SELECT2: A Randomized Controlled Trial to Optimize Patient's Selection for Endovascular Treatment in Acute Ischemic Stroke
Phase: NA
Conditions: Acute Ischemic Stroke
Sponsor: University Hospitals Cleveland Medical Center

 
SELECT 2 Protocol                                                
4 August, 2021 
1 
 
2
 
 
 
 
 
 
PROTOCOL TITLE 
 
SELECT 2:  
A Randomized Controlled Trial to Optimize Patient’s Selection for Endovascular Treatment in 
Acute Ischemic Stroke  
 
 
 
NCT03876457 
 
 
 
 
 
Protocol Version Date:  
 
4 August, 2021 
 
 
 
 
Global Principal Investigator: 
Amrou Sarraj, MD  
Department of Neurology, Stroke Division 
6431 Fannin Street, MSB 7.116 
McGovern Mecical School at UTHealth 
Houston, Texas 77030 
 
 
 
 
Funded by: McGovern Medical School at UTHealth at Houston through an unrestricted grant 
from Stryker Neurovascular 
 
 
 
 
 

SELECT 2 Protocol                                                
4 August, 2021
2 
 
2
 
 
 
 
SELECT 2 
 
AGREEMENT ON THE PROTOCOL 
 
 
By signing below I confirm that: 
 
 
1) I have read this protocol and it contains all necessary details for conducting this study 
 
AND 
 
2)  I agree to conduct the trial in compliance with this protocol and to adhere to all 
regulations that govern the conduct of the study. 
 
 
________________________________________________________         ________________ 
 
 
 
 
                          Date 
 
 
________________________________________________________ 
 
 
 
_________________________________________________________ 
Site Name 
 
 
 
 
 
 
 
 
 
 

SELECT 2 Protocol                                                
4 August, 2021
3 
 
2
 
SELECT 2 Steering Committee 
Dr. Gregory Albers, Professor, Stanford University, Palo Alto, CA 
Dr. Ameer Hassan, Associate Professor, The University of Texas Health Science Center  San 
Antonio, Harlingen, TX 
Dr. M. Shazam Hussain, Director, Stroke Program, Cleveland Clinic, Cleveland, OH 
Dr. Michael Chen, Associate Professor, Rush University, Chicago, IL 
Dr. Michael Abraham, Associate Professor, Kansas University Medical Center, Kansas City, MO 
Dr. Maarten Lansberg, Associate Professor, Stanford University, Palo Alto, CA 
Dr. Marc Ribo, Assistant Professor, Hospital Vall d'Hebron, Barcelona, Spain 
Dr. Vitor Pereira, Associate Professor, Toronto General Hospital & University Network, Toronto, 
Canada 
Dr. Santiago Ortega-Gutierrez, Assistant Professor, The University of Iowa, Iowa City, IA 
Dr. Bruce Campbell, Professor, The University of Melbourne, Melbourne, Australia 
SELECT 2 Neurointerventional Committee 
Dr. Ameer Hassan, Associate Professor, The University of Texas Health Science Center  San 
Antonio, Harlingen, TX 
Dr. Michael Chen, Associate Professor, Rush University, Chicago, IL 
Dr. Michael Abraham, Associate Professor, Kansas University Medical Center, Kansas City, MO 
Dr. Vitor Pereira, Associate Professor, Toronto General Hospital, Toronto, Canada 
Dr. Marc Ribo, Associate Professor, Hospital Vall d'Hebron, Barcelona, Spain 
Dr. Peng R. Chen, Associate Professor, McGovern Medical School at UTHealth, Houston, TX  
Dr. Santiago Ortega-Gutierrez, Assistant Professor, The University of Iowa, Iowa City, IA 
SELECT 2 Imaging Core Lab 
Dr. Clark Sitton, Associate Professor, McGovern Medical School at UTHealth, Houston, TX  
Dr. Roy Riascos, Professor, McGovern Medical School at UTHealth, Houston, TX  

SELECT 2 Protocol                                                
4 August, 2021
4 
 
2
SELECT 2 Statistical Committee 
Dr. Phillip Lavori, Professor (Emeritus), Biomedical Data Science, Stanford University, Palo Alto, 
CA 
Dr. Chunyan Cai, Assistant Professor, Clinical and Translational Sciences, McGovern Medical 
School at UTHealth, Houston, TX  
SELECT 2 Data Safety Monitoring Board 
Chair: Dr. Lawrence R. Wechsler, Professor & Chair, The University of Pittsburgh School of 
medicine, Pittsburgh, PA 
Co-chair: Dr. Stephen Davis, The University of Melbourne, Melbourne, Australia 
Statistician: Dr. Scott Hamilton, Associate Professor, Stanford University School of Medicine, 
Palo Alto, CA 
Voting Member: Dr. Thanh Nguyen, Associate Professor, Boston University School of Medicine, 
Boston, MA 
Voting Member: Dr. Johanna Fifi, Associate Professor, Mount Sinai Health System, New York 
City, NY 
 
 
 
 
 
 

SELECT 2 Protocol                                                
4 August, 2021
5 
 
2
Table of Contents 
SELECT 2 Steering Committee ....................................................................................................................................... 3 
SELECT 2 Neurointerventional Committee .................................................................................................................... 3 
SELECT 2 Imaging Core Lab ............................................................................................................................................ 3 
SELECT 2 Statistical Committee ..................................................................................................................................... 4 
SELECT 2 Data Safety Monitoring Board ........................................................................................................................ 4 
Protocol Synopsis........................................................................................................................................................... 7 
 
Scientific Background .................................................................................................................................... 11 
 
Thrombectomy in Patients with Unfavorable Imaging Profiles (i.e. Large Core) ....................... 12 
 
Rationale for randomization in patients with favorable CT profile (ASPECTS 6-10)  and 
 ................. 15 
 
Rationale for including patients with very large core on advanced perfusion (CTP: rCBF (<30%) 
volume or MRP: ADC < 620 >100cc) ....................................................................................................... 17 
 
Rationale for excluding patients with very large core on CT (ASPECTS 0-2)............................... 18 
 
Imaging selection for thrombectomy ......................................................................................... 19 
 
Thrombectomy efficacy and safety in patients with favorable CT but unfavorable perfusion 
imaging profile ........................................................................................................................................ 23 
 
Rationale and use of iSchemaView RAPID and iSchemaView RAPID ASPECTS ........................... 23 
 
Rationale for including patients with exctracranial ICA occlusion: ............................................. 24 
 
Study Question, Aim, and Hypothesis ........................................................................................................... 25 
 
Methods ........................................................................................................................................................ 26 
 
Study Design................................................................................................................................ 26 
 
Enrollment Inclusion and Exclusion Criteria ............................................................................... 28 
Table 1. The SELECT 2 study inclusion and exclusion criteria ................................................................. 28 
3.2.1.1. 
Specific Neuroimaging Inclusion Criteria ............................................................................ 29 
3.2.1.2. 
Specific Neuroimaging Exclusion Criteria ............................................................................ 29 
 
Enrollment and Randomization .................................................................................................. 30 
 
Remote consent procedure: ....................................................................................................... 30 
 
Endovascular Thrombectomy ..................................................................................................... 35 
 
Medical Management ................................................................................................................. 36 
 
Outcome Measures ..................................................................................................................... 37 
3.7.1.1. 
Primary Outcome ................................................................................................................ 37 
3.7.1.2. 
Secondary Outcomes .......................................................................................................... 37 

SELECT 2 Protocol                                                
4 August, 2021
6 
 
2
3.7.1.3. 
Imaging Outcomes .............................................................................................................. 38 
 
Clinical and Imaging Evaluations .............................................................................................. 38 
 
Table 2. Schedule of Events ........................................................................................................ 40 
 
Assessment and Follow-up Visits ......................................................................................... 41 
 
Sources of Materials .................................................................................................................................... 42 
 
Site Approval and Monitoring Plan ............................................................................................................. 43 
 
Sample Size Calculation and Statistical Analysis Plan ............................................................................... 44 
 
Sample Size justification, Adaptive Enrichment Design, and Statistical Analysis Plan ............... 44 
 
Statistical plan for the second aim ........................................................................................... 51 
 
Poolability analysis across centers ........................................................................................... 51 
 
Feasibility of enrollment ........................................................................................................... 52 
 
 ....................................................................................... 52 
 
SELECT 2 Timetable ....................................................................................................................................... 53 
 
Risk Analysis .................................................................................................................................................. 53 
 
Methods to mitigate risks to subjects in the trial.......................................................................................... 55 
 
Stopping rules or safety triggers for the study .............................................................................................. 56 
 
Imaging Core Lab ........................................................................................................................................... 64 
 
National Data Management Center .............................................................................................................. 65 
 
Data Management Plan ................................................................................................................................. 65 
 
Compliant Handling Plan ............................................................................................................................... 66 
 
Data Safety and Monitoring Board ................................................................................................................ 66 
 
Independent Medical Safety Monitor ........................................................................................................... 67 
 
Adverse Event Reporting ............................................................................................................................... 68 
 
Reporting Procedures for All Adverse Events................................................................................................ 69 
 
Study Design .................................................................................................................................................. 71 
References ................................................................................................................................................................... 72 
Appendix A: Minimization Randomization Algorithm ................................................................................................. 76 
Appendix B. Efficacy and futility bounds for interim and final analysis....................................................................... 80 
Appendix C. List of Approved Devices to be used in the SELECT2 Protocol: ............................................................... 82 
 
 
 

SELECT 2 Protocol                                                
4 August, 2021
7 
 
2
Protocol Synopsis 
 
SELECT 2: 
Ischemic Stroke  
Aims  
 
To evaluate in acute ischemic stroke patients due to a large vessel occlusion in the 
anterior circulation (MCA M1 and ICA):  
 
 If thrombectomy, as compared to medical management, will be efficacious and 
safe in patients with large core on either CT (ASPECTS: 3-5) or advanced 
perfusion imaging ([rCBF<30%] on CTP or [ADC<620] on MRI: 50cc), treated 
within 0-24 hours from last known well. 
 
 Second aim: to look at the correlation of imaging profiles with thrombectomy 
clinical outcomes and treatment effect. This will be evaluated by comparing the 
outcomes in patients with discordant imaging profile and assessing if 
thrombectomy outcome rates and treatment effect will differ in patients with 
discordant imaging profiles (favorable CT/unfavorable perfusion imaging and 
unfavorable CT/favorable perfusion imaging)  
 
a. Evaluate good clinical outcome (90-day mRS 0-2) rates in patients with 
discordant imaging profile (unfavorable CT/favorable perfusion imaging vs 
favorable CT/unfavorable perfusion imaging) treated with thrombectomy.  
 
b. Evaluate the heterogeneity of thrombectomy treatment effect in patients 
with favorable CT/unfavorable perfusion and unfavorable CT/favorable 
perfusion imaging. 
Study Design 
A prospective, randomized, international, multicenter, assessor-blinded controlled 
trial 
Study Sites 
Up to 40 total sites, up to 30 US sites 
General 
Inclusion 
Criteria 
 
1. Adults (18-85 years) with the final diagnosis of an acute ischemic stroke  
2. 
 
3. Last known well to groin puncture or medical management between 0 to 24 
hours 
4. Pre-stroke modified Rankin Scale score (mRS) of 0-1 
5. Eligible for thrombectomy or medical management 
6. Signed Informed Consent obtained 
7. Subject willing to comply with the protocol follow-up requirements 
8. Anticipated life expectancy of at least 3 months 

SELECT 2 Protocol                                                
4 August, 2021
8 
 
2
General 
Exclusion 
Criteria  
 
1. Inability to undergo CT angiography and/or CT perfusion imaging (e.g., renal 
insufficiency, iodine/contrast allergy) 
2. Co-morbid psychiatric or medical illnesses that would confound the 
neurological assessments 
3. Treatment with IV thrombolytic therapy beyond 4.5 hours from last known well 
4. Treated with IV thrombolytic therapy 
well AND any of the following:  
1) age >80,  
2) current anticoagulant use,  
3) history of diabetes AND prior stroke,  
4) NIHSS >25,  
5) ischemic involvement of > 1/3 MCA territory  
5. Current participation in another investigational drug or device study. 
Imaging 
Inclusion 
Criteria 
 
1. Proven large vessel occlusion in ICA or MCA-M1 occlusion (carotid occlusions 
can be cervical or intracranial, with or without tandem MCA lesions) determined 
by MRA or CTA 
2. Large infarct-core lesion on at least one of the following  
2.1. Non-Contrast CT (ASPECTS of 3-5),  
2.2. CT perfusion (rCBF<30%  
 
2.3. MRI-DWI  (ADC<620  
 
Imaging 
Exclusion 
Criteria 
 
1. Patients who have both ASPECTS of 6-10 on non-contrast CT AND core volume 
<50 cc on perfusion imaging 
2. Patients with very large core on non-
 
3. Evidence of intracranial tumor (except small meningioma), acute intracranial 
hemorrhage, neoplasm, or arteriovenous malformation 
4. A significant mass effect with midline shift 
5. Evidence of internal carotid artery dissection that is flow limiting or aortic 
dissection 
6. Intracranial stent implanted in the same vascular territory that precludes the 
safe deployment/removal of the neurothrombectomy device 
7. Acute symptomatic arterial occlusions in more than one vascular territory 
confirmed on CTA/MRA (e.g., bilateral MCA occlusions, or an MCA and a basilar 
artery occlusion). 
8. Signs of established infarct and large area of cerebral edema on non-contrast CT 
Primary 
Outcome 
1. 
Modified Rankin Scale (mRS) at 90 (+/- 15) days. The primary outcome is a shift 
on 90-day mRS. 2nd primary outcome is favorable clinical outcomes: mRS score 
of 0-2. 
Secondary 
Outcomes 
 
1. Safety measured by the incidence of symptomatic intracranial hemorrhage 
(sICH per SITS-MOST), mortality and groin (or arterial access site) hematomas, 
infections or any vascular injury caused by the endovascular procedure 
2. Rates of recanalization (complete and partial) using the modified TICI system 
 

SELECT 2 Protocol                                                
4 August, 2021
9 
 
2
3. Length of hospital stay  
4. Discharge location 
5. NIHSS 
6. Neuro-QoL 
Imaging 
Outcomes 
1. Infarct volume on MRI DWI sequence (or CT if MRI not feasible) 24 hours to 7 
days after randomization 
2. Lesion growth between the RAPID identified ischemic core on baseline imaging 
and the infarct volume 
3. Successful reperfusion defined as DWI lesion volume minus Tmax>6 seconds 
greater than 50% 
4. Recanalization of the primary arterial occlusive lesion, assessed by a modified 
Thrombolysis in Cerebral Infarction scores of 2b (50% to 75% reperfusion), 2c 
(>75% to 99% reperfusion) or 3 (complete reperfusion). 
Imaging 
Assessments 
1. CT images will be read by the appropriately trained clinicians as well as by the 
iSchemaView automated ASPECTS. ASPECTS for patient selection will be 
determined independently by the clinicians prior to any assessment with 
automated ASPECTS. In cases where there is disagreement, the physician 
reading will override the automated software reading. 
2. CTP images with mismatch determination will be read by iSchemaView 
automated RAPID software.   
3. All the images will be adjudicated by a blinded core lab at McGovern Medical 
School at UTHealth.  
Randomization 
 
Randomization will be done in the emergency room using a web-based dynamic 
randomization system. Covariate adaptive randomization will be conducted to 
balance the distribution of the randomization by age (<60, 60-69, 70-79, 80-85 years 
old), presentation NIHSS (6-9, 10-15, 16-20, >20), center, clot location (M1, ICA), 
treatment time window (0-8, 9-16, 17-24 hours from onset to randomization time), 
CTP/MRP core volume (<50cc, 50-100cc, >100cc), presence or absence of target 
mismatch profile (
 and 
hemisphere (right, left).  
 
The randomization algorithm we are going to implement is the algorithm developed 
by Pocock and Simon (1975), i.e., minimization method. Through this algorithm, the 
assignment of a new patient to a treatment group is determined so as to minimize 
the differences between the groups in terms of these important key baseline 
variables. Unlike traditional stratified randomization, the minimization method 
works toward minimizing the total imbalance for all factors together instead of 
considering mutually exclusive subgroups, that is, we will not be creating these 
mutually exclusive subgroups during the randomization. Therefore, this approach is 
not restricted by the number of variables and the possible combinations of levels of 
balancing factors.  
 

