalist considers that the angiographic result is good enough and 
it does not seem reasonable by endovascular thrombectomy techniques to continue the 
procedure to obtain a better revascularization. 
Aside from procedurally administered heparinized saline, IV heparin is prohibited until after 
the 24 hour neuro-imaging has been performed to minimize the risk of intracranial 
hemorrhage.  Blood pressure should be tightly controlled during the first 24 hrs to less than 
185/110 mmHg. If TICI ≥2b is achieved, BP goal should be less than 160/90 mmHg. Given 
the association between hyperglycemia and SICH in patients undergoing IA thrombolysis, 
a target blood glucose level of less than 160 mg/dL is recommended.  
The neurointerventionalist will receive the medication to be injected according to protocol, 
proceeding to inject said medication through a distal access catheter or microcatheter 
located proximal to the residual thrombus (if still present) and distally to the origin of the 
lenticulostriated branches. The administration of placebo / rTPa will be infused for 15 '. The 
superselective catheterization of the occluded branch (s) to perform the administration of 
the medication vs. the injection of said medication from more proximal positions will be at 
the decision of the neurointerventionalist depending on the difficulty of access, risk of distal 
catheterization, patient agitation, occluded branches , etc. It should be recorded in the 
angiography images, that will be sent to the Core Lab, if the placebo / rTPa infusion has 
been performed from M1 or from any of the bifurcation branches (an image of the position 
of the catheter from which the placebo / rTPa injection was made has to be sent). It is 
recommended not to inject the medication / placebo immediately proximal to an occluded 
artery, without exit, because of the risk of directly accumulating a greater concentration of 
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All the patients will be given a 15 minutes IA infusion at a drug concentration of 1.0  mg/ml. 
At 15 minutes of IA treatment onset, the infusion will be stopped and  
the angiographic score assessed. If the angiographic score is improved compared with the 
baseline score the procedure is terminated, otherwise a new angiographic series will be 
repeated in 5-10 minutes before the end of the procedure in front and profile projections.  
If contrast extravasation occurs during the IA administration of alteplase or placebo, it 
could be indicative of active bleeding. In that case, IA drug infusion should be stopped 
immediately. Furthermore, it is recommended the occlusion of the culprit vessel if contrast 
extravasation occurs at an accessible vessel    
 
Study drug will be prepared according to the following steps:  
1. Dilute 3 vials of 10 mgs (alteplase or placebo) in 30 cc of sterile water for injection 
(SWI), to attain a 30 cc solution at a concentration of 1mg/ml 
2. Calculate the volume of cc of infusion and therefore the total dose as per the formula: 
 (Patient’s weight in Kgs multiplied by 0.225) 
 
As shown in the figure, a patient of 80 Kgs will receive 18 cc of infusion for 15 min, totalling 
a dose of 18 mg of alteplase. A patient of 100 Kgs will receive 22.5 cc of infusion for 15 
min, totalling a dose of 22.5 mg of alteplase. 
 
Situations that will lead to NO INCLUSION IN CHOICE: Recovery of the patient ad 
integrum at the table. 
The placebo will consist of a lyophilized white powder containing 0.2 mol/L arginine 
phosphate, 0.01% polysorbate 80, and pH 7.4 after reconstitution.  
 
 
 

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Figure 
 
 
3.3.1 Blinding 
The solutions of alteplase or placebo are limpid, transparent and colourless. Alteplase 
(Actilyse 10 mg powder and solvent for solution for injection and infusion) and placebo will 
be provided in kind by Boëhringer Ingelheim. The secondary conditioning of the 
investigation treatment will be performed by Alcura Health Spain S.A. 
   
3.3.2 Concomitant care and interventions prohibited during the trial 
Patients will receive alteplase upon hospital arrival if indicated according to each 
institutional protocol, and always in agreement with European Stroke Organization and 
national guidelines. The use of anticoagulants and dual antiplatelet therapy will not be 
permitted during the 24 hours after the administration of the experimental therapy. 
 
3.4 Assignment of intervention. Allocations and sequence generation 
Randomization codes will be produced by means of the PROC PLAN of the SAS system, 
with a 1:1 ratio of assignment between both arms, stratifying by centre, and use of IV 
alteplase (no or yes) in blocks multiple of 2 elements. The time of randomization will be 
initiated whenever a full angiogram establishes the patient has an mTICI 2b/3 score. A 
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where the clinical center staffs enter the basic baseline and eligibility information of a 
subject prior to enrolment. If the subject’s eligibility status is confirmed, the computer 
program on the server will make the treatment assignment based on the randomization 
algorithm specified. 
 
3.5 
Outcomes 
3.5.1 Primary outcome 
The primary outcome will be the proportion of patients with a mRS 0 to 1 at 90 days  
3.5.2 Secondary Outcomes 
 The shift analysis of the modified Rankin Scale (mRS), at day 90. The mRS at 90 days 
will be analyzed using a proportional odds model (POM) that combine into single worst 
rank the last two categories (5: severe incapacity and 6: death).  
 Infarct Expansion Ratio on DWI-MRI (continuous variable), at 48h (+/- 24h) of stroke 
 Proportion of patients with excellent outcome (mRS 0-1) at day 90 
 Proportion of patients with/without infarct expansion (dichotomous variable) 
 Infarction Volume on DWI-MRI, at 48h (+/- 24h) of stroke onset 
 