SELECT 2 Protocol                                                
4 August, 2021
10 
 
2
Patients with large core on either CT (ASPECTS 3-5) or perfusion imaging (CTP: 
rCBF<30% or MRP: ADC<620 50cc) or both within 0-24 hrs from last known well 
will be randomized into thrombectomy plus medical management vs medical 
management alone.  
Interventions 
Endovascular Thrombectomy: Patients randomized to endovascular thrombectomy, 
will be treated with t
 and/or aspiration devices 
currently cleared by the FDA. The choice of thrombectomy method, primary 
approach/technique, whether primary aspiration or primary stent-retriever with or 
without aspiration, will be left up to the interventionalist, with any of the FDA-
approved devices approved in the study protocol or a combination of them 
(Appendix C). Standard medical therapy, based on current AHA guidelines, will also 
be provided for all patients.  
 
Medical Management: Patients randomized to medical management only will 
receive standard medical therapy based on current AHA guidelines. Patients will 
receive IV thrombolytic therapy available for use according to practice guidelinesif 
presented within the first 3 hours from last known well and meeting other FDA label 
criteria, or up to 4.5 hours from last-seen-normal and meeting other AHA guidelines.
No procedures or tests required by the protocol will delay fastest possible delivery 
of thrombolytic therapy to potentially eligible subjects. For thrombolysis treated 
thrombolysis 
thrombolysis treated patients 
patients will receive standard DVT prevention therapy.  
Assessment 
and Visits 
 
Clinical assessments will be done at baseline, 24-hours after randomization, 
day 5-7 or hospital discharge (whichever is earlier), 30 days, and 90 days: 
 
1. Baseline: demographics and medical history, CT/CTA/CTP/MRP imaging, 
lab work, hourly blood pressure, NIHSS, mRS 
2. 24 hours (+/- 6 hrs): hourly blood pressure, NIHSS 
3. 24 hour  7 days post-procedure imaging (MRI or CT if MRI not feasible) 
4. Day 5-7 or discharge (whichever is earlier): NIHSS, mRS 
5. Day 30 (+/- 15 days): mRS 
6. Day 90 (+/- 15 days): mRS, Neuro-QoL 
 
 
 
 

SELECT 2 Protocol                                                
4 August, 2021
11 
 
2
Protocol 
 Scientific Background  
Endovascular thrombectomy efficacy and safety was established initially up to 6 hours from 
stroke onset (the early time window) from several randomized controlled trials (MR CLEAN1, 
REVASCAT2, ESCAPE3, SWIFT PRIME4, and EXTEND-IA5
only on patients with favorable imaging profiles (minimal ischemic changes) on CT defined as 
imaging defined as small core infarct with a large area of 
mismatch. Later, two trials (DAWN6 and DEFUSE 37) extended the safety and efficacy up to 24 
hours (the late time window). The late window trials utilized advanced perfusion images with 
the same criteria of small core infarct and a large area of mismatch. As a result, these inclusion 
criteria excluded patients with unfavorable imaging profiles (significant ischemic changes), 
including patients with ASPECTS <6 or core infarct volume > 50-70 cc. Thus, thrombectomy 
efficacy and safety in these patients with unfavorable profiles (large core) on imaging is not 
established.  
 
Moreover, the different trials used different imaging modalities for including or excluding 
patients, simple imaging with non-contras
imaging with small infarct core and mismatch, with the vast majority of the patients having 
favorable imaging profile on at least one modality (CT and/or perfusion imaging). Thus: 
 
1.  The correlation between the different imaging profiles and thrombectomy outcomes is 
not established and the optimal imaging selection prior to thrombectomy is unknown. 
2. Many patients were not represented in the trials, especially those with discordance 
between the two imaging modalities.  
 

SELECT 2 Protocol                                                
4 August, 2021
12 
 
2
 Thrombectomy in Patients with Unfavorable Imaging Profiles (i.e. Large Core)   
 
Endovascular thrombectomy is safe and efficacious in selected patients with acute ischemic 
strokes (AIS) due to large vessel occlusion (LVO) in the anterior circulation up to 24 hours after 
the stroke onset. The majority of the early window trials used simple imaging with CT with 
2-4. EXTEND-IA5 was the only early window trial that solely used 
perfusion imaging criteria (core infarct volume < 70cc with a mismatch ratio of > 1.2 & 
mismatch volume > 10 cc). The trial only enrolled 70 patients. Most of the SWIFT PRIME4 
patients were included based on perfusion imaging with limited infarct core but some were 
Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trial included 
a limited number of patients with an ASPECTS < 6. Based on the results of these trials, the 
American Heart Association recommended the use of thrombectomy in patients with large 
-6 hours)8. 
 
Both the trials assessing thrombectomy safety and efficacy in the late time window used 
perfusion imaging. The DAWN6 only included core infarct volume of up to > 50 cc on perfusion 
images and the trial excluded patients with involvement of >1/3rd of MCA territory on simple 
CT. The DEFUSE 37 
efficacy of late window thrombectomy is only established in patients with a small core, CT 
the late window trials had very small infarct core, with median (IQR) core infarct volume of 8 (2-
18) cc in the DAWN6 trial and 9 (2-25) cc in DEFUSE 37.  
 
Despite the lack of data on patients with low ASPECTS, the American Heart Association has 
concluded that thrombectomy may be reasonable in patients with CT ASPECTS< 6 presenting 
within 6 hours of symptom onset while suggesting the need for additional randomized trial 

SELECT 2 Protocol                                                
4 August, 2021
13 
 
2
data8. This population of patients represents a good portion of the patients encountered in 
daily practice without strong evidence from randomized trials to support treatment decision.  
 
Data from a few prospective and retrospective non-randomized studies reported reasonable 
rates of good clinical and safety outcomes after thrombectomy in patients with unfavorable 
Treatment in Acute Ischemic Stroke (SELECT): A Prospective Multicenter Cohort Study of 
ators were allowed to enroll patients with unfavorable imaging 
profiles/large core on either CT or advanced perfusion imaging or both. The treatment decision 
in these patients, thrombectomy vs. medical management, was not randomized and rather 
based on the discretion of the site investigators. The study found that patients with unfavorable 
imaging profile on either or both imaging modalities formed a significant proportion of the daily 
clinical practice with up to 1/4th of patients demonstrating significant ischemic changes on one 
or both imaging modalities. In SELECT, thrombectomy was associated with improved functional 
independence in patients with an unfavorable profile on one or both imaging modalities (EVT: 
30% vs MM: 13%, Adjusted OR: 2.92, 95%CI=1.00-7.91, p=0.041). Thrombectomy was also 
associated with a significant shift towards better outcomes across the full distribution of 
modified Rankin Scale scores (adjusted OR: 2.01, 95%CI=1.00-4.03, p=0.049). (Figure 1).  
 
2
8
2
6
9
16
16
10
16
24
12
6
42
29
0%
10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
M E DI CA L M A N A G E MEN T ( N= 4 3)
THR OM B E C TOM Y  (N=6 2 )
mRS=0
mRS=1
mRS=2
mRS=3
mRS=4
mRS=5
mRS=6
Figure 1. Modified Rankin Scale (mRS) distribution bars representing 90day clinical outcomes in 
patients with unfavorable profile on one or both imaging modalities, stratified by thrombectomy vs 
medical management only. 

SELECT 2 Protocol                                                
4 August, 2021
14 
 
2
 
For safety outcomes, symptomatic intracranial hemorrhages rates (EVT: 7% vs MM only: 13%, 
p=0.26) and mortality (EVT: 29% vs MM only: 42%, p=0.17) did not statistically differ between 
thrombectomy and medical management only arms. 
 
In a post-hoc analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment 
for Acute Ischemic Stroke in The Netherlands (MR CLEAN), the investigators compared the rates 
of good outcome in patients with CTP ischemic core volume>70 cc, who received 
thrombectomy or medical management. The rate of good outcome (mRS 0-2) was 8% in the 
thrombectomy vs 0% in the medical management group. The rate of mortality was 38% versus 
33%, respectively10. In another secondary analysis of MR CLEAN trial, thrombectomy patients 
with ASPECTS 0-4 had 9% rate of good outcome (mRS=0-2), compared to 0% in medical therapy 
patients. Mortality rate was lower in the thrombectomy group (36% vs 42%). Similarly, in 
patients with ASPECTS 5-7, thrombectomy patients had 32% good outcome versus 13% in 
medical management patients with a slightly lower mortality rate (24% vs 26%, respectively)11.  
 
In a retrospective multicenter study12, the outcome rates in patients who received 
thrombectomy were compared between those with CT ASPECTS<7 versus those with CT 
unfavorable and favorable CT profiles. There was no statistically significant difference in good 
clinical outcome mRS 0-
intracerebral hemorrhage (9% vs 9%, p=1.0), or mortality (20% vs 22%, p=0.8).  
 
Rebello et al. (2017) compared the outcomes of patients with unfavorable CTP profile [rCBF 
<30%] >50 cc who underwent thrombectomy versus matched controls who had medical 
management only13. The results showed that compared to medical management, 
thrombectomy was statistically associated with favorable shift in the distribution of 90-day 
modified Rankin scale (mRS) (odds ratio: 2.56; 95%CI: 2.50-8.47; p=0.04), higher rates of good 

SELECT 2 Protocol                                                
4 August, 2021
15 
 
2
clinical outcome (mRS=0-2) (thrombectomy=25% vs medical therapy=0%; p=0.04), as well as 
smaller infarct volumes (mean [SD], thrombectomy=87 [77] vs medical therapy=242 [120] mL; 
p<0.001). There were no statistically significant differences between the groups for safety 
outcomes including parenchymal hematoma type 2 (p>0.99), hemicraniectomy (p=0.10), and 
90-day mortality (p=0.75).  
 
These contrasting results with some reporting a potential signal for benefit and others 
reporting no difference in good outcome rates between thrombectomy and medical 
management alone, along with the lack of higher level of evidence from randomized trials 
support the need for randomized trials to test the efficacy and safety of thrombectomy in 
patients with unfavorable imaging profiles. The current status of inadequate evidence results in 
different treatment approaches in patients with unfavorable imaging profiles, with some 
patients being treated with thrombectomy while the majority receiving medical management 
only. 
 
We hypothesize that endovascular thrombectomy is safe and efficacious in patients with acute 
ischemic strokes due to large vessel occlusion in the anterior circulation (ICA, MCA/M1) with 
large ischemic lesion volumes on simple (non-contrast CT head) or advanced perfusion imaging 
(CT or MRI perfusion) as compared to medical management only up to 24 hours.  
 
 Rationale for randomization in patients with favorable CT profile (ASPECTS 6-
10)  and unfavorable perfusion imaging profile (CTP: rCBF <30% volume or 
MRP: ADC <620 50cc) 
Most of the early window (0-6 hours) trials limited the use of perfusion imaging for patient 
selection. Only SWIFT PRIME4 and EXTEND  IA5 used perfusion imaging to exclude patients 
with the larger ischemic core (> 50-70 cc).  Recently a patient-level meta-analysis of early 
window trials examining the impact of perfusion imaging parameters was published, including 
more than 1700 patients from 6 randomized controlled trials14. The study demonstrated 8% 
good outcome in patients with ischemic core volume of 70 cc or more treated with 

SELECT 2 Protocol                                                
4 August, 2021
16 
 
2
thrombectomy compared to 0% in patients treated with medical management only. In a 
univariate shift analysis, the study showed the benefit of thrombectomy, which disappeared 
once adjusted for confounders. No difference in symptomatic ICH (EVT  0%, MM  12%, 
p=0.24) was reported. Thus, true evidence of efficacy in this patient group is still lacking. The 
recommendation for using only simple CT imaging for patient selection in the early window 
(within 6 hours) was recently rescinded from the American Heart Association stroke guidelines8. 
 
In an analysis of our recently concluded SELECT trial within early window (thrombectomy within 
6 hours of stroke onset), functional independence rates were 101/173 (58%) in patients with 
ASPECTS score of 6 or more and with ischemic core volume of < 50cc. This rate reduced to 6/18 
(33%) in patients with ASPECTS scores of 6 or more but ischemic core volume of 50-100 cc, 
which approached the medical management only rates reported in early window 
thrombectomy trials. The safety outcomes  symptomatic ICH (8/173 (5%) vs 3/18 (17%), 
p=0.072), neurological worsening (14/173 (8%) vs 5/18 (28%), p=0.023) and mortality (15/173 
(9%) vs 7/18 (39%), p=0.001) also significantly increased in the subgroup when ischemic core 
volume was large. Thus, in these patients the outcomes changed significantly as the infarct core 
volume increased on perfusion imaging: the good outcomes reduced in half, while the safety 
outcomes doubled. With a limited representation of this subgroup in clinical trials assessing 
thrombectomy in the early window, no conclusive evidence is available and there is equipoise 
to justify randomization between thrombectomy and medical management alone. 
 
In the late window, no randomized evidence exists for the efficacy of thrombectomy in these 
patients. Two randomized controlled trials (DAWN6 & DEFUSE 37) assessing the efficacy and 
safety of thrombectomy in the late window used both simple (CT) as well as advanced 
perfusion imaging to exclude patients. The DAWN6 study only included patients with ischemic 
core volume of up to 50cc, while the DEFUSE 37 trial included patients with up to 70 cc of 
ischemic core volume. However, only 18 of the 182 randomized patients had ischemic core 

SELECT 2 Protocol                                                
4 August, 2021
17 
 
2
volume between 50-70cc. Thus, no substantial conclusion of efficacy and safety of 
thrombectomy can be made within this subgroup for the late window as well. 
 
 Rationale for including patients with very large core on advanced perfusion 
(CTP: rCBF (<30%) volume or MRP: ADC < 620 >100cc) 
Limited non-randomized evidence of thrombectomy efficacy is available in the published 
literature. A recently published study, a meta-analysis of 7 early window randomized controlled 
trials by Campbell et al.14 has suggested benefit of thrombectomy in patients presenting with 
infarct core of >100 cc. Campbell et al. demonstrated that although functional independence 
rates remain very low, these patients continue to benefit from thrombectomy. For infarct core 
volumes up to 125 cc, the number needed to treat for any benefit remains below 10 for most 
functional outcomes and less than 5 for any functional improvement. In the light of these 
recently available evidence, these patients may have a low likelihood of functional 
independence but could still have better functional outcome than patients treated with medical 
management only. Thus, the protocol was amended to include these patients in the study. 
Stringent safety monitoring of mortality and symptomatic ICH is employed to ensure patient 
safety. The amended inclusion criteria will allow for:  
1) Assessment of population with CTP/MRP core infarct >100cc  
2) More generalizability of the study findings 
3) No dependency on perfusion criteria, which will allow for the population to be 
treated based on non-contrast CT only. Providing data on the efficacy and safety of 
thrombectomy selection based on a non constrast CT, which is more readily 
available, would result in an increased thrombectomy availability to centers without 
perfusion imaging.  
Although no upper limit is specified for infarct core volume measurements on CT or MR 
perfusion imaging, the infarct size is still expected to be limited, to an extent, given imaging 
non-

SELECT 2 Protocol                                                
4 August, 2021
18 
 
2
patients with 
area of cerebral edema on non-contrast 
CT  
 Rationale for excluding patients with very large core on CT (ASPECTS 0-2)  
There are no previously published data to describe the outcomes in this patient population. We 
did not have any patients with ASPECTS 0-2 who received a thrombectomy in SELECT trial. The 
90-day mRS distribution for patients with ASPECTS 0-2 is shown in Figure 2.  Since, no data for 
thrombectomy efficacy and safety is available, these patients were excluded from the trial. 
 
 
 
0
0
0
0
0
0
0
0
29
0
29
0
43
0
0%
20%
40%
60%
80%
100%
MEDICAL MANAGEMENT (N=7)
THROMBECTOMY (N=0)
ASEPCTS 0-2
mRS=0
mRS=1
mRS=2
mRS=3
mRS=4
mRS=5
mRS=6
4
5
4
3
15
27
26
11
7
30
7
8
37
16
0%
20%
40%
60%
80%
100%
MEDICAL MANAGEMENT (N=27)
THROMBECTOMY (N=37)
ASPECTS 3-5
mRS=0
mRS=1
mRS=2
mRS=3
mRS=4
mRS=5
mRS=6
Figure 2. Modified Rankin Scale (mRS) distribution bars representing 90day clinical outcomes in large core patients 
stratified by ASPECTS score. 

SELECT 2 Protocol                                                
4 August, 2021
19 
 
2
 Imaging selection for thrombectomy  
 
Thrombectomy is a highly effective treatment for anterior circulation LVO patients based on the 
results of several recent randomized clinical trials1-7. However, the imaging modalities and the 
patient populations enrolled, varied between the studies. For example, the Multicenter 
Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the 
Netherlands (MR CLEAN)1 used non-contrast head CT (NCCT) with the inclusion criteria of less 
than one third of the MCA, while the Solitaire with the Intention for Thrombectomy as Primary 
Endovascular Treatment trial (SWIFT PRIME)4 and the Randomized Trial of Revascularization 
with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to 
Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset  
(REVASCAT)3, in spite of using NCCT, applied a more stringent inclusion criterion of the Alberta 
4 were 
treated by CT-Perfusion/ iSchemaView RAPID (CTP/RAPID), while some in REVASCAT3 were 
treated based on MRI 
Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE)2 used 
-Angiography collaterals, 
as well as placing some consideration of the CT-Profusion profile. Extending the Time for 
Thrombolysis in Emergency Neurological Deficits 
 Intra-Arterial trial (EXTEND-IA)5 was the 
sole early window trial that purely based imaging selection on advanced perfusion imaging 
using CTP/RAPID.  
 
This resulted in uncertainty in regards to optimal patient selection when it comes to imaging 
modality prior to thrombectomy as reflected in the current AHA guidelines, and the guideline 
recommending against using advanced perfusion imaging for patients presenting in early time 
window was recently rescinded8.  
 

SELECT 2 Protocol                                                
4 August, 2021
20 
 
2
The recent trials evaluating thrombectomy effectiveness in the late time window -  Clinical 
Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention 
With TREVO (DAWN)6 and Endovascular Therapy Following Imaging Evaluation For Ischemic 
Stroke 3 (DEFUSE3)7 used advanced imaging perfusion (CTP and MR-Perfusion) utilizing the 
RAPID software along with NCCT criteria to select patients. As a result, the recent AHA 
guidelines also recommend the use of both CT and advanced perfusion imaging for patient 
selection in thrombectomy8.  
 
In conclusion, the optimal imaging selection modality prior to thrombectomy is still unknown. 
Furthermore, the restrictive imaging inclusion criteria and correlation with outcomes, both 
functional independence, and safety outcomes are still yet undetermined. To measure the 
correlation between the two different imaging modalities and clinical outcomes, patients with 
discordant imaging profiles should be compared. 
 
The highest level of evidence comes from a randomized controlled trial comparing 
thrombectomy outcome rates as well as safety parameters in patients selected by CT only vs CT 
plus perfusion imaging. However, a randomized trial is not feasible given the level of evidence 
from RCTs in the late window patients treated based on favorable perfusion imaging profiles 
(DAWN6 and DEFUSE 37). Additionally, the current AHA guidelines recommend the use of 
perfusion imaging for selection of patients in the late window8.  
 
Since the clinical trials evaluating thrombectomy largely included patients with favorable 
profiles on both CT and perfusion imaging, the vast majority of the currently available data is on 
these patients. Thus, the correlation between the thrombectomy outcome rates with different 
imaging profiles, specifically with discordance profiles between CT and perfusion images, is not 
well established. However, those patients with discordant imaging profiles on both modalities 
are frequently encountered in real-world practice. There is currently no evidence from 
randomized trials to guide the treatment decision in these patients. Many of these patients 

SELECT 2 Protocol                                                
4 August, 2021
21 
 
2
may be excluded from the treatment based on the unfavorable profile on one imaging modality 
as preferred by the treating center or physician. Moreover, it is unclear if a favorable profile on 
advanced perfusion imaging with an unfavorable profile on non-contrast CT will provide 
improved prognostic value of thrombectomy when compared to patients with unfavorable 
perfusion imaging and favorable CT, or vice versa. 
 
The SELECT trial was the first and only study to document discordance between imaging 
selection profiles. In SELECT, we observed that the two imaging modalities (CT and CT 
perfusion) had an agreement with favorable profiles in 81% of patients and an unfavorable 
profile on both modalities in 4% of patients. Discordance between the two imaging modalities 
was observed in 15% of patients with 7% showing favorable CT but unfavorable CTP and 8% 
showing unfavorable CT but favorable CTP. The agreement between imaging modalities and 
outcomes are shown in Figure 3. 
 
Figure 3. 
CT & Favorable CTP): High agreement between CT and CTP profiles prior to thrombectomy. Similar profile to 
patients enrolled in prior RCTs; B (Unfavorable CT & Favorable CTP): Patients who would have been excluded by CT 
but treated based on favorable CTP; C (Favorable CT & Unfavorable CTP): Patients who would have been excluded 
by CTP but qualified by favorable CT; D (Unfavorable CT & Unfavorable CTP). 

SELECT 2 Protocol                                                
4 August, 2021
22 
 
2
As shown above, discordance between imaging profiles was not uncommon and clinical 
outcomes differed based on the presence and type of discordant imaging profiles. Patients with 
discordant profiles showed outcomes better than patients with both imaging modalities 
demonstrating an unfavorable profile.  
 
The two groups where both imaging modalities (CT and perfusion imaging) agree: 
1. Unfavorable profiles on both: the results would not contribute to the comparison of 
imaging selection.  
2. Favorable profile on both: there is, as detailed, strong evidence from RCTs supporting 
thrombectomy in both early and late time windows; thus randomizing these patients to 
compare imaging selection for thrombectomy is unethical and not feasible. 
 
In SELECT 2, in order to compare the outcomes between imaging selection modalities, we 
propose to examine the correlation between the discordance in imaging profile and outcome 
rates, both functional independence as well as safety outcomes. We also propose to examine if 
there is a heterogeneity of treatment effect of thrombectomy in patients with discordant 
imaging profile (favorable CT/unfavorable perfusion imaging and unfavorable CT/favorable 
perfusion imaging).  
 
Based on the SELECT trial results, patients with unfavorable CT/ favorable CTP had 48% good 
outcomes vs favorable CT/unfavorable CTP with 32% good outcomes (16% absolute difference). 
A superiority margin at 15% will be set between the two discordance groups and good outcome 
rates between patients with discordant imaging profiles will be compared. If those differences 
do not reach the statistical margin, then among patients with discordant imaging profile who 
met the inclusion criteria for SELECT 2 and treated with thrombectomy, the outcome rates did 
not differ. 
 

SELECT 2 Protocol                                                
4 August, 2021
23 
 
2
In addition to comparing the rates of good outcomes between patients treated with 
thrombectomy in patients with discordant profiles, thrombectomy treatment effect 
heterogeneity will be assessed in patients with favorable CT/ unfavorable perfusion imaging 
and those with unfavorable CT/favorable perfusion imaging. If no heterogeneity exists, then 
thrombectomy benefit is not modified in the two scenarios when the two imaging modalities 
disagree.  
 
 Thrombectomy efficacy and safety in patients with favorable CT but 
unfavorable perfusion imaging profile 
 
Early window trials demonstrated the superiority of thrombectomy over standard medical 
management in patients selected by either favorable CT (ESCAPE and REVASCAT) or favorable 
perfusion imaging (EXTEND-IA and a portion of SWIFT-PRIME). Thus, in patients with favorable 
CT profile, thormbectomy is proven superior to standard medical management in early window. 
Late window trials, DAWN6 and DEFUSE 37 proved thrombectomy efficacy and safety in patients 
with favorable CT and perfusion imaging profiles. If thrombectomy is proven better than 
medical management only in patients with favorable CT but unfavorable perfusion imaging, 
then regardless of the perfusion imaging findings, patients with favorable CT would benefit 
from thrombectomy and thus, should be treated with thrombectomy. 
 
 Rationale and use of iSchemaView RAPID and iSchemaView RAPID ASPECTS 
 
iSchemaView RAPID: At the conclusion of the CT/MR Perfusion scan, the technologist sends the 
sequences from the console to RAPID for automated processing. The RAPID software was 
developed based on data from DEFUSE 1 and was prospectively validated in DEFUSE 2. The 
system provides fully automated processing of brain images. The RAPID output maps, which 
identifies the volume and location of ischemic core and perfusion lesions, are emailed to 

SELECT 2 Protocol                                                
4 August, 2021
24 
 
2
investigators (protected health information is automatically removed) and auto-sent to PACS 
for viewing within 5 minutes of completion of the scan. Immediately after the images are 
available, the investigator will review the results of the RAPID mismatch map, simple (Non-
contrast) CT and the CTA to determine assignment in the specified group. The accuracy of the 
software for identifying the size and location of perfusion and diffusion lesions has been 
established by extensive validation and testing on blood flow phantoms; the software received 
FDA 510K clearance for clinical use in 2013. The agreement between local investigators and the 
Imaging Core Lab for identification of the mismatch profile in DEFUSE 215 
CI 0·83 1·0. Identification of core and penumbral volumes will be done in accordance with the 
procedures followed in DAWN6 and DEFUSE 37 trials. 
 
iSchemaView RAPID ASPECTS: Inter-rater reliability of ASPECTS score has been shown to be 
fair16. In a recent study, Automated ASPECTS has been shown to have a much higher agreement 
s by two board-
certified 
17. The 
automated ASPECTS score is included as an investigational tool in the study. ASPECTS for 
patient selection will be determined independently by appropriately trained clinicians prior to 
any assessment with automated ASPECTS. In case of disagreements, ASPECTS scores provided 
by the clinicians will override the ASPECTS score by iSchemaView RAPID ASPECTS. In addition, 
the use of perfusion imaging in all patients will also help verify if a large core is present in these 
patients. 
 
 
 Rationale for including patients with exctracranial ICA occlusion: 
 
Patients with extracranial ICA occlusion, as of now, do not have a proven treatment for 
revascularization and the rates of recanalization achieved by the only currently FDA approved 
treatment, IV tissue plasminogen activator have been poor18-19. Another issue with these 
patients is the 

SELECT 2 Protocol                                                
4 August, 2021
25 
 
2
of cases with intracranial ICA occlusion, because of low flow, the contrast used for obtaining CT 
angiogram does not reach the level of occlusion and thus the occlusion appears to be 
extracranial on the conventional CT angiogram20. The only way to confirm the diagnosis of 
psuedoextracranial occlusion is to obtain an angiogram using fluoroscopy in the angio suite. 
Such cases form a significant number of patients presenting with extracranial occlusion who 
may benefit from the thrombectomy procedure, but are excluded from the trial based on the 
appearance on CT angiogram. Including cases with extracranial ICA occlusion on CTA will allow 
for enrollment of these patients. Randomized controlled trials such as ESCAPE and REVASCAT 
reported 40 (12.7%) and 31 (10.3%) patients with extracranial ICA occlusions. EXTEND-IA in 
early window and DEFUSE 3 in late time window also allowed for inclusion of patients with 
extracranial ICA, though did not report the number of patients enrolled with extracranial ICA.  
 Study Question, Aim, and Hypothesis 
Study aims: are to evaluate in acute ischemic stroke patients due to a large vessel occlusion in 
the anterior circulation (MCA M1 and ICA):  
 Primary aim: If thrombectomy plus medical management as compared to medical 
management alone will be efficacious and safe in patients with large core on either CT 
(ASPECTS 3-5) or perfusion imaging (CTP: rCBF<30% or MRP: ADC <620 50cc), treated 
within 0-24 hours from last known well. We hypothesize that patients with unfavorable 
profiles (large core) treated with thrombectomy on either imaging modality will have 
significantly better outcomes than large core patients treated with medical 
management only.  
 
 Second aim: The second aim is to look at the correlation of imaging profiles with 
thrombectomy clinical outcomes and treatment effect. It will be evaluated by 
comparing the outcomes in patients with discordant imaging profile and assessing if 
thrombectomy outcome rates and treatment effect will differ in patients with 

SELECT 2 Protocol                                                
4 August, 2021
26 
 
2
discordant imaging profiles (favorable CT/unfavorable perfusion imaging and 
unfavorable CT/favorable perfusion imaging).  
 
A) 
Evaluate good clinical outcome (90-day mRS 0-2) rates in patients with 
discordant imaging profile (unfavorable CT/favorable perfusion imaging vs 
favorable CT/unfavorable perfusion imaging) treated with thrombectomy.  
 
B) 
Evaluate the heterogeneity of thrombectomy treatment effect in patients 
with favorable CT/unfavorable perfusion and unfavorable CT/favorable perfusion 
imaging. 
 Methods 
 Study Design   
 
SELECT 2 is a prospective, multicenter, randomized open-label clinical trial evaluating: 1) the 
efficacy and safety of thrombectomy in patients with unfavorable imaging profiles (large core) 
on either CT or perfusion imaging or both treated within 0 to 24 hours from last-known-well; 
and 2) the correlation between CT and CT/MR perfusion imaging profiles and 90 day clinical 
outcomes (good mRS scores, 0-2) in LVO patients treated with thrombectomy within 0 to 24 
hours from last-known-well.  
 
On presentation to the EVT capable center enrolling patients in SELECT 2 trial, patients will 
receive a simple (non-contrast CT), CT angiography and CT/MR Perfusion with mismatch 
determination using automated RAPID software. The physicians will evaluate the CT scans and 
provide ASPECTS score. The CT image will also undergo processing by iSchemaView RAPID 
ASPECTS software as an investigational tool and the results will be available to the physicians 
for review. ASPECTS for patient selection will be determined independently by appropriately 
trained clinicians prior to any assessment with automated ASPECTS. 
 

SELECT 2 Protocol                                                
4 August, 2021
27 
 
2
Patients with unfavorable imaging profiles on either CT (ASPECTS 3-5) or perfusion imaging 
(CTP: rCBF<30% or MRP: ADC <620 50cc) or both within 0-24 hrs from last-known-well will be 
randomized into thrombectomy plus medical management vs medical management alone.  
 
 
 

SELECT 2 Protocol                                                
4 August, 2021
28 
 
2
 Enrollment Inclusion and Exclusion Criteria 
 
Adult patients with AIS due to LVO in the anterior circulation (ICA and MCA occlusions in the 
M1 segment) who are normal or with minimal deficits at the time of their strokes (mRS 0-1), 
have received the pre-specified imaging profile (NCCT, CTA and CTP/MRP) prior to the 
treatment decision, and will be treated with thrombectomy (groin puncture time) plus medical 
management or medical management alone within 24 hrs from their last-known-well are 
eligible for the study (Table 1). A screening log of all patients with LVO presenting within 24 
hours of symptom onset who receive thrombectomy, in addition to non-enrolled patients who 
qualify for SELECT 2 large core definition on imaging, will be kept. Clinical data will be collected 
to evaluate which method best correlates with patient outcome after thrombectomy. 
Mechanical thrombectomy includes the use of stent retrievers ( e.g. Trevo®, Solitaire®, 
EmboTrap Revascularization Devices) and/or aspiration devices (e.g. MicroVention SOFIA 
Catheter, and Penumbra) as recommended by AHA (American Heart Association) guidelines. 
Please review Appendix C for a list of all approved devices. 
 
 
Table 1. The SELECT 2 study inclusion and exclusion criteria  
Inclusion 
Criteria 
1) Adults (18-85 years) with the final diagnosis of an acute ischemic stroke  
2
 
3) Last known well to groin puncture or medical management between 0 to 24 
hours 
4) Pre-stroke modified Rankin Scale score of 0-1 
5) Eligible for thrombectomy or medical management 
6) Signed Informed Consent obtained 
7) Subject willing to comply with the protocol follow-up requirements 
     8) Anticipated life expectancy of at least 3 months 

SELECT 2 Protocol                                                
4 August, 2021
29 
 
2
Exclusion 
Criteria 
1) Inability to undergo CT-Angiography and/or CT/MR Perfusion imaging (e.g., 
renal insufficiency, iodine/contrast allergy) 
2) Co-morbid psychiatric or medical illnesses that would confound the neurological 
assessments 
3) Treatment with IV thrombolytic therapy beyond 4.5 hours from last known well 
4) Treated with IV thrombolytic therapy 
AND any 
of the following:  
   - age >80  
   - current anticoagulant use 
   - history of both diabetes AND prior stroke 
   - NIHSS >25 
   - ischemic involvement of more than third of the MCA territory  
5) Current participation in another investigational drug or device study. 
 