Proportion of patients with angiographic improvement on the Arterial Occlusive Lesion 
(AOL) scale. AOL describes arterial patency at the site of occlusion based on the 
degree of luminal opening (none, partial, or complete) with further qualification based 
simply on the presence (grades 2 or 3) or absence (grades 0 or 1) of any downstream 
flow. 
3.5.3 Tertiary outcomes 
 
Barthel Scale score of 95 to 100, at day 90 
 
Ischemic worsening (≥ 4 points in the NIHSS score) within 72 hours of stroke onset 
not attributable to stroke recurrence 
 
Quality of life measured with the EuroQol Group 5-Dimension Self-Report 
Questionnaire (EQ-5D-3L) at 90 days  
 
3.5.4 Pre-specified subgroup analysis 
Proportion of patients with improved mTICI 2b score in the following subgroups: 
1. IV Alteplase use on admission (yes versus no) 
2. MT started within 7.3h of symptoms onset versus MT started between 7.4h and 24h. 
3. Admission serum glucose concentration≤100 mg/dL versus >100 mg/dL 
4. Males vs. Females 
5. Baseline angiographic score mTICI2b brain reperfusion versus baseline angiographic 
score eTICI2c/3 brain reperfusion  
 

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3.5.5 Safety outcomes 
1. Mortality at 90 days 
2. sICH rates at 24 hours.  
 
All ICH will be classified by a central core-lab using the ECASS3 criteria. Symptomatic 
ICH will be defined as per the ECASS3 definition: deterioration in NIHSS score of ≥4 
points within 24 hours from treatment and evidence of any apparently extravascular 
blood in the brain in the 24 hours follow-up imaging scans. The incidence of any 
asymptomatic hemorrhage measured at 24 hours will also be compared. 
  
3.5.6 Adverse events (AEs) and Serious Adverse Events (SAEs) 
3.5.6.1 Definitions and Classification 
 
An Adverse Event (AE) is any untoward medical occurrence in a patient temporarily 
associated with the use of the investigational drug, whether or not considered related to 
the investigational drug. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of the drug, whether or not considered related to the 
drug. 
Any AE experienced by the study subject after enrolment (equal to the time of 
randomization) must be recorded in the CRF. 
All AEs and SAEs will be monitored and collected from the time of enrolment (defined as 
time of randomization) through 90 day follow-up visit. All SAEs and SUSAR must be 
reported to CRA or designee within 24 hours of becoming aware of their occurrence in 
order to comply with regulatory reporting requirements. In the event that the eCRF is 
unavailable a written form sent by e-mail or fax is acceptable (the required form will be filed 
in the ISF) 
Underlying (pre-existing) symptoms or diseases are not reported as Adverse Events (AEs) 
unless there is an increase in severity or frequency during the course of the investigation, 
but they need to be reported in the eCRF as Relevant Medical History.   
Death should not be recorded as an adverse event, but should only be reflected as an 
outcome to another specific AE/SAE.  
A qualified medical investigator must review all information available to determine the 
seriousness, causality, severity and outcome of the AE as well as to assess whether it 
meets the criteria for classification as a serious adverse event, which requires immediate 
notification to the sponsor or its designated representative.  
All AEs and the treatment and follow-up required must be documented in the subject’s 
medical records and in the eCRF.  

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A procedural complication may constitute an AE if it results in an untoward change from 
the subject’s baseline health. 
 
Serious Adverse Event (SAE) is defined as an adverse event that:  
a) Led to a death, injury or permanent impairment to a body structure or a body 
function.  
b) Led to a serious deterioration in health of the subject, that either resulted in:  
- A life-threatening illness or injury, or  
- A permanent impairment of a body structure or a body function, or  
- In-patient hospitalization or prolongation of existing hospitalization, or  
- In medical or surgical intervention to prevent life threatening illness  
c) Led to foetal distress, foetal death or a congenital abnormality or birth defect.  
Note: Planned hospitalization for pre-existing condition, or a procedure required by the 
Clinical Investigation Plan, without a serious deterioration in health, is not considered a 
serious adverse event. 
Abnormal laboratory findings (e.g. clinical chemistry, hematology, urinalysis) or other 
abnormal assessments (e.g. ECG, vital signs) that are judged by the investigator as 
clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE or 
SAE as previously defined. Clinically significant abnormal laboratory findings or other 
abnormal assessments that are detected during the study or are present at baseline and 
significantly worsen following the start of the study will be reported as AEs or SAEs.  
However, clinically significant abnormal laboratory findings or other abnormal assessments 
that are associated with a disease reported in the medical history, unless judged by the 
investigator as more severe than expected for the subject’s condition, or that are present 
or detected at the start of the study and do not worsen, will not be reported as AEs or 
SAEs. 
 
3.5.6.2 
Recording of AEs and SAEs 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostic reports) relative to 
the event. The investigator will then record all relevant information regarding an AE/SAE 
into the CRF. It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to the sponsor in lieu of completion of the appropriate AE/SAE CRF pages 
and forms. For each adverse event, start and stop dates, action taken, outcome, intensity 
and relationship to study drug (causality) must be documented. If an AE changes in 
frequency or intensity during a study, a new entry of the event must be made in the CRF. 
The investigator will attempt to establish a diagnosis of the event based on signs, 
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signs/symptoms should be documented. All details of any treatments initiated due to the 
adverse event should be recorded in the subject’s notes and the CRF/form. 
 