3.2.1.1. 
Specific Neuroimaging Inclusion Criteria 
1. Proven large vessel occlusion in ICA or MCA-M1 occlusion (carotid occlusions can be cervical 
or intracranial, with or without tandem MCA lesions) determined by MRA or CTA 
2. Large infarct-core lesion on at least one of the following  
2.1. Non-Contrast CT (ASPECTS of 3-5)*,  
2.2. CT perfusion (rCBF<30%  
 
2.3. MRI-DWI  (ADC<620  
 
 
*ASPECTS 0-2 are not included in this study due to the expected poor outcome in these patients.  
 
3.2.1.2. 
Specific Neuroimaging Exclusion Criteria 
 
1. Patients who have both ASPECTS of 6-10 on non-contrast CT AND core volume <50 cc on 
perfusion imaging 
2. Patients with very large core on imaging 
 

SELECT 2 Protocol                                                
4 August, 2021
30 
 
2
3. Evidence of intracranial tumor (except small meningioma) acute intracranial 
hemorrhage, neoplasm, or arteriovenous malformation 
4. Significant mass effect with midline shift 
5. Evidence of internal carotid artery dissection that is flow limiting or aortic dissection 
6. Intracranial stent implanted in the same vascular territory that precludes the safe 
deployment/removal of the neurothrombectomy device 
7. Acute symptomatic arterial occlusions in more than one vascular territory confirmed on 
CTA/MRA (e.g., bilateral MCA occlusions, or an MCA and a basilar artery occlusion). 
8. Signs of established infarct and large area of cerebral edema on non-contrast CT 
 
 
 Enrollment and Randomization 
 
All patients who meet the clinical criteria listed above are eligible for SELECT 2 clinical enrollment. 
This includes both patients who are directly admitted to the study site and patients who are 
transferred from an outside hospital. The time of enrollment is the time when the informed 
consent is signed by the patient or their authorized legal representative. All patients or their 
surrogates will provide written informed consent. If a surrogate has provided informed consent, 
an attempt will be made to assess the competence of the patient again at day 1, discharge and 
at every follow-up in-person visit within 90 days of the procedure with the study team, if an in-
person visit is feasible. If the patient is able to provide consent, informed written consent 
procedure will be reattempted, if an in-person visit is feasible.  
 
      Remote consent procedure:  
A remote consent process to prevent delay in treatment is developed and included in the 
SELECT 2 protocol for participating sites that may want to implement such process. This remote 
consenting process will be utilized in cases when the patient himself/herself cannot provide an 
informed consent with the surrogate not being present on enrollment site. The key 
requirements of the process include provision of information regarding the study procedure in 
entirety followed by opportunity to ask questions and provision of contact information, and 

SELECT 2 Protocol                                                
4 August, 2021
31 
 
2
receive completed ICF document with signature by the surrogate. An example of such process is 
described below. In places where only a legally authorize representative can consent for a 
research study, appropriate modifications will be made to the process described below. 
 
1. Provision of information regarding the study procedure in entirety followed by 
opportunity to ask question: 
1.1. This can be achieved by an audio call, a video call or a teleconferencing service. The 
identity of the surrogate should be confirmed by providing acceptable ID documents 
before providing patie
 identifiable information. 
1.2. The surrogate should be encouraged to ask question. A contact number should be 
provided to the surrogate in case they have any further questions as they consenting 
process progress or later on. 
2. Complete ICF document: 
2.1. The treating center should transmit all pages of ICF document to the surrogate. All 
pages of ICF document, completed by the surrogate should be received by the 
treating center prior to enrollment and randomization of the patient. 
2.2. Documents with incomplete information, i.e. absence of signature, absence of full 
legal name and absence of date and time of informed consent or missing pages of ICF 
document would not be considered adequate and must be received en-block and 
completed prior to enrollment and subsequent randomization into the study. 
3. Confirmation of the identity: 
The surrogate identity should be confirmed by providing acceptable ID documents 
before any identifiable information is shared and tthe completed informed consent 
form is transmitted. 
4. Transmission of the information through a HIPAA compliant medium: 
4.1. A HIPAA compliant secure medium should be used to transmit the data to the 
surrogate and receive the ICF back from the surrogate. These can include a secure 
institutional email with implemented HIPAA security features, Adobe Sign platform 

SELECT 2 Protocol                                                
4 August, 2021
32 
 
2
approved for transmission of healthcare information or a fax number that is in 
possession of the intended recipient . 
4.2. If the surrogate is present at the remote site, where the patient was first received 
before being transferred to the treatment center, the secured email from the Health 
Service Provider (HSP) at remote treatment site or fax machine under direct control 
and access of the HSP for the patient at remote treatment site can be used to 
transmit the information to and from the LAR. 
5. Decreasing the burden of responsibilities from the surrogate as much as possible: 
5.1. The study will ensur that ethe surrogate will receive assistance from the on-site ER 
physician/Nurse/research coordinators to decrease the burden of the consenting 
process including connecting with the surrogate, transferring the study information 
to the surrogate and returning the signed form to the study enrollment site. Use 
video conferencing if possible to establish the contact with the surrogate, provide 
ample opportunity to ask questions and answer all questions in detail. Request 
assistance from on-site healthcare personnel whenever available, provide protocol 
training to them beforehand and consider including them as the study personnel. 
Follow-up with another video call 15-20 minutes after the first contact to provide 
another opportunity to ask questions and assist in the process of signing and 
transmitting the ICF.  
6. Documentation in the ICF 
6.1. A complete documentation of the consenting process 
name, relationship to the patient, method of transmission of ICF, mode of 
communication and verification of identity should be included in the ICF. 
  
 
 

SELECT 2 Protocol                                                
4 August, 2021
33 
 
2
An example of such a procedure is provided below: 
 Contact the appropriate surrogate by telephone/videoconferencing. 
 Confirm the identity of the surrogate and how he/she is related to the patient. 
 Discuss the study details, including procedures, study device and potential risks and 
benefits. Discuss the ICF and give instructions about where the surrogate needs to sign 
and date/time. The study will ensure that  the surrogate will receive assistance from the 
on-site ER physician/Nurse/research coordinators to decrease the burden of the 
consenting process including connecting with the surrogate, transferring the study 
information to the surrogate and returning the signed form to the study enrollment site. 
 Provide the ICF through a secure medium (Adobe Sign/email/fax). 
 Provide the surrogate with a phone number to call you back in the event that she/he has 
questions. Follow-up with a phone/videoconferencing call after 15-20 minutes if they 
have any questions or need any help completing and returning the ICF. 
 The surrogate should return the entire, signed and dated ICF back. The ICF is not valid and 
you cannot proceed with study enrollment unless all pages are received and appropriately 
filled out/signed/dated/timed. 
 
After obtaining consent and ensuring all inclusion and exclusion criteria are met, randomization 
will be done in the emergency room prior to treatment using a web-based dynamic 
randomization system. Our randomization algorithm will be accessible to the study 
investigators and staff through a separate web page accessible only through the 
REDCAP database module. Covariate adaptive randomization will be used to balance the 
distribution of age (<60, 60-69, 70-79, 80-85 years old), presentation NIHSS (6-9, 10-15, 16-20, 
>20), center, clot location (M1, ICA), treatment time window (0-8, 9-16, 17-24 hours from onset 
to randomization time), CTP/MRP core volume (<50cc, 50-100cc, >100cc), presence or absence 
of target mismatch profile (
and hemisphere 
(right, left) between the two treatment groups.  
 

SELECT 2 Protocol                                                
4 August, 2021
34 
 
2
The randomization algorithm we are going to implement is the algorithm developed by Pocock 
and Simon (1975)27, i.e., minimization method. Through this algorithm, the assignment of a new 
patient to a treatment group is determined so as to minimize the differences between the 
groups in terms of these important key baseline variables. Unlike traditional stratified 
randomization, the minimization method works toward minimizing the total imbalance for all 
factors together instead of considering mutually exclusive subgroups, that is, we will not be 
creating these mutually exclusive subgroups during the randomization. Therefore, this 
approach is not restricted by the number of variables and the possible combinations of levels of 
balancing factors. Further details about Randomization can be found in Appendix A. 
 
Eligible patients will be randomized into thrombectomy plus medical management vs medical 
management alone at a 1:1 ratio. The minimization algorithm is intended to balance the 
baseline characteristics between the two study arms, thrombectomy vs. medical management. 
The algorithm is not intended at the level of imaging profile subgroup. When a new patient is 
enrolled, the site will enter the stratification factor values into the dynamic randomization 
webpage and the treatment assignment will be determined immediately. An emergency 1-800 
number will be provided if web-based randomization is not available due to exigent 
circumstances.  
The assignment of the patients based on site assessment will be considered final for the 
primary analysis. A 1-800 number will be provided to the study investigators, where the case 
and imaging can be discussed with highly experienced vascular neurologists. A pre-specified 
secondary analysis based on core lab imaging assessment will be performed to address the 
cases where the core lab assessment differs from the site imaging assessment. 
 
 

SELECT 2 Protocol                                                
4 August, 2021
35 
 
2
 Endovascular Thrombectomy  
 
 
The goal for femoral artery puncture will be within 45 minutes of randomization; femoral artery 
puncture must occur within 90 minutes of the completion of the qualifying imaging. Patients 
and/or suction (aspiration) 
thrombectomy systems currently cleared by the FDA for thrombus removal in patients 
experiencing an acute stroke within 24 hours of symptom onset following the published 
instructions for use for these devices. The devices which will be used are FDA-approved stent 
retrievers: the Trevo Retriever, the Solitaire Revascularization Device, EmboTrap 
Revascularization Device and Tigertriever Revascularization Device; and/or the aspiration 
devices approved by the FDA (e.g. MicroVention SOFIA Catheter, and the Penumbra 
thrombectomy system) permitted in the study. Please review Appendix C for a list of all 
approved devices. The choice of thrombectomy method, primary approach/technique, whether 
primary aspiration or primary stent-retriever with or without aspiration, will be left up to the 
interventionalist, with any of the FDA-approved devices approved in the study protocol or a 
combination of them (Appendix C). The study database will collect the thrombectomy method, 
and the devices used in the thrombectomy procedure. 
Standard medical therapy, based on current AHA guidelines, will also be provided for all 
patients. Although any cleared neurothrombectomy device (Appendix C) can be used in the 
study, only the Solitaire Revascularization Device and Trevo Retriever are FDA-cleared to be 
indicated as a treatment in acute ischemic stroke patients to reduce their disability from the 
stroke. Individual investigators may use any of these devices or any combination of these 
devices to remove thrombus from the ICA, MCA M1 segment or, if needed, from M2 segments 
of the intracranial circulation. These are all approved anatomic locations for these devices. The 
use of thrombectomy devices should be performed in accordance with the indications for use 
and within the trial protocol. Any deviation from the on-label use of the device outside of the 
SELECT 2 protocol should be recorded in the appropriate case report form in detail. If there is 
severe stenosis of the common carotid artery or the proximal internal carotid artery, 

SELECT 2 Protocol                                                
4 August, 2021
36 
 
2
investigators may also use devices for angioplasty or for stenting of the carotid artery as 
is not 
currently approved by the FDA for stroke treatment and cannot be used in SELECT 2.  
 
Sites will use local protocols for femoral access, sedation, heparin infusion, monitoring, etc. 
Sites will perform a cervical injection of the involved carotid circulation as a baseline 
 
injection of the involved carotid circulation will also be obtained. Imaging will cover the full 
region of the normal circulation in AP and latera
 
the entire venous phase. All brain imaging from stroke onset through hospital discharge, 
including the MRI, CTP/MRP, and CT, as well as angiographic images obtained for the diagnostic 
and therapeutic portions of the procedure, will be transmitted to the core lab. The use of 
general anesthesia is left to the local investigators but discouraged by the study given the 
concerns of worse outcomes associated with that.  
In cases of extracranial ICA occlusions, immediate stenting will be discouraged and delayed 
stenting  (beyond 72 hours) will be preferred to reduce the risk of hemorrhagic transformation 
because of requirements of antiplatelet therapy/heparin to prevent re-occlusion. 
 
 Medical Management 
 
Patients randomized to medical management alone will receive standard AHA guideline-
directed medical therapy, which will include  IV thrombolytic therapy available for use 
according to practice guidelines in patients presenting within the first 3 hours from last-seen-
normal and meeting other FDA label criteria, or up to 4.5 hours from last-seen-normal and 
meeting other AHA guidelines. No procedures or tests required by the protocol will delay 
fastest possible delivery of thrombolytic therapy to potentially eligible subjects. The study 
database will collect the names of all thrombolytic drugs administered during the study, the 
route, the time of start of administration, and the dose administered. For non- thrombolysis 
treated patients, this will include aspirin 325 mg on day 1 followed by aspirin 81 mg or 325 mg 

SELECT 2 Protocol                                                
4 August, 2021
37 
 
2
thereafter, which will be determined by treating physician, and standard deep venous 
thrombosis prevention therapy. Equivelent regimens of the aspirin will be allowed in countries 
where aforementioned doeses are not commercially available. Intravenous anticoagulation and 
dual anti-platelet therapy will be discouraged without clear documented reasoning. Post-
thrombolysis patients will be treated based on standard study site protocols for these patients. 
 
 Outcome Measures 
 
3.7.1.1. 
Primary Outcome 
 
The primary outcome #1 will be the distribution of mRS scores at 90 days.  The primary 
outcome #2 will be the percentage of good outcome (mRS 0-2) at 90 days. The definition of 
- 15) days, 
measured by a modified Rankin scale (mRS) score of 0-2. The determination of mRS scores will 
be performed by certified raters unaware of the treatment arm or the baseline clinical and 
radiographic characteristics of the individual patient by in person interview or by telephone if 
in-person visit is not possible.  
The shift in the modified Rankin Scale score is better equipped to capture potential 
improvement in the functional outcomes as compared to a binary (dichotomized) outcome with 
intervention. Since the study population is composed of acute stroke patients with significant 
ischemic changes (unfavorable imaging profiles), the potential shift across modified Rankin 
Scale Score categories, not only the functional independence, is of clinical significance. For 
details, a change of mRS score of 5  completely bedridden to mRS score of 4  ambulating with 
a wheelchair and to mRS score of 3  ambulating with a cane is a successful outcome for 
thrombectomy. We will still have the dichotomized outcome as our second primary outcome.  
 
3.7.1.2. 
Secondary Outcomes 
 
Secondary outcome measures include: 1) safety as measured by the incidence of symptomatic 
intracranial hemorrhage (sICH) (SITS-MOST)21
-point 

SELECT 2 Protocol                                                
4 August, 2021
38 
 
2
increase on the NIHSS score within 24 hours due to the stroke itself), mortality and groin (or 
arterial access site) hematomas, infections or any vascular injury caused by the endovascular 
procedure, 2) rates of recanalization (complete and partial) using the modified TICI system 
location. 
 or an 
NIHSS of 0-1 
 
3.7.1.3. 
Imaging Outcomes 
 
Imaging endpoints are:  1) infarct volume on MRI DWI sequence (or CT if MRI not feasible) 24 
hours to 7 days after randomization; 2) lesion growth between the RAPID identified ischemic 
core on baseline imaging and the infarct volume; 3) successful reperfusion defined as DWI 
lesion volume minus Tmax>6 seconds greater than 50%; and 4) the proportion of subjects with 
recanalization of the primary arterial occlusive lesion. The technical efficacy of the endovascular 
procedure will be assessed by a modified Thrombolysis in Cerebral Infarction scores of 2b (50% 
to 75% reperfusion), 2c (>75% to 99% reperfusion) or 3 (complete reperfusion).22  
 
 Clinical and Imaging Evaluations  
 
Clinical assessments will be performed at baseline, 24 hours after randomization, hospital 
discharge, 30 days, and 90 days (Table 2). Clinical assessments include the modified Rankin 
Scale, the NIHSS, and quality of life measure (Neuro-QoL).23  
CT images will be read by appropriately trained clinicians as well as by the iSchemaView 
automated ASPECTS prior to randomization. ASPECTS for patient selection will be 
determined independently by the clinicians prior to any assessment with automated 
ASPECTS. In cases where there is disagreement, the physician reading will override the 
automated software reading. CTP images with mismatch determination will be read by 
iSchemaView automated RAPID software. All the images including baseline and follow-up 
MRI and CT images will be assessed independent of each other and blinded to treatment 
allocation at the core imaging laboratory at SELECT 2 Core Lab at McGovern Medical 

SELECT 2 Protocol                                                
4 August, 2021
39 
 
2
School at UTHealth at Houston. Angiographic studies from the endovascular procedure will 
be assessed at SELECT 2 Core Lab.  
 