3.5.6.3 Prompt Reporting of SAEs 
SAEs require immediate action. Once an investigator becomes aware that an SAE has 
occurred, he/she will immediately notify the clinical coordinator via telephone within one 
working day. The study SAE form must be completed as thoroughly as possible with all 
available details of the event, signed by the investigator (or appropriately qualified 
designee), and reported into the eCRF or to the study manager, within one working day of 
first becoming aware of the event. The equivalent SAE page should be filled in on the 
CRF. 
If the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before reporting the event and completing the form. The 
form will be updated when additional information is received. 
The investigator will always provide an assessment of causality at the time of the initial 
report. In accordance with local IEC requirements, the investigator must also notify their 
Ethics Committee of any SAEs according the guidelines of the Ethics Committee. The 
investigator and others responsible for subject care should institute any supplementary 
investigations of SAEs based on their clinical judgment of the likely causative factors. 
This may include seeking further opinion from a specialist in the field of the adverse event 
or requesting extra tests. If a subject dies, any post-mortem findings, including 
histopathology will be provided if available. No medical help, diagnosis, or advice should 
be withheld from the subject due to an inability to contact the study manager/medical 
monitor. 
When entered a SAE into the eCRF, an alert will be received by the designed persons 
(i.e.: monitor) 
 
3.5.6.4 Evaluating AEs and SAEs 
3.5.6.4.1 Assessment of Intensity 
 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study. The assessment will be based on the investigator’s clinical judgement. 
The intensity of each AE and SAE recorded in the CRF or SAE form should be assigned to 
one of the following categories: 
Mild 
Awareness of sign, symptom, or event, but easily tolerated 
Moderate 
Discomfort enough to cause interference with usual activity and may 
warrant intervention 

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Severe 
Incapacitating with inability to do normal daily living activities or 
significantly affects clinical status, and warrants intervention 
 
An AE that is assessed as severe should not be confused with an SAE. Severity is a 
category utilised for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. An event is defined as “serious” when it meets one of the pre-defined 
outcomes as previously described in Section 3.5.7.1 Definitions and Classification. 
 
3.5.6.4.2 Assessment of Causality 
 
The Principal Investigator or a medically-qualified designee must assess the relationship 
between investigational drug and the occurrence of each AE/SAE. The investigator will use 
clinical judgment to determine the relationship. Alternative causes, such as natural history 
of the underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the investigational drug administration will be considered and 
investigated. The investigator will also consult the study drug information in the 
determination of his/her assessment. The causal relationship to the study drug assessed 
by the Investigator (or medically qualified delegate) should be assessed using the following 
classifications: 
Unrelated 
No temporal association, or the cause of the event has 
been identified, and the event determined to be due to a 
concurrent illness or effect of another drug reaction and is 
not related to the study drug. 
Possibly related 
Temporal association, but other aetiologies are likely to be 
the cause; however, involvement of the study drug cannot 
be excluded based on available information 
Probably related 
Temporal association and there is no other reasonable 
medical explanation for the event based on available 
information 
 
 
3.5.6.4.3  Assessment of Expectedness 
 
Expected adverse reaction, the nature or severity of which is consistent with the applicable 
study drug information (e.g. Investigators’ Brochure) for an unapproved medicinal product). 
Unexpected adverse reaction, the nature or severity of which is not consistent with 
information in the study drug information. 

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3.5.6.4.4  Follow-up of AEs and SAEs 
 
After the initial AE/SAE report, the investigator is required to actively follow each subject 
and provide further information into the eCRF pertinent forms on the subject’s condition. All 
AEs and SAEs documented at a previous visit/contact and are designated as on-going, will 
be reviewed at subsequent visits/contacts. All AEs and SAEs will be followed until 
resolution, until the condition stabilizes, until the event is otherwise explained, or until the 
subject is lost to follow-up. Once resolved, the appropriate AE/SAE CRF page(s) will be 
updated. The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or 
SAE. This may include additional laboratory tests or investigations, or consultation with 
other health care professionals. New or updated information will be recorded on the 
originally completed SAE form, with all changes signed and dated by the investigator.  
 
3.6 
Statistical methods 
3.6.1 General Remarks 
 
The statistical analysis will be carried out in accordance with the principles specified in the 
International Conference on Harmonization (ICH) Topic E9 (CPMP / ICH / 363/96)45. A 
detailed Statistical Analysis Plan (SAP)46 agreed upon by the sponsor and the Project 
Statistician will be available before the un-blinding of the data base. This SAP will follow 
the general regulatory recommendations given in the ICHE947 guidance, as well as other 
specific guidance on methodological and statistical issues 48. Also, it will stick to the 
recommendations given by the consensus documents of the scientific journals49,50,51 to 
improve reliability and value of medical research literature by promoting transparent and 
accurate reporting of clinical research studies. 
The SAS System 52  (Release 9.4, or an upgraded version), or equivalent validated 
statistical software, will be the statistical software used to analyze the data sets.  
A summary of the overall approach to statistical analysis is presented hereafter. 
 
3.6.2 Sample size calculation 
A sample size of 100 patients per treatment arm in a 1:1 allocation will have at least 80% 
statistical power for the primary outcome (mRS with 0-1 score values) assuming a rate of 
40% in the control arm and a 21% benefit in the experimental arm (odds ratio (OR) of 2.33) 
for a 5% two-sided type I error. This sample size will also guarantee the study power for 
that relative treatment benefit even if the success rate in the control group rises up to 
≈56%. No study losses are accounted for since all randomised patients will be included in 
the analysis. 

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3.6.3 Data Blind Review (DBR) 
 
The Data Blind Review (DBR) will be performed before lock of database. Data will be 
examined for compliance with the trial protocol by the monitor and the data manager. 
Deviations will be sent to the project statistician to plan listings for the Data Blind Review 
(DBR). The objective is to carry out the population selection and definition of the final study 
populations as well as a preliminary assessment of the quality of the trial data. 
 
3.6.4 Analysis populations 
 
There will the following analysis populations for this study:  
1) Modified Full Analysis Set (mFAS): All patients who are randomized into the study 
and who have received the investigational medicinal product (IMP) will be included 
in the mFAS population.  
2) Per Protocol Population: Per protocol (PP) patient sets will be defined as those 
patients included in the mFAS set without major protocol deviations that might 
impact the study’s main assessments. These deviations will be assessed during the 
data review prior to database lock.  
3) The Safety population is defined as all randomized participants who received the 
investigational drug (any of the tree arm treatment). In this study the Safety 
population will have the same definition than the mFAS subset and thus, all safety 
analysis will be conducted on the mFAS population. 
 
The precise reasons for excluding participants from each population will be fully defined 
and documented independently of the randomization codes during the Data Blind Review 
and before the database lock.  
 
3.6.5 Randomisation Procedure 
Randomisation codes were produced by means of the PROC PLAN of the SAS system, 
with a 1:1 ratio of assignment between both arms, stratifying by centre, and use of IV 
alteplase (no or yes), in blocks multiple of 2 elements. The codes will released to the 
manufacturer site, which is independent from the study sponsor and be managed from the 
eCRF in a blinded manner. 
 

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3.6.6 Inferential Analysis 
No inferential analysis will be performed for the baseline comparability. The inferential 
analyses will be limited to the efficacy variables, and the adverse events. For adverse 
events the following criteria is predefined: bleeding events (major, minor, overall), organ-
system according to the MedDRA codes, and the MedDRA preferred-terms with at least 
10% overall prevalence or at least the 5 more prevalent preferred-terms. 
 
3.6.6.1 Primary endpoint  
The proportion of patients with a mRS 0 to 1 at 90 days will be estimated using a log-
binomial regression model including the stratification variables, except centre. In the 
unexpected event that the model does not fit, the Poisson regression model with long-link 
and robust variance estimator will be used instead53,54,55,56,57. 
 
3.6.6.2 Secondary endpoints and safety outcomes 
 
Binary outcomes 
Binary efficacy and safety (mortality at 90 days and sICH rates at 24 hours) outcomes will 
be analysed as described for the primary endpoint. 
  
Shift outcomes 
The shift analysis of the modified Rankin Scale (mRS) will be analyzed using the 
proportional odds model58, combining into single worst rank the last two categories (5: 
severe incapacity and 6: death) and the stratification variables except centre. The common 
odds ratio can also be interpreted as the average shift over the total ordinal outcome scale 
caused by the treatment under study59,60,61. The stratified non-parametric van Elteren 
test62, using modified ridit scores which is as a direct extension of the extension of the 
Wilcoxon's rank-sum test for 2-samples, will be calculated as a sensitivity analysis to 
compare the modified Rankin scale as an ordinal rather than a binary outcome, without 
assuming proportional odds63,64. 
The median of the absolute values the 95% confidence interval (95%CI) will calculated 
using the Hodges-Lehmann methods (i.e. median of all cross differences between 
treatments based on the Mann-Whitney distribution)65,66. 
 
Continuous outcomes  
Continuous variables will be analyzed using Mixed Models67, including in the model the 
baseline measurement, the stratification variables except centre, treatment as well as the 
interaction between treatment and time, declaring time as categorical. The variance-

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covariance matrix will be fixed initially as unstructured. If this analysis fails to converge, the 
following structures will be tested in the following order until convergence: AR(1) (Auto-
Regressive first order), Toeplitz and CS (Compound Symmetry). Contrasts between 
dialysis groups will be performed by time-point. The treatment effect will be estimated 
through adjusted means –Least Square Means (LSMeans) – its standard error – Standard 
Error of Mean (SEM)- and its 95%CI. Differences between treatments will be estimated 
through the differences between LSMeans, SEM and 95%CI.  
 
3.6.6.3 General strategy for the rest of variables 
The rest of variables will be analyzed according to the following strategy: the Fisher’s exact 
test to compare categorical variables, the dependent or independent t-test for continuous 
Gaussian-distributed variables and the Mann-Whitney for ordinal and non-Gaussian 
continuous data. The survival function for death as well as the median [95% confidence 
interval -95%CI-] will be estimated by means of the Kaplan-Meier method. Group 
comparisons will be conducted using the stratified the log-rank test and, hazard ratios -HR- 
(95%CI) were taken from the Cox model68.  
 
3.6.7 Multiplicity adjustments and interim analysis 
The 
analysis 
will 
follow 
the 
principles 
specified 
in 
the ICHE9
69  and the 
CPMP/EWP/908/9970 Points to Consider on Multiplicity issues in Clinical Trials guidelines.  
No interim analysis is planned for this study. For this reason, there is no statistical criterion 
for early termination of the trial.  
 
3.6.8 Handling of missing data 
The handling of missing data will follow the principles specified in the ICH-E932 and the 
CPMP/EWP/1776/99 Rev1. Guideline on Missing Data in confirmatory trials Guidelines71.  
Missing data on the primary outcome or other binary efficacy secondary outcomes will be 
considered as failures, irrespectively to the reason for missingness. For mRS the worst 
case imputation will be used (i.e. imputing the worst category of the scale). With regards to 
the continuous variables, mixed models72,73,74 are robust to the presence of missing at 
random (MAR) and conducts the analysis with all participants despite the presence of 
missingness. Of note, this method calculates the estimations based on the variance-
covariance structure but without any formal imputations.  
 