 

SELECT 2 Protocol                                                
4 August, 2021
40 
 
2
 Table 2. Schedule of Events   
PROCEDURES 
Screenin
g 
Enrollme
nt 
Baseline/ 
randomizati
on 
Thromb
ectomy
Day 1 
(24 hrs 
+/-6 hrs)
5-7 Day 
follow-
up (or 
dischar
ge) 
Day 30 
(+/-15 
days)
Day 90 
(+/-15 
days)
Day 
365  
(+/-60
days)
Screen Failure Log 
X 
 
 
 
 
 
 
 
Inclusion and Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
Informed Consent  
 
X 
 
 
 
 
 
Demographics 
 
 
X 
 
 
 
 
 
Physical Exama 
 
 
X 
 
 
 
 
 
Vital Signsb 
 
 
X 
 
 
 
 
 
Baseline Labsc 
 
 
X 
 
 
 
 
 
Serum HCG (if 
applicable) 
 
 
X 
 
 
 
 
 
Medical History  
 
 
X 
 
 
 
 
 
Baseline Medications 
 
 
X 
 
 
 
 
 
Baseline Characteristics 
 
 
X 
 
 
 
 
 
NIHSSe 
 
 
X 
 
X 
X 
 
 
Modified Rankin Scaled 
 
 
X 
 
 
X 
X 
X 
X
Neuro-QoLd
 
 
 
 
 
 
 
X 
X
Thrombectomy  
Timepoints/Procedural 
Data 
 
 
 
X 
 
 
 
 
Post Treatment Hourly 
Blood Pressure Form 
(Treatment + 24 hrs)e 
 
 
X 
X 
X 
 
 
 
Baseline Imaging (Head 
CT/CTA/CTP/MRI) 
 
 
X 
 
 
 
 
 
Post Procedure Imaging 
(MRI 24 hours-7 days or 
CT if MRI not feasible) 
 
 
 
 
X 
 
 
Image CRF completion 
by core lab (CT ASPECTS 
Score, CT Angio 
ASPECTS score, CT 
perfusion score, Angio  
mTICI, Capillary Index 
Score, Post-
 
 
X 
X 
X 
X 
 
 

SELECT 2 Protocol                                                
4 August, 2021
41 
 
2
a. Physical exam at baseline as per standard of care (SOC).  b. Vital Signs (BP and HR) recorded 
at baseline as per SOC. c. Labs (evaluation includes CBC with Platelets, Creatinine, Glucose, INR, 
activated PTT, and Pregnancy test (if applicable): at baseline as per SOC. d. If possible, 30 and 
90-day visits should be completed in person. The telephone is allowed if the only option. e. for 
medical arm: recording blood pressure readings starts from either thrombolytics administration 
(if applicable) or randomization, for EVT arm recording blood pressure readings starts from the 
end of the thrombectomy procedure. f.Head CT/CTA/CTP/MRI: will be read centrally. 
 
 
Assessment and Follow-up Visits 
 
Baseline visit: The inclusion/exclusion page of the case report form must be completed to 
determine if the patient meets the eligibility requirements for the study. If the patient is 
eligible, then the consent form will be obtained by the patient or authorized representative.  
 
24-hour 
The items listed for this visit in Table 2 should be performed 
between 18 and 30 hours from the time of the procedure.  
 
Discharge visit: The items listed for this visit in Table 2 should be performed either on day 5/7 
or the day of hospital discharge (whichever comes first).  
 
30-day visit (+ / - 15 days): The items listed for this visit in Table 2 should be performed on day 
t be performed by an mRS certified evaluator who is blinded 
to treatment allocation. If possible, this visit should be completed in person. Telephone is 
allowed if the only option.  
 
90-day visit (+ / - 15 days and preferably an in-person visit): The items listed for this visit in 
Table 2 should be performed on d
treatment/procedural, 
hemorrhage)f 
AE Reporting 
 
 
 
 
X 
X 
X 
X 
SAE Reporting 
 
 
 
 
X 
X 
X 
X 
Crossover explanations 
 
 
X 
 
 
 
 
 
Protocol Deviation 
 
 
X 
 
X 
X 
X 
X 

SELECT 2 Protocol                                                
4 August, 2021
42 
 
2
mRS certified evaluator who is blinded to treatment allocation. The Neuro-QoL will also be 
completed on 90-day visit by an evaluator who is blinded to treatment allocation. If possible, 
this visit should be completed in person. Telephone is allowed if the only option.  
 
365-day visit (+ / - 60 days):  The mRS score must be performed by an mRS certified evaluator 
who is blinded to treatment allocation. The Neuro-QoL will also be completed on 360-day visit 
by an evaluator who is blinded to treatment allocation. Patients who were enrolled in the study 
at a date before the addition of the 365-day follow up visit, will be consented (remotely or in 
person) to complete the visit. The supplemental informed consent can be obtained verbally or 
in-
participate in the study. 
 
Neurological worsening: If clinical worsening (defined as a 4 point increase on the NIHSS 
score) occurs prior to discharge, a CT scan or MRI should be obtained as soon as 
possible.Neurological worsening is a reportable adverse event. 
 Sources of Materials 
Information on the 
record. Study coordinators at the site will complete the SELECT 2 case report forms to 
collect basic demographic and medical information about the patients. Data will 
subsequently be entered into the REDCAP electronic data capture system. Imaging data 
will be uploaded on DICOM (all patient identifiers are removed by the software prior to 
log that documents all acute stroke patients treated by thrombectomy in the cath lab as 
well as patients who met the imaging criteria but were not enrolled in the study at their 
center, and the reason for exclusion of patients not enrolled. Serious adverse events (SAEs) 
will be reported within 24 hours of the event in the REDCAP electronic data capture 
system.  

SELECT 2 Protocol                                                
4 August, 2021
43 
 
2
 Site Approval and Monitoring Plan 
Site approval: The University of Texas Health Science Center at Houston is the administration 
center and conducts data monitoring, core image lab reading and statistical analyses. Sites are 
selected for participation based on their experience in conducting clinical trials, their acute 
stroke treatment, and thrombectomy volumes, and only after an extensive discussion and 
vetting process by the principal investigator and documentation of interventionist experience, 
prior clinical trial enrollments, well-established research infrastructure, commitment to 
conducting clinical research, fast treatment times and efficient workflow. Sites will have a 
requirement of at least 100 thrombectomy procedures/year. Sites will commit to 
randomization and treatment criteria based on agreed upon contract. Selected sites will have 
access to emergent CT/CT perfusion and/or MR imaging 24/7. Prior to activating a site, we will 
verify that RAPID is functional at the site. Sites will be activated for enrollment after test cases 
processed with RAPID have ensured good quality maps. 
 
Monitoring for imaging quality: The Imaging Core Lab will monitor image quality throughout 
the study. If significant inadequacies or protocol errors are noted at a site, enrollment will be 
halted. Enrollment will resume after all imaging problems have been resolved and repeat 
dummy runs have been obtained that demonstrate adequate image quality. 
 
Monitoring for bias: 
plan will protect the study from enrollment, randomization, and treatment bias. Sites will 
report their volume of endovascular stroke procedures (within 24 hrs) each month on a 
screening log. If a SELECT 2 eligible patient is treated with endovascular thrombectomy outside 
the SELECT 2 study, an explanation will be required detailing why the patient was not enrolled. 
The second component of the plan involves tracking of patients who are consented but not 
randomized. These patients will require an explanation of why the patient was not randomized 
as well as documentation whether endovascular thrombectomy was performed outside of the 
study. A third component involves monitoring of crossover after randomization. The Executive 

SELECT 2 Protocol                                                
4 August, 2021
44 
 
2
Committee will review the data described above for each site every 6 months. If evidence of 
enrollment bias is suspected, it will be investigated. If confirmed, the site will be placed on 
probation. If additional incidents of suspected bias are confirmed, the site will be withdrawn. 
Routine monitoring of the clinical sites for the source to database verification will be performed 
by the UT Houston site. 
 
 Sample Size Calculation and Statistical Analysis Plan 
 
 Sample Size justification, Adaptive Enrichment Design, and Statistical Analysis 
Plan 
 
The study will implement a novel adaptive enrichment design that will not only allow the trial to 
stop early for efficacy but also allow to select and evaluate the treatment effect in a most 
promising subpopulation if futility rule is triggered at the interim (or final) analyses in the 
overall population. This adaptive design has been developed, well-studied, and implemented 
for the DEFUSE 3 studies24. The details and theory of this adaptive enrichment design are 
summarized in Lai et al (2014)25 and Lai et al (2018)26. This adaptive enrichment design is an 
extension of standard group sequential design with an enrichment feature25. It will test for 
efficacy or futility with two interim analyses and a final analysis. This adaptive design was 
chosen because the preliminary data from the SELECT study suggest a potential heterogeneity 
in thrombectomy treatment effect based on the different imaging profiles. By adopting this 
adaptive design, we expect to reallocate future accrual and study treatment effects only in a 
most promising subpopulation when there is evidence to show that EVT is futile in the overall 
population at interim (or final) analyses. By limiting the subsequent enrollment only in the most 
promising subpopulation, a larger number of patients will eventually be enrolled in this 
subgroup for efficacy testing compared to traditional designs.  
 
This design uses the Generalized Likelihood Ratio (GLR) statistic (Kullback-Leibler criterion) as 
criteria to identify the subgroup, which has the best chance of showing a benefit from EVT. 

SELECT 2 Protocol                                                
4 August, 2021
45 
 
2
Through these criteria, it can achieve optimal balance simultaneously between the estimated 
size of the treatment effect and the sample size of the subgroup. By considering the CTP core 
volume and treatment time window, the patients are split into six disjoint groups, that is Group 
1 (ASPECTS 3-5 and CTP/MRP core volume <50cc) at early time window 0-12 hours (denoted as 
G1A), Group 1 at late time window 12-24 hours (denoted as G1B), Group 2 (ASPECTS 6-10 and 
CTP/MRP core volume 50cc) at early time window (denoted as G2A), Group 2 at late time 
window (denoted as G2B), Group 3 (ASPECTS 3-5 and CTP/MRP core volume 50cc) at early 
time window (denoted as G3A), and Group 3 at late time window (denoted as G3B). 
Considering a prior assumption that the EVT effect is largest in the patients with good imaging 
profile and treated within the shortest time window, we assume that the highest effect of EVT 
will be observed in G1A. Then the effects get decreased gradually in G1B, G2A, G2B, G3A, and 
the lowest effect will be observed in G3B. According to this adaptive design, when a most 
promising subgroup needs to be selected at the time of interim (or final) analysis, we will 
compare the GLR statistic among five cumulative groups, that is, G1A, G1A+G1B (i.e., Group 1), 
G1A+G1B+G2A, G1A+G1B+G2A+G2B (i.e., Group 1+Group 2), and G1A+G1B+G2A+G2B+G3A.  
Primary analysis:  The primary endpoint is the distribution of scores on the modified Rankin 
Scale (mRS) at day 90. The null hypothesis will be tested at the interim and final analysis using a 
normal approximation of the Wilcoxon-Mann-Whitney test (the GLR test). The principle of the 
intention to treat will be applied for the primary analysis. An additional analysis of the primary 
endpoint will be the same rank-based analysis comparing the 90-day mRs distribution between 
treatment groups while stratifying for prognostically important covariates. We will use the 
Generalized Cochran-Mantel-Haenszel test (CMH) to evaluate whether there is a uniform shift 
on the mRS distribution from one group to the other after stratification. The CMH test will be 
stratified by these variables used in the covariate adaptive randomization. For age, NIHSS, 
treatment time window, and CTP core volume, we will consider them as continuous variables in 
this adjusted analysis. 
 

SELECT 2 Protocol                                                
4 August, 2021
46 
 
2
Power and sample size considerations Based on prior reported data, the following distributions 
were projected on the mRS at 90 days in EVT and MM groups for SELECT 2 in the overall 
population. 
mRS at day 90 
0 
1 
2 
3 
4 
5 
6 
Total 
Endovascular group 
4% 
8% 
12% 
16% 
19% 
13% 
28% 
100% 
Medical group 
1% 
4% 
9% 
14% 
19% 
10% 
43% 
100% 
 
This distribution corresponds to a standardized effect of 0.34 for the primary analysis.  Based on 
these data, the fixed sample size for a non-adaptive design requires a total of 376 patients 
(188/arm) to have 90% power at an alpha of 5% (Wilcoxon-Mann-Whitney test); We add 
additional 184 patients for the adaptive design to reach a maximum sample size of 560. We will 
conduct two interim analyses when we reach the number of patients at 200 and 380. Through 
extensive simulation studies, we have shown that with 560 patients in total for the adaptive 
design, we will have around 91% power to test for a standardized effect size of 0.34 in the 
overall population (assuming homogeneous EVT effect across six disjoint groups) by controlling 
an overall (one-sided) Type I error rate at 2.5%. 
 
Efficacy and futility bound At each analysis (two interim analyses and the final analysis), an 
efficacy bound will be set to decide if the study should be stopped for efficacy while controlling 
the overall (one-sided) Type I error rate at 2.5%.  At each interim analysis, a futility bound will 
be set to decide if the study should continue recruitment in the overall group, shift accrual and 
testing to a subgroup, or stop the trial entirely. When the futility bound is crossed and the 
optimal subgroup is selected, the maximum analyzed sample size will not be fixed but a random 
variable (smaller than the fixed maximum sample size 560). Due to the reduction in the 
maximum number of patients available for analysis at the end of the study, our design allows 

SELECT 2 Protocol                                                
4 August, 2021
47 
 
2
an easier futility stop after subgroup selection.  Further details regarding efficacy and futility 
bounds at interim and final analyses is provided in Appendix B. 
 
First interim analysis (n=200 randomized and completed 90-day follow-up): The null 
hypothesis is tested in the entire patient cohort: 
1. If neither efficacy nor futility bound is crossed, the trial continues enrollment to the 2nd 
interim analysis. 
2. If the efficacy bound is crossed, the trial stops and efficacy is declared in the overall cohort. 
3. If the futility bound is crossed, the optimal subgroup is selected based on the GLR statistic 
and the null hypothesis is tested in this selected subgroup:  
3.1. If neither bound is crossed, the trial will continue with enrollment limited to the 
selected subgroup 
3.2. If the efficacy bound is crossed, the trial stops and efficacy is declared in the selected 
subgroup 
3.3. If the futility bound is crossed, the trial stops for futility. 
Note: the futility bound is relaxed as described above, based on the expected maximum 
number of patients in the trial at completion (i.e. 560 minus the number of patients already 
enrolled in the groups that will no longer be open for enrollment). 
 