No formal imputations will be performed for the rest of variables and the analyses will be 
based on the Available Data Only (ADO) approach. 
 

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3.6.9 Subgroup analysis 
The following 5 subgroups are declared of special interest and they will be investigated for 
the proportion of patients with improved mTICI 2b score: 
 
IV Alteplase use on admission (yes versus no) 
 
MT started within 7.3h of symptoms onset versus MT started between 7.4h and 24h. 
 
Admission serum glucose concentration<100 mg/dL versus >100 mg/dL 
 
Males vs. Females 
 
Baseline angiographic score 2b brain reperfusion versus baseline angiographic score 
eTICI2c/3 brain reperfusion  
 
No other subgroup analyses are planned. In case of any post-hoc subgroup analysis, they 
will be justified and identified as data-driven and, they will follow the principles and 
regulatory recommendations75.  
 
The following strategy will be conducted before splitting the analysis into subgroups: 
1. Test of the overall treatment effect 
2. Test of the treatment-by-subgroup interaction at the 10% level of significance 
3. Test of the treatment effect in each subgroup category 
 
If the three criteria are met, then the subgroup analysis will be given the maximal level of 
evidence for this analysis. However, this subgroup analysis is predefined as exploratory 
and the interpretation should be taken with caution. If any of the criterion are not meet, the 
chances of type I error increase are higher and this will have an impact in the 
interpretation. 
 
3.7 Study feasibility 
The sites participating in CHOICE performed in 2016 575 MT procedures that were 
registered in the Sistema Online d’Informació de l’Ictus Agut (SONIIA) Registry. For pooled 
data analysis of five RCTs of MT reported an average rate of 38% of mTICI2b score and 
an average rate of 50,3% of mTICI3 score at the end of MT. These figures allow to 
estimate that the total potential annual accrual rate at the participating sites is sufficient to 
terminate the trial within the allotted recruitment duration of 24 months.  
4. DATA MANAGEMENT / MONITORING AND QUALITY CONTROL 
4.1 Data collection methods 
An electronic Case Report Form (eCRF) will be completed for each study subject, 
summarizing all clinical screening and study data. Subjects will only be referred to in the 
eCRF by their subject number and initials in order to retain subject confidentiality. 

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4.2 Data management 
Data will be captured in an eCRF and the Investigator is responsible for ensuring the 
prompt and accurate reporting of study data into the eCRF. The eCRF is reachable via the 
internet at any time. The system uses a secured data connection (with Secure-Sockets-
Layer protocol, SSL) to transfer the data from the study centres to the central database. 
Data management documentation will be prepared by the Medical Statistics CRO in 
charge of the eCRF and data management. 
The data collection will be monitored by external qualified staff and entered into a remote 
access database (electronic Case Record Form eCRF). The eCRF will be managed by the 
IDIBAPS. This system will meet the general76 and specific77 standards of Good Clinical 
Practice and the highest requirements of computer validation78,79,80,81, with restricted user-
level access, equipped with filters to detect inconsistencies and traceability of all 
information to closure end thereof. Any data transfer will be done using secure SSL 
connection with encryption. Export for archiving of the clinical database including audit 
trails in hard- and software independent storage formats will be provided by IDIBAPS. 
 
Furthermore the technical support will be provided for the study centers during the study 
duration (administration of logins, roles and rights).  
 
In case of scheduled, unscheduled analyses or other needed reports the data will be 
exported from the database. In a further process these data will be checked, prepared and 
delivered for these purposes.  
 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
 
When the database has been declared to be complete and accurate, the database will be 
locked. Any changes to the database after that time can only be made by written 
agreement between the sponsor and the Medical Statistics core facility and with a sound 
justification and full traceability of the process. 
 
At the end of the study the entire database will be exported. The final data management 
process contains the plausibility, consistency and range checks of the data. The missing 
data will be identified as well. Data Clarification Forms will be generated for data 
clarification.  
 
After all data management processes are completed, the cleaned data will be available for 
the statistical analysis. The final data will be delivered in a defined SAS data format, 
including a data management report as well. 

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4.3 Data monitoring 
Study monitoring will be performed by ANAGRAM-ESIC. Best conduct of the study will be 
ensured through frequent contacts by phone and in person with the responsible 
Investigator, in accordance with ANAGRAM-ESIC Standard Operating Procedures, with 
the purpose of facilitating the work and fulfilling the objectives of the study. Site visits will 
enable the Monitor to maintain current, personal knowledge of the study through review of 
the records, comparison with source documents, and observation and discussion of the 
conduct of the study with the Investigator. The Monitor is responsible for monitoring 
adherence to the Protocol and completion of the eCRF. They are also responsible for the 
organization, monitoring, supply of study materials and quality assurance of the study. 
In order to ensure the accuracy of data, direct access to source documents by the 
representatives of both the Study Monitor and Regulatory Authorities is mandatory. 
The trial will be managed by a Steering Committee, with Chair, Ángel Chamorro. There will 
also be an independent Data Safety Monitoring Board (DSMB) –- chaired by Tudor Jovin. 
The Steering Committee comprising investigators from each participating centre and a 
Neurointerventional 
Committee, 
with 
Chair 
Jordi 
Blasco, 
will 
comprise 
neurointerventionalists from each participating centre. A Neuroimaging Core Lab with 
Chair Luis San Román, will manage all the imaging data collected in the trial. A Patient’s 
recruitment Board with Chair Monica Millán will supervise that patient’s accrual in the trial 
abide to anticipated estimations. 
  
4.4 Screening log and Codi Ictus Catalonia (CICAT) 
Each collaborating site is requested to complete a screening log of all patients treated with 
mechanical thrombectomy who are not included in the trial. The log is used to monitor 
recruitment and identify barriers to recruitment at that site. Further, data from the CICAT 
registry, a government-mandated, prospective, hospital-based dataset will also be used to 
cross-check the information reported in the screening logs. Indeed, CICAT reports 
prospectively all Stroke Code activations in Catalonia, and capture information about the 
presence of LVO (TICA, MCA M1 or M2, tandem or basilar occlusion) and 
revascularization treatments used. 
 
4.5 Data auditing 
The Steering Committee has assigned a CRO to this study whose duties are to aid the P.I. 
and the Steering Committee members in the maintenance of complete, legible, well 
organized, and easily retrievable data. Personnel from CRO will ensure that the study 
complies with relevant Good Clinical Practices (GCPs). Periodic monitoring visits will be 
made throughout the investigation to assure that the investigator’s obligations are being 

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fulfilled. Monitoring visits will be performed to verify data accuracy and ensure queries are 
resolved.  
 
4.6  Independent Committees 
- Data Safety Monitoring Board (DSMB) 
An independent Data Safety Monitoring Board will be established. The purpose of the 
DSMB is to review, on a regular basis, accumulating data from the on-going trial. The 
DSMB will be composed of two stroke neurologists and a statistician who are not 
participating in the study and are not affiliated with the sponsor. The role of the DSMB will 
be to: 1/Review the occurrence of AEs and 2/ Make recommendations to the Executive 
Committee regarding safety of the study. A strict control of predefined AEs and SAEs will 
be ensured through monitoring by the CRO. 
A Data Safety Monitoring Board (DSMB) wills follow-up the safety of the study. Although 
the DSMB will review data in a blinded manner (Group A and B), the date of the SAP 
closure will be set before the first unblinded review so that the study will maintain the 
integrity and will avoid any operational bias. Any potential analysis amendment will be 
traced and justified, if applicable. The study followed the regulatory recommendations 
regarding the functions and procedures of these committees82. 
 
- Independent Imaging Core Lab (ICL) 
An independent Imaging Core Lab will be established. The purpose of the ICL is to review, 
on a regular basis, accumulating imaging data from the on-going trial. The ICL will be 
composed of two neuro-radiologists, a stroke neurologist and one physicist. The role of the 
DSMB will be to: 1/Review the occurrence of AEs and 2/ Make recommendations to the 
Executive Committee regarding safety of the study. A strict control of predefined AEs and 
SAEs will be ensured through monitoring by the CRO. 
 
4.7  Training of investigators and site personnel 
The training of the Investigator, and appropriate clinical site personnel will be the 
responsibility of the Study Coordinating Group and may be conducted during local 
investigator meeting, a site initiation visit, or other appropriate training sessions. Training 
will include, but not be limited to, the study protocol, eCRF completion, neurological scale 
evaluation and site personnel responsibilities. All Investigators and site personnel that are 
trained must have their training documented.  
Prior to the initiation of the study and subject enrolment, the Study Coordinating Group or 
designee will visit each site where the trial is conducted. The Sponsor or designee will 
ensure that the site personnel are informed about and understand the clinical study 
requirements. 

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Specific training will be offered to research team professionals. 
 
5. ETHICS AND DISSEMINATION 
5.1 Research Ethics approval  
 
Clinical Research Ethics Committee of the hospital Clínic, which will act as the CEIm for  
this research project and approve Study Protocol and the patient information sheet and 
informed consent form, as applicable to this type of regulation studies. The Clinical 
Research Ethics Committee will also approve any revision or modification of the research 
protocol, the informed consent form or the patient information sheet. 
This study will be conducted according to the provisions of the RD 1090/2015 of December 
4, which regulates clinical drug trials, the Royal Legislative Decree 1/2015 of July 24, Law 
on guarantees and rational use of medicines and medical devices, the Royal Decree 
577/2013 of 26 July, which regulates pharmaco-surveillance and, all in what is applicable 
to them, and the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, 
October 2013) and good clinical practice guidelines. 
The trial will be conducted in agreement with the International Conference on 
Harmonization (ICH) guidelines on Good Clinical Practice (GCP). 
 
5.2 Consent 
 
Patient or his/her representative will sign the specific approved version of informed 
consent form at hospital arrival before participating in the clinical trial and inclusion of its 
clinical data into the electronic CRF.  
A signed informed consent, indicating full and complete understanding of the study, should 
be obtained prior to initiating the randomization process or any study procedures, unless 
the site has been granted an explicit waiver of consent or allowance for verbal consent 
from the CEIm. This specific allowance of verbal consent will be requested by a telephone 
call in presence of a waiver (neurologists) for patients that are transferred from other 
centers without accompanying relatives in the ambulance, in order to not delay patient’s 
allocation. 
Given the characteristics of the study that will be carried out in the context of an 
emergency situation, the basic ethical principles: autonomy, beneficence, non-maleficence 
and justice have been taken into consideration: 
- Beneficence and non-maleficence are fully respected, being both alternatives according 
to the best treatment criteria. 
- Patients’ autonomy is respected to make their own decisions regarding their subsequent 
monitoring. 