Second interim analysis (n=380 randomized and completed 90 day follow-up): After the first 
interim analysis, the trial proceeds to this stage under two scenarios: (1) continuing enrollment 
in the overall population (i.e., option 1 above) and (2) limiting enrollment to a selected 
subgroup (i.e., option 3.1 above). When scenario (1) happens, the testing at the 2nd interim 
analysis is identical to the first interim analysis. When scenario (2) happens, the null hypothesis 
is tested in that selected subgroup: 
1. If neither bound is crossed, the trial continues to the final analysis with an enrollment of 
560-380=180 additional patients limited to the selected subgroup 

SELECT 2 Protocol                                                
4 August, 2021
48 
 
2
2. If the efficacy bound is crossed, the trial stops and efficacy is declared in the selected 
subgroup 
3. If the futility bound is crossed, the trial stops for futility. 
Final analysis (n=560 randomized and completed 90-day follow-up): After the 2nd interim 
analysis, the trial proceeds to the final stage under two scenarios: (1) continuing enrollment in 
the overall population and (2) limiting enrollment to a selected subgroup.  
When scenario (1) happens, the null is tested in the overall population: 
1. If the efficacy bound is crossed, EVT is declared efficacious in the overall population. 
2. If the efficacy bound is not crossed, the optimal subgroup is selected and the null is tested 
in that group: 
2.1. If the efficacy bound is crossed, EVT is declared efficacious in that subgroup 
2.2. If the efficacy bound is not crossed, EVT will be declared of no benefit. 
When scenario (2) happens, that is, limiting enrollment to a subgroup (either selected at the 1st 
or 2nd interim analyses), the null hypothesis is tested in that selected subgroup only. Efficacy or 
lack thereof will be declared as per options 2.1 and 2.2 above. 
Operating characteristics of the adaptive design: We have conducted simulations (5000 
simulated trials) to evaluate the performance of the adaptive design (max n=560) and compare 
it to a traditional fixed sample-size design (fixed n=560) under various scenarios (see Table 3, 
below).  For the simulations the effect size is expressed as a standardized effect with normal 
approximation, where a standardized effect of 0.32 or 0.30 corresponds to a conservative 
projected effect of EVT (anticipated effect 0.34; see section of Power and sample size 
considerations). We assume that we will observe the number of patients in G1A, G1B, G2A, 
G2B, G3A, G3B with 14%, 6%, 14%, 6%, 42%, and 18%, respectively. 
 
 

SELECT 2 Protocol                                                
4 August, 2021
49 
 
2
Scenario
Standardized effect in groups   
G1A, G1B, G2A, G2B, G3A, G3B 
Average 
standar
d. effect
Adaptive Design 
Fixed Design 
Average 
No. 
randomized 
Power 
Number 
randomized 
Power 
#0 
0 
0 
0 
0 
0 
0 
0 
426 
2.0% 
560 
2.5% 
#1 
0.32 0.32 0.32 0.32 0.32 0.32 
0.32 
376 
86.0% 
560 
95.8% 
#2 
0.3 0.3 0.3 0.3 0.3 0.3 
0.3 
393 
81.1% 
560 
93.3% 
#3 
0.4 0.4 0.4 0.4   0 
 0 
0.16 
500 
74.1% 
560 
45.7% 
 
 
 
 
 
 
#4 
0.4  0.4 0.4 0.4 -0.1 -0.1 
0.1 
502 
78.5% 
560 
21.2% 
#5 
0.4  0.4 0.3 0.3 0 
-0.1 
0.122 
513 
67.1% 
560 
29.2% 
#6 
0.5 0.5 0 
0 
0 
0 
0.1 
503 
70.6% 
560 
21.2% 
#7 
0.5 0 
0 
0 
0 
0 
0.07 
503 
60.5% 
560 
12.8% 
Table 3. Under the null (Scenario #0), the adaptive design controls the total Type 1 error below 2.5%, stops 
early for futility 59.1% of the time, and the average number of randomizations is 426. If the effect is 
uniform across cells at 0.32 (scenario #1), the fixed-sample design is optimal, but the adaptive design 
results in only a small loss of power (from 95.8% to 86.0%), but reduced the expected sample size (from 
560 to 376). We observed similar findings when the effect is uniform across cells at 0.3 (scenario #2). The 
adaptive design performs much better (higher power and smaller expected sample size) than the fixed-
sample design when the effect size distribution across the subgroups is in accord with the biological 
assumptions (scenarios #3, #4 and #5). If the effect is concentrated only in Group 1 (scenario #6) or Group 
1A (scenario #7), the adaptive design maintains power (70.6% in scenario #6 and 60.5% in scenario #7) 
while the conventional design collapses (21.2% power in scenario #6 and 12.8% in scenario #7). 

SELECT 2 Protocol                                                
4 August, 2021
50 
 
2
Secondary analyses: Our secondary endpoint is the proportion of patients with mRS 0-2 at day 
90 (indicating functional independence). The difference in the proportions of patients with mRS 
0-2 between treatment arms will be assessed using logistic regression. We will adjust for the 
variables we used in adaptive randomization program in the logistic regression model. Other 
secondary endpoints include (1) the safety outcomes measured by the incidence of sICH, 
neurological worsening, mortality, groin hematomas, infections or vascular injury, (2) infarct 
volume, lesion growth, successful reperfusion, and recanalization rate, (3) length of hospital 
stay, and (4) discharge disposition. The exploratory analyses on secondary outcomes will 
include descriptive statistics (mean [± standard deviation, SD] or median and interquartile range 
for continuous variables and frequency [percentage] for discrete variables) and appropriate test 
for secondary outcome variables between two groups. For binary outcomes (e.g., sICH, 
neurological worsening, mortality, groin hematomas, infections or vascular injury, successful 
reperfusion, recanalization), Chi-
compare the incidence between two treatment groups for large core patients. We will also 
apply the logistic regression model on these outcomes after adjusting for the variables we used 
in adaptive randomization program. The adjusted odds ratio (OR), as well as 95% confidence 
interval will be reported. For the length of stay, mean ± SD and median (Interquartile range) will 
be calculated for each group. For continuous variables (e.g., the length of stay and infarct 
volume), two sample t-test or Wilcoxon rank sum test as appropriate will be applied to 
compare them between two groups. For discharge disposition, frequency and percentage of 
each disposition will be reported and Chi-
will be applied to compare its distribution between two groups.  
 
Subgroup analyses: Subgroup analyses of the effect of thrombectomy on the primary and 
secondary endpoints will be performed.  Subgroups will be defined based on the stratification 
variables, key demographic factors (such as race and ethnicity), thrombolysis vs. no 
thrombolysis, CTP vs. MRI selection, and witnessed vs. unwitnessed symptom onset, wake-up 
vs non-wake-up stroke, and TICI 0-2a vs. TICI 2b/3 results in the cath lab. An additional 

SELECT 2 Protocol                                                
4 August, 2021
51 
 
2
subgroup analysis will be performed in patients who present with extracranial ICA occlusion. 
Also, an additional subgroup analysis will be performed in patients based on thrombolytic 
therapy received. 
 
 Statistical plan for the second aim 
 
The second aim is to compare outcomes in patients with discordant imaging profiles. Good 
outcome rates (90-day mRS 0-2) will be compared between EVT patients with favorable 
CTP/unfavorable CT and EVT patients with unfavorable CT/favorable CTP. Logistic 
regression model will be applied and odds ratio as well as 95% CI will be calculated. If there 
is a significant difference in the outcome, we will evaluate whether any patient 
characteristics could be potential confounders and can explain these differences. 
 
We will also assess the heterogeneity of the treatment effect of thrombectomy comparing 
to medical management between patients with favorable CT/unfavorable CTP and patients 
with unfavorable CT/favorable CTP. We will assess the heterogeneity by evaluating the 
interaction effect in the logistic regression model between treatment groups (EVT vs MM) 
and imaging profile (favorable CT/unfavorable CTP vs unfavorable CT/favorable CTP). If the 
interaction term is statistically significant, we will examine patient characteristics and other 
baseline clinical characteristics for possible correlations or confounding factors. 
 
 Poolability analysis across centers 
 
The data from all investigative sites will be pooled based on the assumption of comparable 
clinical aspects such as the common protocol used, adequate monitoring on protocol 
compliance, and the centralized data gathering and validation systems across all study 
sites.  
 

SELECT 2 Protocol                                                
4 August, 2021
52 
 
2
We will assess the poolability across the sites by evaluating the interaction effect between 
treatment groups and sites. If the interaction term is statistically significant, we will 
examine patient characteristics and other baseline clinical characteristics for possible 
correlations or confounding factors. Sites with fewer than five subjects will be combined 
based on geographic region. 
 Feasibility of enrollment 
The study is planning to involve 30 high volume centers with volumes of 150-200 
thrombectomies/site/year. Based on SELECT data, roughly 20% of the patients have 
unfavorable imaging profiles on either CT or CTP, with ~30 patients/site/year eligible to 
participate in the study. Assuming 50% of the patients consenting to participate in the 
study and at 30 sites coming onboard in a gradual fashion, the study will complete the 
enrollment target (560 patients) in nearly 2 years.  
 
(LTFU) 
All effort is put forth to ensure near complete follow-up, in particular with the assessment of 
the primary outcome (mRS at 90 days), death (mRS=6), and stroke recurrence.  If the primary 
outcome (mRS at 90 days) cannot be assessed in the clinic, it will instead be obtained by phone 
using a structured interview.  
within the window of 60 to 120 days from randomization, we will use multiple imputation 
method  to impute 90-day mRS. Specifically, using the data from patients with available 90-day 
mRS, we will build ordinal logistic regression based on patient baseline features and prior mRS 
scores to impute 90-day mRS.  
 
 

SELECT 2 Protocol                                                
4 August, 2021
53 
 
2
 SELECT 2 Timetable 
 Risk Analysis  
Description and analysis of all increased risks to the research subjects: 
 
Potential complications of MRI scan include localized twitching sensation due to the magnetic 
field changes during the scan, anxiety due to claustrophobia and allergic reaction to the 
contrast agent. The allergic reaction may include headache, nausea, rash, hives, nasal 
congestion, sneezing, itching or swelling. If a severe reaction occurs, swelling of the throat, 
chest tightness, or a marked drop in blood pressure may occur. In addition, pain, bleeding, 
bruising, coldness or inflammation at the injection site may occur. Precautions will be taken for 
early detection and rapid treatment if such reactions occur.  
 
Potential complications of CT scan include radiation exposure and allergic reaction to CT 
contrast agents. The iodinated contrast administration may also result in transient and rarely 
permanent renal failure due to nephrotoxicity. 
Year 1:
-Site initiations and 
IRB approvals
-Begin enrollment
Year 2: 
-Continue 
enrollment
Year 3:
-Complete enrollment
-Data analysis for the 
primary endpoint
-Publication of results
Year 4: 
-Complete data of one-year 
follow up assessment
-Complete data analysis
-Publication of results of one-
year follow up assessment

SELECT 2 Protocol                                                
4 August, 2021
54 
 
2
Radiation doses: 
Combined scanning with comprehensive stroke imaging, which includes a non-contrast head 
CT scan, perfusion imaging, and CT angiography of the cervicocranial vessels starting at the 
National Council on Radiation Protection and Measurement, the average annual radiation dose 
per person in the U.S. is 620 millirem (6.2 milliSieverts). 
 
Reactions to contrast agents: 
Mild 
Nausea, Vomiting, Headache, Cough, Nasal stuffiness, altered taste, Flushing, Itching, Rash, 
Hives, Sweats, Swelling of eyes or face 
 
Moderate 
Mild hypotension, Tachycardia or Bradycardia, Bronchospasm, Wheezing, Dyspnea, Laryngeal 
edema, Generalized or diffuse erythema 
 
Severe 
Cardiopulmonary arrest, clinically manifested arrhythmias, profound hypotension, Convulsions, 
Unresponsiveness, Respiratory failure, Laryngeal edema. The rate of major reactions (e.g., 
anaphylaxis, death) is very low, estimated at one in 170,000 administrations. 
 
Potential complications of endovascular thrombectomy include stroke; new clot in an artery; 
total blockage of an artery; infection and pain in the region of insertion site; lack of blood flow 
to the brain; rupture or puncture of an artery; significant tearing of the vessel wall; bleeding 
requiring blood transfusion; allergic reaction to contrast dye; abnormal low blood pressure 
requiring treatment; temporary closing of the artery (vessel spasm); formation of or 
dislodgments of clots which block the arteries (embolism). In rare circumstances, the procedure 
could result in death. At the puncture site in the groin, a blood clot or other blood vessel injury 

SELECT 2 Protocol                                                
4 August, 2021
55 
 
2
may occur and require blood transfusion or surgical repair. Infection may occur at the puncture 
site; this could cause pain and require additional medications. There is some chance of an 
allergic reaction or renal injury due 
procedure. Minor allergic reactions may include a rash or hives. There is also the possibility of a 
serious allergic reaction that could include shortness of breath and swelling, drop in blood 
pressure, and even death. Patients will be closely monitored for these reactions and receive 
prompt treatment to reverse any allergic reactions. 
  Methods to mitigate risks to subjects in the trial 
Methods to mitigate risks to subjects in the trial include the exclusion of subjects with bleeding 
disorders and selection of subjects via neuroimaging to minimize the risk of symptomatic 
intracranial hemorrhage. Computed Tomography (CT) scans will be performed for neurological 
identify new strokes, hemorrhage, or edema. Hospitals will follow their local standard of care 
safety procedures in order to reduce the risk of kidney dysfunction caused by contrast agents. 
Only investigators who are trained and experienced with the use of the devices allowed within 
the trial are eligible to participate. The adaptive design will eliminate subgroups with an 
unfavorable therapeutic response. Patients will be carefully screened for CT, MRI, and 
endovascular treatment contraindications according to the inclusion/exclusion criteria and 
excluded from enrollment if any are present. Radiation exposure during all tests will be 
minimi
endovascular procedure. All CT sequences, including the CTP sequence, meet all FDA guidelines 
for radiation exposure.  
 
To address the concerns of safety in early window for patients with favorable CT / unfavorable 
CTP profile in early window treated with medical management, consecutive monitoring of 
safety outcomes will be carried out for these patients. If the rates of safety outcomes e.g. 
mortality increases by >20% in patients treated by medical management only compared to 

SELECT 2 Protocol                                                
4 August, 2021
56 
 
2
thrombectomy, enrollment within the group will be halted pending data safety monitoring 
board recommendations. 
 
Although no upper limit is specified for infarct core volume measurements on CT or MR 
perfusion imaging, the infarct size is still expected to be limited, to an extent, given that the 
-contrast CT i.e. ASPECTS 2  
and patients with Signs of established infarct and large area of cerebral edema on non-
contrast CT
 
 
To reduce the risk of hemorrhagic transformation in cases with extracranial ICA occlusion, 
immediate stenting of the extracranial lesion will be strongly discouraged and stenting beyond 
72 hours of procedure will be strongly encouraged. Use of dual antiplatelet therapy and heparin 
will also be discouraged. 
   Stopping rules or safety triggers for the study 
All participating centers are carefully selected to include only centers with high-volume and 
experienced interventionalists. The study PI reserves the right to terminate sites that 
significantly deviate from standard-of-care. Further, sites that violate the study inclusion or fail 
to produce timely data will be subject to possible termination.   
 
The SELECT 2 has established the following two-step stopping rules for safety based on sICH 
and mortality rates using Bayesian method (Thall, Simon, and Estey, 1995)28.  
Since it is plausible that the safety concerns will increase with increment in ischemic core 
volume, consecutive monitoring of symptomatic ICH and mortality will be carried out in 
endovascular patients with CTP/MRP core volume of >100 cc and endovascular patients with 
 
 
 

SELECT 2 Protocol                                                
4 August, 2021
57 
 
2
For sICH: 
1) Step 1 for sICH: check whether the posterior probability that the rate of symptomatic 
ICH (NIHSS worsening of 4 or more points associated with sICH per SITS-MOST definition 
assessed within 24 hours after randomization) in one of the endovascular group is >35% 
exceeds the cut-off 0.95. That is, check whether Pr{ 
 >  0.35 | data} > 0.95, where the 
sICH rate in this endovascular group is denoted as 
.  
 
In the event that Step 1 for sICH in one of the endovascular group is triggered, step 2 for sICH 
for that group will be executed. Otherwise, continue the trial. 
 
2)  Step 2 for sICH: if Step 1 for sICH in one of the endovascular group is triggered, check 
whether the posterior probability that the sICH rate in this endovascular group is higher 
than the corresponding medical management by 10% exceeds the cut-off 0.95. That is, 
check whether Pr{ 
 > 
 +10% | data} > 0.95, where the sICH rate in the 
corresponding medical management group is denoted as 
.  
In the event that Step 2 for sICH in of the endovascular group is triggered, patient enrollment 
will be placed on hold and a meeting of the DSMB will be conducted to discuss the events and 
make a determination on the continuation of the trial. 
 
, we will conduct the two-step 
stopping rules for sICH after we enroll 50, 100, 150, 200, and 250 in this group (the maximum 
number of patients to be enrolled into the endovascular group is 280 and we expect 80% of 
.). We assign a weakly informative prior distribution 
for both 
 and  
, that is, a beta distribution with two shape parameters at 0.35 and 0.65, 
which centers at 0.35 with an effective sample size of 1.  
 
 

SELECT 2 Protocol                                                
4 August, 2021
58 
 
2
The rule of step 1 for sICH in this group can be pre-determined in the following table. 
Find your number of patients with CTP/MRP core volume 
 in 
the left-side column. The step 1 for sICH will be triggered if the number of sICHs is in the range 
in the right-side column (the range is inclusive): 
 
# of patients with CTP/MRP core volume 
 
# of sICHs 
50 
24-50 
100 
44-100 
150 
63-150 
200 
82-200 
250 
101-250 
 
For endovascular patients with CTP/MRP core volume >100cc, we will conduct the two-step 
stopping rules for sICH after we enroll 20 patients in this group and then conduct monitoring 
after every 10 patients in t
>100cc, that is, among 280 endovascular patients, around 56 endovascular patients are with 
CTP/MRP core volume >100cc.). Similarly, we assign a weakly informative prior distribution for 
both 
 and  
, that is, a beta distribution with two shape parameters at 0.35 and 0.65, which 
centers at 0.35 with an effective sample size of 1.  
The rule of step 1 for sICH in this group can be pre-determined in the following table. 
Find your number of endovascular patients with CTP/MRP core volume >100cc in the left-side 
column (we provide the table up to 100 patients, but if we enroll more than 100 patients in this 
group, we will run the algorithm and identify the # of sICHs which will trigger the rule). The step 
1 for sICH will be triggered if the number of sICHs is in the range in the right-side column (the 
range is inclusive): 
 

SELECT 2 Protocol                                                
4 August, 2021
59 
 
2
# of patients with CTP/MRP core volume 
>100cc in the endovascular group 
# of sICHs 
20 
11-20 
30 
16-30 
40 
20-40 
50 
24-50 
60 
28-60 
70 
32-70 
80 
36-80 
90 
40-90 
100 
44-100 
 
For endovascular patients with Extracranial Occlusions, we will conduct the two-step stopping 
rules for sICH after we enroll 20 patients in this group and then conduct monitoring after every 
10 patients in this group (We expect 10% of patients will have isolated extracranial ICA 
occlusions, that is, among 280 endovascular patients, around 28 endovascular patients are with 
extracranial ICA occlusions). Similarly, we assign a weakly informative prior distribution for both 
 and  
, that is, a beta distribution with two shape parameters at 0.35 and 0.65, which 
centers at 0.35 with an effective sample size of 1.  
The rule of step 1 for sICH in this group can be pre-determined in the following table. 
Find your number of endovascular patients with Extracranial ICA occlusions in the left-side 
column (we provide the table up to 100 patients, but if we enroll more than 100 patients in this 
group, we will run the algorithm and identify the # of sICHs which will trigger the rule). The step 
1 for sICH will be triggered if the number of sICHs is in the range in the right-side column (the 
range is inclusive): 
 
 

SELECT 2 Protocol                                                
4 August, 2021
60 
 
2
 
# of patients with extracranial ICA 
occlusions 
# of sICHs 
20 
11-20 
30 
16-30 
40 
20-40 
50 
24-50 
60 
28-60 
70 
32-70 
80 
36-80 
90 
40-90 
100 
44-100 
 
For mortality, 
1) Step 1 for mortality: check whether the posterior probability that the rate of mortality 
at Day 90 in one of the endovascular group is > 40% exceeds the cut-off 0.95. That is, 
check whether Pr{ 
 >  0.40 | data} > 0.95, where the mortality rate in this 
endovascular group is denoted as 
.  
 
In the event that Step 1 for mortality in one of the endovascular group is triggered, step 2 for 
mortality in this group will be executed. Otherwise, continue the trial. 
 
2)  Step 2 for mortality: if Step 1 for mortality in one of the endovascular group is 
triggered, check whether the posterior probability that the mortality rate in this 
endovascular group is higher than the corresponding medical management by 10% 
exceeds the cut-off 0.95. That is, check whether Pr{ 
 > 
 +10% | data} > 0.95, where 
the mortality rate in the corresponding medical management group is denoted as 
.  
 

SELECT 2 Protocol                                                
4 August, 2021
61 
 
2
In the event that Step 2 for mortality in one of the endovascular group is triggered, patient 
enrollment will be placed on hold and a meeting of the DSMB will be conducted to discuss 
the events and make a determination on the continuation of the trial. 
 
, we will conduct the two-step 
stopping rules for mortality after we enroll 50, 100, 150, 200, and 250 in this group (the 
maximum number of patients to be enrolled into the endovascular group is 280 and we expect 
.). We assign a weakly informative prior 
distribution for both 
 and  
, that is, a beta distribution with two shape parameters at 0.4 
and 0.6, which centers at 0.4 with an effective sample size of 1.  
 
The rule of step 1 for mortality in this group can be pre-determined in the following table. 
Find your number of patients with CTP/MRP core volume 
 in 
the left-side column. The step 1 for mortality will be triggered if the number of deaths is in the 
range in the right-side column (the range is inclusive): 
 
# of patients with CTP/MRP core volume 
 
# of deaths 
50 
26-50 
100 
49-100 
150 
71-150 
200 
92-200 
250 
113-250 
 
For endovascular patients with CTP/MRP core volume >100cc, we will conduct the two-step 
stopping rules for mortality after we enroll 20 patients in this group and then conduct 
volume will >100cc, that is, among 280 endovascular patients, around 56 endovascular patients 

SELECT 2 Protocol                                                
4 August, 2021
62 
 
2
are with CTP/MRP core volume >100cc.). Similarly, we assign a weakly informative prior 
distribution for both 
 and  
, that is, a beta distribution with two shape parameters at 0.4 
and 0.6, which centers at 0.4 with an effective sample size of 1. 
 
The rule of step 1 for mortality in this group can be pre-determined in the following table. 
Find your number of endovascular patients with CTP/MRP core volume >100cc in the left-side 
column (we provide the table up to 100 patients, but if we enroll more than 100 patients in this 
group, we will run the algorithm and identify the # of deaths which will trigger the rule). The 
step 1 for mortality will be triggered if the number of deaths is in the range in the right-side 
column (the range is inclusive): 
 
# of patients with CTP/MRP core volume 
>100cc in the endovascular group 
# of deaths 
20 
12-20 
30 
17-30 
40 
22-40 
50 
26-50 
60 
32-60 
70 
35-70 
80 
40-80 
90 
44-90 
100 
49-100 
 
For endovascular patients with Extracranial ICA occlusions, we will conduct the two-step 
stopping rules for mortality after we enroll 20 patients in this group and then conduct 
monitoring after every 10 patients in this group (We expect 10% of patients to have isolated 
extracranial ICA occlusion, that is, among 280 endovascular patients, around 28 endovascular 
patients are with extracranial ICA occlusions). Similarly, we assign a weakly informative prior 

SELECT 2 Protocol                                                
4 August, 2021
63 
 
2
distribution for both 
 and  
, that is, a beta distribution with two shape parameters at 0.4 
and 0.6, which centers at 0.4 with an effective sample size of 1. 
 
The rule of step 1 for mortality in this group can be pre-determined in the following table. 
Find your number of endovascular patients with Extracranial ICA occlusions in the left-side 
column (we provide the table up to 100 patients, but if we enroll more than 100 patients in this 
group, we will run the algorithm and identify the # of deaths which will trigger the rule). The 
step 1 for mortality will be triggered if the number of deaths is in the range in the right-side 
column (the range is inclusive): 
 
# of patients with Extracranial ICA 
occlusions 
# of deaths 
20 
12-20 
30 
17-30 
40 
22-40 
50 
26-50 
60 
32-60 
70 
35-70 
80 
40-80 
90 
44-90 
100 
49-100 
 
These rules only serve as guides and do not substitute for the independent decision-making of 
the DSMB in the determination of whether the study should be stopped for safety reasons. The 
decision to stop the study will be made by the DSMB after review of all adverse events based 
on its own independent decision making. The investigators and the sponsor will not be 
informed of the interim grouped results. 

SELECT 2 Protocol                                                
4 August, 2021
64 
 
2
 Imaging Core Lab 
All baseline and follow-up CTs, CT-Angiograms (CTAs) and CTP/MRP images will be reviewed by 
a central lab core at UTH. Dr. Clark Sitton, Associate Professor, Diagnostic and Interventional 
Imaging and Dr. Roy Riascos, Professor, Diagnostic and Interventional Imaging at UT McGovern 
Medical School will serve on the imaging core lab. All images will be sent to the central lab core 
in a de-identified manner. All radiology interpretations will occur independently of any 
knowledge of clinical factors. Blinding of imaging core lab at UT Houston will be ensured. We 
have several neuroradiologists at the institute and the neuroradiologist for the core lab will not 
participate in the care of a patient enrolled in the trial. Also, the neuroradiologists, while 
evaluating images will assess the CT images at a different time than the MRIs. They will also not 
be aware of the treatment and other clinical variables. 
 
A) Parenchymal (e.g., non-contrast head CT) Imaging - the ASPECT score will be determined 
(baseline study only). Follow up studies will be determined for stroke location as well as for the 
presence of any hemorrhage and hemorrhage grading.  
B) CT-Angiograms of the head  identify the vessel occlusion location and collateral scoring 
system.  
C) CTP-Advanced analysis through the RAPID software (RAPID, non-commercial research 
version iSchemaView, Inc.) will be utilized to identify potentially salvageable brain tissue. Brain 
tissue at risk for infarction will be distinguished from minimally hypo-perfused tissue if the time 
to maximum (Tmax) delay is more than 6 seconds. Irreversibly injured brain (hypo-perfused 
tissue will be diagnosed if the relative cerebral blood flow is less than 30% of that in normal 
tissue.  
D) Conventional Angiograms  identify and grade reperfusion using the modified TICI scoring 
system.  
 

SELECT 2 Protocol                                                
4 August, 2021
65 
 
2
 National Data Management Center 
Data management and site monitoring will be performed by the University of Texas at Houston 
(UTH). The UTH will create the database and set up the interface on the REDCAP where clinical 
site personnel will enter the data into the electronic CRF. Data quality assurance processes 
include: (1) logic and rule checks built into the database; (2) monitoring by the 
Data Manager at the UTH; (3) central monitoring by the statistical programmer at the 
ring by the Study Coordinators. 
 Data Management Plan  
Individual data elements will be collected locally and then entered into a password-protected 
web-based, secure central database, REDCAP. Biostatistics/Epidemiology/Research Design 
(BERD) Core at The University of Texas Health Science Center  Houston will act as the data 
coordination center. Data quality will be maintained by establishing a written Data 
Management Plan describing all applicable aspects of the data management process including:  
 
Developing a database that meets all verification and validation requirements of FDA rule 21 
CFR 11, including reference to all pertinent FDA-provided guidelines;  
 Developing a Data Clarification Plan which describes  
 Edit check logic for all variables specified,  
 CRF pages referenced by edit check,  
 Types of query responses: manual, site notification and clinical query;  
 Query text;  
 Establishing a data audit strategy and associated procedures.  
 

SELECT 2 Protocol                                                
4 August, 2021
66 
 
2
The database, housed in a Zone 100 secure server at UT-Houston, will be frozen and data will 
be audited prior to database lock by the statistical center. All data will be identified and 
subjected to a 100% audit, with all errors corrected.  
 Compliant Handling Plan 
FDA-approved devices and medications. Any individual patient or family member complaints 
regarding adverse events or morbidity will be handled locally by each inst
center.  
 
In the event dissemination of protected patient health information (PHI) or any other 
confidential information occurs, local investigators are bound to report to their risk 
management department as well as the coordinating site and study sponsor. On a case by case 
basis, the PI reserves the right to terminate any participating centers if mismanagement of such 
data is discovered.  
 Data Safety and Monitoring Board  
SELECT 2 will have an independent Data and Safety Monitoring Board (DSMB) to oversee study 
at 90 days, the incidence of symptomatic intracranial hemorrhage per SITS-MOST definition 
within 24 hours after randomization 
deterioration NIHSS neurological status vs. post deterioration and associated with brain 
hemorrhage), and the incidence of significant neurologic deterioration prior to discharge 
vs. post deterioration and not attributed to sedation). Patients in both arms will also be 
including 
perforation, arterial dissection, access site complication requiring surgical repair or blood 

SELECT 2 Protocol                                                
4 August, 2021
67 
 
2
transfusion, embolization and device failure. SAEs will be reported within 24 hours of 
awareness of the event. 
 
The DSMB will meet in person or by teleconference, on a sem
elapse between DSMB reviews of cumulative safety data after the first participant has been 
enrolled. The DSMB will monitor the study according to the guidelines specified in the study 
protocol and the operating procedures established at the initial meeting unless the DSMB 
determines during the course of the trial that modification of the guidelines is in the best 
interest of the study and its participants. The DSMB charter can be found as an attachment to 
the protocol. 
 Independent Medical Safety Monitor 
In addition to the DSMB, an independent Medical Safety Monitor (MSM) will be appointed for 
the SELECT2 trial. The independent MSM will not be involved in the study and will not have 
conflict of interest. He/she will be responsible for ongoing monitoring of reports of SAEs 
submitted by the clinical centers in real time to ensure good clinical practice and to identify 
safety concerns quickly. The MSM may suggest protocol modifications to prevent the occurance 
of particular AEs, e.g., modifying the protocol to require frequent measurement of laboratory 
values predictive of the event or to improve expeditious identification of the SAEs. In the event 
of unexpected SAEs or an unduly high rate of SAEs, the MSM will promptly contact the DSMB. 
In the event that MSM is unavailable for an extended period of time (i.e., extended vacation, 
sabbatical, illness, etc.), a back-up MSM will be nominated by the study PI and approved by the 
DSMB. 
 
 
 

SELECT 2 Protocol                                                
4 August, 2021
68 
 
2
 Adverse Event Reporting 
Consideration of adverse events will hereafter consist of adverse events, serious adverse 
events, and adverse device effects, including anticipated adverse device effects and 
unanticipated adverse device effects. 
 
 Adverse event (AE) is defined as any untoward/undesirable clinical occurrence in a 
clinical investigation of a subject, which does not necessarily have a causal relationship 
with the treatment under investigation. An adverse event can, therefore, be any 
unfavorable and/or unintended sign, symptom, or disease temporally associated with 
the use of a device product, whether or not considered related to the device product. 
Only abnormal laboratory values that are deemed clinically significant by the 
investigator will be classified as adverse events. 
 Serious adverse event (SAE) is defined as any untoward/undesirable adverse experience 
that results in any of the following outcomes: 1) death; 2) a life-threatening adverse 
experience; 3) inpatient hospitalization or prolongation of existing hospitalization; 4) a 
permanent/persistent or significant disability/incapacity or a congenital anomaly/birth 
require hospitalization may be  considered a serious adverse event when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
This 
ics and/or intracranial stents. 
 Anticipated Adverse Device Effect (AADE) is defined as any adverse effect related to the 
device or procedure, which is identified in the protocol or the instructions for use for 
the device. 
 Unanticipated Adverse Device Effects (UADEs) is defined as any serious adverse effect 
with a device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application, or any other 

SELECT 2 Protocol                                                
4 August, 2021
69 
 
2
unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of subjects. 
  Reporting Procedures for All Adverse Events 
All Adverse Events, whether or not attributed to the study and/or the devices, observed by the 
investigator or reported by the subject, will be recorded from the time of randomization 
through Day 90. All recorded adverse events will be provided to the data safety monitoring 
board (DSMB) at the time of review for decision-making. 
 
The following attributes will be assigned by the reporting investigator: 
1. Description of event 
2. Date of onset 
3. Date of resolution (if applicable) 
4. Seriousness 
5. Relationship to the study device and/or procedure(s) 
6. Severity 
7. Action(s) taken 
8. Outcome(s) 
 
Severity is defined as a measure of the intensity of a reaction, effect or experience. The 
measurement(s) are described as mild, moderate, severe, life-threatening or death. The event 
itself, however, may be of relatively minor medical significance. The severity of Adverse Events 
is assessed according to the following index scale: 
 
 Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
 

SELECT 2 Protocol                                                
4 August, 2021
70 
 
2
 Moderate 
priate instrumental 
Activities of Daily Living. 
 Severe 
hospitalization indicated; disabling; limiting self-care Activities of Daily Living. 
 
consequences 
Urgent intervention indicated 
 Death related to AE 
 
The relationship of an AE to the study device or procedure will be graded as follows: 
 Unrelated 
 Unlikely 
 Reasonable possibility 
 Definitely 
 
Serious Adverse Events All Serious Adverse Events and Unanticipated Adverse Device Effects 
including deaths will be reported to the MSM, the Coordinating Center (McGovern Medical 
School) and the FDA, as required. 
 