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- Distributive justice is respected since the study is equally based on all patients who meet 
the selection criteria and excludes differences based on social or economic levels/ 
conditions. 
 
Written Informed Consent must be given after the context of the study has been fully 
explained in a language that is easily understood by the subject or his/her representative. 
The subject or his/her representative must also be given the opportunity to ask questions 
and have those questions answered to his/her satisfaction.  
Written Informed Consent must be recorded appropriately by means of the subject’s, or 
his/her representative dated signature. The consent process must be documented in the 
subject’s medical chart.  
 
5.3 Confidentiality 
Investigators, who use information about the health of their research participants, are 
required except in specific circumstances, to get written permission to use their 
participant’s protected health information (PHI) for the research study. Each participating 
clinical center is expected to comply with its individual performance site’s requirements 
established for compliance of the local confidentiality policies.  
All study data will be collected in an anonymous way, through the eCRF and no personal 
data will be extracted from investigational sites in any case. 
 
5.4 Record Retention  
The Investigator will maintain all essential trial documents and source documentation, in 
original format, that support the data collected on the study subjects in compliance with the 
ICH/GCP guidelines. Documents must be retained for at least 25 years as per Spanish 
and European guidelines.  
The Investigator will take measures to ensure that these essential documents are not 
accidentally damaged or destroyed. If for any reason the Investigator withdraws 
responsibility for maintaining these essential documents, custody must be transferred to an 
individual who will assume responsibility. Sponsor must receive written notification of this 
custodial change. 
 
5.5 Dissemination policy 
A writing committee will be formed to review and publish the data from the study. This 
committee will consist of the Steering Committee and a subset of investigators. The writing 
committee will write/review all drafts of abstracts and full-length manuscripts and will 
choose the appropriate journal (for manuscripts) or meeting (for abstracts) for submission. 

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The CHOICE Steering Committee commits that when the study is completed, the data 
from this study will be published within 3 months, regardless of the outcome of the study 
and the trial will be listed on the clinical trials website. 
All information concerning the CHOICE trial supplied to the investigators by the Steering 
Committee and not previously published is considered confidential and shall remain the 
sole property of the CHOICE Steering Committee. The investigator agrees to use this 
information only in accomplishing the study and will not use it or the data generated from 
the study for other purposes without first obtaining written authorization from CHOICE 
Steering Committee. 
 
It is understood that CHOICE Steering Committee may disclose this information as 
required to other CHOICE clinical investigators or to government regulatory agencies. The 
investigator understands that she or he has the obligation to provide complete test results 
and all data collected during this study to the Steering Committee. 
 
 

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6. APPENDICES 
6.1 Abbreviations and Acronyms 
 
AE  
Adverse Event 
AEMPS  
Agencia Española del Medicamento y Productos 
Sanitarios 
AHA/ASA 
American Heart Association/American Stroke 
Association AMI Acute Myocardial Infarction 
ASPECTS  
Alberta Stroke Program Early CT score 
CICAT 
Codi Ictus Catalonia 
CRF  
Case Report Form 
CT 
Computerized Axial Tomography 
CTA  
Computerized Axial Tomography Angiography 
CTP  
Computerized Tomography Perfusion 
CRO  
Contract Research Organization 
EMS  
Emergency Management of Stroke 
GCP  
Good Clinical Practice 
IA  
Intra-arterial 
ICA  
Internal Carotid Artery 
ICH  
Intra-cerebral Hemorrhage 
IMS III  
Interventional Management of Stroke Trial III 
INR  
International Normalized Ratio 
ISF 
Investigator’s Site Folder 
IV  
Intravenous 
IVT  
Intravenous Thrombolysis 
LVO  
Large Vessel Occlusion 
MAR  
Missing at random 
MCA  
Middle Cerebral Artery 
MCD  
Mechanical Clot Disruption 
mFAS  
Modified Full Analysis Set 
MRA  
Magnetic Resonance Angiography 
mRS  
Modified Rankin Scale 
MT   
Mechanical thrombectomy   
mTICI  
Modified Treatment In Cerebral Infarction scale 
M1 
Proximal segment of the MCA from the origin to 
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or sphenoidal segment 
NIHSS  
National Institute of Health Stroke Scale 
OR  
Odds Ratio 
PCI  
Percutaneous Coronary Intervention 
Pp  
Per Protocol 
PROBE  
Prospective randomized open blinded end-point 
RACE  
Rapid Arterial oCclusion Evaluation 
RCT   
Randomized controlled trial 
RD  
Royal Decree 
rt-PA  
Recombinant tissue Plasminogen Activator 
SAE  
Serious Adverse Event 
SICH  
Symptomatic Intra-Cerebral Hemorrhage 
SONIIA  
Sistema ONline d'Informació de l'Ictus Agut 
SUSAR  
Suspected 
Unexpected 
Serious 
Adverse 
Reaction 
SWFI  
Sterilized Water for Injection 
 
 
 
 

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6.2  INFORMED CONSENT 
 
 
 
ATTACHED AS A SEPARATE DOCUMENT 
 
 
 