 
 

SELECT 2 Protocol                                                
4 August, 2021
71 
 
2
 Study Design 
 
 

SELECT 2 Protocol                                                
4 August, 2021
72 
 
2
References 
1. Berkhemer O, Fransen P, Beumer D et al. A Randomized Trial of Intraarterial Treatment for 
Acute Ischemic Stroke. New England Journal of Medicine. 2015;372(1):11-20. 
doi:10.1056/nejmoa1411587 
2. Jovin T, Chamorro A, Cobo E et al. Thrombectomy within 8 Hours after Symptom Onset in 
Ischemic Stroke. New England Journal of Medicine. 2015;372(24):2296-2306. 
doi:10.1056/nejmoa1503780 
3. Goyal M, Demchuk A, Menon B et al. Randomized Assessment of Rapid Endovascular 
Treatment of Ischemic Stroke. New England Journal of Medicine. 2015;372(11):1019-1030. 
doi:10.1056/nejmoa1414905 
4. Saver J, Goyal M, Bonafe A et al. Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-
PA Alone in Stroke. New England Journal of Medicine. 2015;372(24):2285-2295. 
doi:10.1056/nejmoa1415061 
5. Campbell B, Mitchell P, Kleinig T et al. Endovascular Therapy for Ischemic Stroke with 
Perfusion-Imaging Selection. New England Journal of Medicine. 2015;372(11):1009-1018. 
doi:10.1056/nejmoa1414792 
6. Nogueira R, Jadhav A, Haussen D et al. Thrombectomy 6 to 24 Hours after Stroke with a 
Mismatch between Deficit and Infarct. New England Journal of Medicine. 2018;378(1):11-
21. doi:10.1056/nejmoa1706442 
7. Albers G, Marks M, Kemp S et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by 
Perfusion Imaging. New England Journal of Medicine. 2018;378(8):708-718. 
doi:10.1056/nejmoa1713973 
8. Powers W, Rabinstein A, Ackerson T et al. 2018 Guidelines for the Early Management of 
Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the 

SELECT 2 Protocol                                                
4 August, 2021
73 
 
2
American Heart Association/American Stroke Association. Stroke. 2018;49(3). 
doi:10.1161/str.0000000000000158 
9. Sarraj A, Hassan A, Gupta R et al. Optimizing Patient Selection For Endovascular Treatment In 
Acute Ischemic Stroke (Select): A Prospective Non-Randomized Multicenter Cohort Study 
Of Imaging Selection - European Stroke Organisation Conference: Late Breaking 
Abstracts. European Stroke Journal. 2018;3(1_suppl):587-620. 
doi:10.1177/2396987318773967 
10. Borst J, Berkhemer O, Roos Y et al. Value of Computed Tomographic Perfusion Based 
Patient Selection for Intra-Arterial Acute Ischemic Stroke Treatment. Stroke. 
2015;46(12):3375-3382. doi:10.1161/strokeaha.115.010564 
11. Yoo A, Berkhemer O, Fransen P et al. Effect of baseline Alberta Stroke Program Early CT 
Score on safety and efficacy of intra-arterial treatment: a subgroup analysis of a 
randomised phase 3 trial (MR CLEAN). The Lancet Neurology. 2016;15(7):685-694. 
doi:10.1016/s1474-4422(16)00124-1 
12. Logan C, Maingard J, Phan K et al. Borderline Alberta Stroke Programme Early CT Score 
Patients with Acute Ischemic Stroke Due to Large Vessel Occlusion May Find Benefit with 
Endovascular Thrombectomy. World Neurosurgery. 2018;110:e653-e658. 
doi:10.1016/j.wneu.2017.11.068 
13. Rebello L, Bouslama M, Haussen D et al. Endovascular Treatment for Patients With Acute 
Stroke Who Have a Large Ischemic Core and Large Mismatch Imaging Profile. JAMA 
Neurology. 2017;74(1):34. doi:10.1001/jamaneurol.2016.3954 
14. Campbell B, Majoie C, Albers G et al. Penumbral imaging and functional outcome in patients 
with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus 
medical therapy: a meta-analysis of individual patient-level data. The Lancet Neurology. 
2019;18(1):46-55. doi:10.1016/s1474-4422(18)30314-4 

SELECT 2 Protocol                                                
4 August, 2021
74 
 
2
15. Lansberg M, Straka M, Kemp S et al. MRI profile and response to endovascular reperfusion 
after stroke (DEFUSE 2): a prospective cohort study. The Lancet Neurology. 
2012;11(10):860-867. doi:10.1016/s1474-4422(12)70203-x 
16. Gupta A, Schaefer P, Chaudhry Z et al. Interobserver Reliability of Baseline Noncontrast CT 
Alberta Stroke Program Early CT Score for Intra-Arterial Stroke Treatment 
Selection. American Journal of Neuroradiology. 2012;33(6):1046-1049. 
doi:10.3174/ajnr.a2942 
17. Freidrich B, Monch s, Berndt M et al. Software-Based, Automated Calculation of the ASPECT 
Score In Patients Suffering From Emergent Vessel Occlusions in the Anterior Circulation  
Clinical Feasibility And Reliability: European Stroke Organisation Conference: Late Breaking 
Abstracts. European Stroke Journal. 2018;3(1_suppl):587-620. 
doi:10.1177/2396987318773967 
18. Wolpert SM, Bruckmann H, Greenlee R et al. American Journal of Neuroradiology Jan 1993, 
14 (1) 3-13. 
19. Pechlaner R, Knoflach M, Matosevic B et al. Recanalization of Extracranial Internal Carotid 
Artery Occlusion after i.v. Thrombolysis for Acute Ischemic Stroke. PLoS ONE. 
2013;8(1):e55318. doi:10.1371/journal.pone.0055318. 
20. Grossberg J, Haussen D, Cardoso F et al. Cervical Carotid Pseudo-Occlusions and False 
Dissections. Stroke. 2017;48(3):774-777. doi:10.1161/strokeaha.116.015427 
21. Mazya M, Egido J, Ford G et al. Predicting the Risk of Symptomatic Intracerebral 
Hemorrhage in Ischemic Stroke Treated With Intravenous Alteplase. Stroke. 
2012;43(6):1524-1531. doi:10.1161/strokeaha.111.644815 
22. Zaidat O, Yoo A, Khatri P et al. Recommendations on Angiographic Revascularization 
Grading Standards for Acute Ischemic Stroke. Stroke. 2013;44(9):2650-2663. 
doi:10.1161/strokeaha.113.001972 

SELECT 2 Protocol                                                
4 August, 2021
75 
 
2
23. Cella D, Lai J, Nowinski C et al. Neuro-QOL: Brief measures of health-related quality of life 
for clinical research in neurology. Neurology. 2012;78(23):1860-1867. 
doi:10.1212/wnl.0b013e318258f744 
24. Albers G, Lansberg M, Kemp S et al. A multicenter randomized controlled trial of 
endovascular therapy following imaging evaluation for ischemic stroke (DEFUSE 
3). International Journal of Stroke. 2017;12(8):896-905. doi:10.1177/1747493017701147 
25. Lai T, Lavori P, Liao O. Adaptive choice of patient subgroup for comparing two 
treatments. Contemporary Clinical Trials. 2014;39(2):191-200. 
doi:10.1016/j.cct.2014.09.001 
26. Lai T, Lavori P, Tsang K. Adaptive enrichment designs for confirmatory trials. Statistics in 
Medicine. 2018;38(4):613-624. doi:10.1002/sim.7946 
27. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors 
in the controlled clinical tria. Biometrics. 1975;31:103 115 
28. Azur MJ, Stuart EA, Frangakis C, et al. Multiple imputation by chained equations: What what 
is it and how  does  it  work?  Int  J  Methods  Psychiatr  Res. 2011;20:40-49 
 
 
 
 
 

SELECT 2 Protocol                                                
4 August, 2021
76 
 
2
Appendix A: Minimization Randomization Algorithm 
Randomization will be done in the emergency room using a web-based dynamic randomization 
system. Covariate adaptive randomization is planned to be developed and implemented to 
balance the distributions of important key baseline variables between the two treatment arms. 
The key variables include age (<60, 60-69, 70-79, 80-85 years old), presentation NIHSS (6-9, 10-
15, 16-20, >20), center, clot location (M1, ICA), treatment time window (0-8, 9-16, 17-24 
hours from onset to randomization time), CTP/MRP core volume (<50cc, 50-100cc, >100cc), 
15 cc) and hemisphere (right, left).  
  
The randomization algorithm we are going to implement is the algorithm developed by Pocock 
and Simon (1975), i.e., minimization method. Through this algorithm, the assignment of a new 
patient to a treatment group is determined so as to minimize the differences between the 
groups in terms of these important key baseline variables. Unlike traditional stratified 
randomization, the minimization method works toward minimizing the total imbalance for all 
factors together instead of considering mutually exclusive subgroups, that is, we will not 
creating these mutually exclusive subgroups during the randomization. Therefore, this 
approach is not restricted by the number of variables and possible combinations of levels of 
balancing factors.  
  
 
 
 

SELECT 2 Protocol                                                
4 August, 2021
77 
 
2
Details of the minimization randomization algorithm and its implementation 
  
Part I: Specification 
This section provides a general framework for a study with the implementation of the 
minimization algorithm proposed by Pocock and Simon (1975). 
 
Assumptions and Notations: 
Assume there are  treatments denoted as 
 with the randomization ratio as 
 
Assume there are  variables to be balanced in the minimization algorithm denoted as 
. 
For the variable 
, suppose there are 
 levels and denote the level of 
 as 
. 
 
Algorithm: 
When a new patient enters to the study, denote the observed level of the variable 
 for this 
patient as , 
 
Step 1: Calculate the number of existing patients who are at the same level of the variable 
 as 
this patient in treatment , denoted as 
, 
. So we can obtain 
,
. 
 
Step 2: Regarding to the variable 
, if we assign this patient to treatment , we should have 
+1 patients at treatment  who have the same level of the variable 
 as this 
patient. We obtain the amount of imbalance which would arise by assigning the patient to 
treatment  as 
. 
Here, 
 is a function to measure the amount of variation for any set of non-negative 
integers . Then we can calculate the overall imbalance for all  variables arising when 
assigning the patient to treatment  by taking a weighted average, that is, 

SELECT 2 Protocol                                                
4 August, 2021
78 
 
2
, 
where 
 denotes the weight for the variable 
.  
 
 
Step 3: Find 
=
 and assign the patient to treatment 
with the highest probability 
among all treatments. 
If we consider variance function for , according to Freedman and White (1978), the total 
imbalance arising when assigning the patient to treatment  can be simplified as follow 
. 
 
Therefore, 
=
  
 
Part II: Implementation in SELECT2 
 
Two treatment groups: 
 and
 with 1:1 ratio.  
 
Level 
Weight 
age 
<60, 60-69, 70-79, 80-85 years 
old 
4 
presentation NIHSS  
6-9, 10-15, 16-20, >20 
4 
clot location  
M1, ICA 
3 
treatment time window from 
onset to randomization time 
0-8, 9-16, 17-24 hours 
3 
CTP/MRP core volume 
<50cc, 50-100cc, >100cc 
2 
Target mismatch profiles 
mismatch 
mismatch ratio < 1.8 or 
mismatch volume < 15 cc or 
both 
 

SELECT 2 Protocol                                                
4 August, 2021
79 
 
2
hemisphere 
right, left 
1 
center 
 
1 
 
For the first patient to be enrolled, we assign this patient to one of the treatments using equal 
randomization. Then before we assign next patients, we will calculate 
 and 
, if 
, 
then assign next patient to 
 with a probability . Here, we set 
; if 
, then assign 
patient to 
 with probability 0.5; if 
, then assign patient to 
 with probability=1-
. 
 
 
References 
Pocock, S.J. and Simon, R., Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics. v31. 103-115. 
 
Pocock, S.J., Allocation of Patients to Treatment in Clinical Trials. Biometrics.  v35. 183-197 
 
Freedman, L.S. and White, S.J., On the use of Pocock and Simon's method for balancing 
treatment numbers over prognostic factors in the controlled clinical trial. Biometrics. v32. 691-
694 
 
 

SELECT 2 Protocol                                                
4 August, 2021
80 
 
2
Appendix B. Efficacy and futility bounds for interim and final analysis 
At the th interim analysis, let 
 be the sum of the ranks of Rankin scores from the 
endovascular group in the patient subgroup 
, 
. In our trial, we defined 
6 groups 
with 
 denotes the entire patient population and 
 denote the subgroups of G1A, 
G1A+G1B, G1A+G1B +G2A, G1A+G1B +G2A +G2B, G1A+G1B +G2A +G2B +G3A, respectively.  
The standardized Wilcoxon statistic for patient subgroup 
is  
 
where, 
 and 
 denote the numbers of patients enrolled into the endovascular group and 
medical management group at the th interim analysis, respectively.  
At the th interim analysis, we will terminate the trial and claims efficacy for the endovascular 
group if the following efficacy bound is crossed, that is, 
 
Otherwise, we will proceed to the subgroup selection if the following futility bound is crossed, 
that is, 
 
where 
 
When the above criteria is satisfied, a subgroup   with the largest value of 
 for 
 is 
chosen. The future enrollment of the trial will include patients of this subgroup only, while the 
maximum total sample size is still N=560.  
Similar to testing the efficacy and futility in the entire population, at stage , we will terminate 
the trial and claim efficacy for the endovascular group in this selected subgroup if the following 
efficacy bound is crossed 
 
We may also terminate for futility if  
 

SELECT 2 Protocol                                                
4 August, 2021
81 
 
2
If neither the efficacy nor futility bound for the entire population ever occurs, the trial proceeds 
to the final stage and we terminate the trial and claim efficacy for the endovascular group if 
 
Under our design setting (maximum sample size N=560 and conducting interim analysis at 
N=200 and N=380 with type I error at 0.025 and power at 0.9), we obtain 
 for our efficacy and futility boundaries. We assume 
to be the projected 
treatment effect given the maximum sample size for testing the hypothesis: 
, 
 using the fixed-sample-size test and is calculated as 
 . Here,  denotes the Rankin score in the medical management group and  denotes 
the Rankin score in the endovascular group. The rationale of this set-up is detailed in section 
3.1 of Lai et al (2014). 
 
Reference 
Lai T, Lavori P, Liao O. Adaptive choice of patient subgroup for comparing two 
treatments. Contemporary Clinical Trials. 2014;39(2):191-200. doi:10.1016/j.cct.2014.09.001 
Lai T, Lavori P, Tsang K. Adaptive enrichment designs for confirmatory trials. Statistics in 
Medicine. 2018;38(4):613-624. doi:10.1002/sim.7946 
 
 

SELECT 2 Protocol                                                
4 August, 2021
82 
 
2
Appendix C. List of Approved Devices to be used in the SELECT2 Protocol: 
Stent-Retriever Devices: 
1. K173352 - Trevo ProVue Retriever and Trevo XP ProVue Retriever 
2. K162539 - Solitaire 2 Revascularization Device 
3. K173452 - EmboTrap II Revascularization Device 
4. K203219 - Trevo XP ProVue Retriever, Trevo NXT ProVue Retriever 
5. K193576 - Solitaire Platinum and Solitaire X Revascularization Devices 
6. K193063 - Embotrap III Revascularization Device 
7. K203592 - Tigertriever and Tigertriever 17 Revascularization Device 
 
 
Aspiration Devices: 
1. K173761 - Penumbra System (Reperfusion Catheter JET 7) 
2. K173200 - SOFIA Plus Aspiration Catheter 
3. K183464 - AXS Universal Aspiration System 
4. K191768 - AXS Vecta Aspiration System 
5. K190338 - Zenith Flex Aspiration System 
6. K193380 - Cerenovus Large Bore Catheter; Cerenovus Aspiration Tubing Set 
7. K201689 - Riptide Aspiration System 
8. K202182 - ZOOM Reperfusion Catheters; ZOOM Aspiration Tubing 
9. K211476 - ZOOM 71 Reperfusion Catheter; ZOOM Aspiration Tubing