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6.3  
Modified Rankin scale  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.4  
Angiographic assessment: The mTICI score 
The Thrombolysis in Cerebral Infarction (TICI) scale was originally proposed in a position 
statement that attempted to standardize clinical trial design and reporting for IAT.83,84.The 
TICI scale specifically addresses the extent of tissue reperfusion, as represented by the 
capillary blush on DSA. TICI is graded by visually estimating how much of the initial 
antegrade capillary blush defect (or target downstream territory [TDT] is reperfused 
(numerator). The TICI scale distinguishes no perfusion (TICI grade 0; Figure 2), minimal 
flow past the occlusion but no perfusion (grade 1; Figure 3), minor partial reperfusion 
(grades 2a; Figures 4 and 5), major partial reperfusion (2b; Figure 2), and complete 
reperfusion without any flow defects (grade 3; Figures 3 and 4). The original TICI system 
defined TICI 2b as restoration of more than two thirds of the TDT. This is in contrast to the 
subsequent modification (modified treatment in cerebral ischemia [mTICI]) introduced by 
the IMS investigators, which uses a threshold of more than half of the TDT. 85  The 
advantage of mTICI is its simplicity (ease of visually estimating 1/2 versus 2/3 reperfusion), 
and previous work has demonstrated excellent inter-rater agreement for distinguishing 
<50% versus ≥50% reperfusion of the downstream territory.86 
 
Fig 2 
 
 
Top, Anteroposterior (first 2 boxes) and lateral (last 2 boxes) in an early arterial and late 
capillary phases depicting TICI 0 at baseline. Bottom, Same phases depicting TICI 2b 
after intra-arterial therapy. Black arrow indicating the target arterial lesion (TAL): middle 
cerebral artery/M1 horizontal segment occlusion (TAL) distal to the lenticulostriate (LS). 
Black half circles approximate the target downstream territory (TDT; the presumed area 
supplied by the TAL). 
 
 

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Fig 3 
 
 
Top, Anteroposterior (left) and lateral (right) in an early arterial and late capillary phases 
depicting TICI 1 at baseline. Bottom, Same phases depicting TICI 3 after intra-arterial 
therapy. Black arrow indicating the target arterial lesion (TAL): middle cerebral artery/M1 
horizontal segment occlusion (TAL) distal to the lenticulostriate (LS). Black half circles 
approximate the target downstream territory (TDT; the presumed area supplied by the 
TAL). Ischemic arteriovenous shunting is noted with opacification of straight sinus (right 
bottom corner). 
 
Fig 4 
 
 
Top, Anteroposterior (first 2 boxes) and lateral (last 2 boxes) in an early arterial and late 
capillary phases depicting thrombolysis in cerebral infarction (TICI) 0 at baseline. Bottom, 
Same phases depicting TICI 3 after IAT. Black arrow indicating the target arterial lesion 
(TAL): Distal ICA proximal to the ophthalmic artery. Black half circles approximate the 

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target downstream territory (TDT; the presumed area supplied by the TAL). Early ischemic 
arteriovenous shunting is noted in the right lower corner. 
 
Fig 5 
 
 
Top, Anteroposterior (first 2 boxes) and lateral (last 2 boxes) in an early arterial and late 
capillary phases depicting TICI 0 at baseline. Bottom, Same phases depicting TICI 2a 
after intra-arterial therapy. Black arrow indicating the target arterial lesion (TAL): middle 
cerebral artery/M1 horizontal segment occlusion (TAL) distal to the lenticulostriate (LS). 
Black half circles approximate the target downstream territory (TDT; the presumed area 
supplied by the TAL). 
 
Fig 6 
 
 
Top, Anteroposterior (first 2 boxes) and lateral (last 2 boxes) in an early arterial and late 
capillary phases depicting TICI 0 at baseline. Bottom, Same phases depicting TICI 2a 

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after intra-arterial therapy. Black arrow indicating the target arterial lesion (TAL): middle 
cerebral artery/M1 horizontal segment occlusion (TAL) distal to the lenticulostriate (LS). 
Black half circles approximate the target downstream territory (TDT; the presumed area 
supplied by the TAL).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.5 
Study assessments 
Assessments 
Baseline 
information 
 
 
 
Procedure/ 
Allocation 
Follow 
up 24h 
(-/+12h)  
post-
randomiz
ation 
 
Follow up 
48h 
(-/+ 24h) 
post-
randomiza
tion  
Follow up 
5 days 
(±2 d) 
post-
random, or 
discharge 
(whatever 
occurs first) 
Follow up 
90 days (± 
14 d) post-
random 
Admission 
Details 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
Eligibility 
Criteria 
 
X 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
Randomizatio
n 
 
X 
 
 
 
 
Blood test 
Including INR 
X 
 
 
 
 
 
mRS 
X1 
 
 
 
₵ 
₵ 
NIHSS 
assessment 
X 
 
₵ 
₵ 
₵ 
₵ 
NCCT / MRI 
X 
 
X 
 
 
 
CT-P/ DWI-
MRI 
X 
 
 
 
 
 
Angiogram 
 
X 
 
 
 
 
Blinded Study 
medication 
administration 
 
X 
 
 
 
 
Post-MT 
angiography 
 
X 
(if 
applicable) 
 
 
 
 
MRI (DWI/T2 
sequences) 
Or NCCT if MRI 
not possible 
 
 
 
X 
 
 
Stroke 
etiology 
 
 
 
 
 
X 
Procedure 
Details  
 
X 
 
 
 
 
Barthel Scale 
 
 
 
 
 
X 
EuroQol EQ-
5D 
 
 
 
 
 
X 
(S) AEs 
…..on an ongoing basis….. 
Relevant 
Meds 
X 
X 
X 
X 
X 
 
1 This mRS score should be based on subject’s score prior to the stroke symptom onset. 
₵ To be done by an accredited local evaluator  
 
 
 

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6.6  
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