POSITIVE: PerfusiOn Imaging Selection of Ischemic STroke PatIents for EndoVascular ThErapy
Phase: NA
Conditions: Ischemic Stroke
Sponsor: Medical University of South Carolina

POSITIVE: PerfusiOn imaging Selection of Ischemic STroke 
PatIents for EndoVascular ThErapy 
NCT01852201 
Protocol Version 9.0 
10-13-2015
IRB Approval Date: 10/13/2015 

 
 
 
 
POSITIVE: PerfusiOn imaging Selection of Ischemic  
STroke PatIents for EndoVascular ThErapy 
 
 
 
Dr. Aquilla S. Turk, III 
Professor 
Medical University of South Carolina 
 
Dr. David Fiorella 
Stony Brook Medical Center 
 
Dr. J Mocco 
Vanderbilt University 
 
Dr. Adnan Siddiqui 
SUNY Buffalo, NY 
 
 
 
 
Version 9.0 
10-13-2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
2 
 
 
Study Title: POSITIVE: PerfusiOn imaging Selection of Ischemic STroke PatIents for 
EndoVascular ThErapy 
 
 
 
Version Number: 
9 
 
Version Date: 
10-13-2015 
 
Study Center: 
______________________________ 
 
 
 
 
 
 
I, the undersigned, have read and understand the protocol specified above and agree on 
its content.  I agree to perform and conduct the study as described in the protocol and in 
accordance with the relevant parts of the appropriate regulatory requirements and the 
pertinent individual country laws/regulations. 
 
 
 
 
Investigator 
 
______________________________________________ 
Print name  
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
3 
 
 
Primary Contacts 
 
Sponsors 
 
Clinical Study Management 
Dr. Aquilla Turk 
Medical University of South Carolina 
Charleston, SC 29485 
(843) 792-3164 
Monitoring 
Vanderbilt University Medical Center 
Department of Neurosurgery 
Nashville, TN 37232 
(615) 343-6485 
Data Management 
Statistical and Data Management Center 
Vanderbilt University Medical Center 
Nashville, TN 37232-8618 
Core Laboratory 
Dr. Max Wintermark 
Stanford University, Department 
of Radiology, Neuroradiology Division 
300 Pasteur Drive, Room S047 
Stanford, CA  94305-5105 
(650) 498-1481 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
4 
Study Synopsis: 
Title:  POSITIVE: PerfusiOn imaging Selection of Ischemic STroke PatIents for 
EndoVascular ThErapy 
 
Objective:  The primary objective of this randomized trial is to determine the safety and 
efficacy of intra-arterial reperfusion in Acute Ischemic Stroke (AIS) patients ineligible 
for or refractory to treatment with IV-tPA as selected by physiologic imaging criteria for 
mechanical thrombectomy within 6-12 hours of symptom onset or time last seen normal.  
 
Study Design:  This study will be a prospective, randomized, multi-centered 
international trial that will enroll up to 200 patients at up to 35 centers. 
 
Patient Population: AIS patients, ineligible for or refractory to treatment with IV-tPA, 
(patients seen within 6 hours of symptom onset will be immediately considered for 
endovascular therapy according to the site’s standard of care. Likewise, patients 
presenting beyond 12 hours will be treated according to the site’s standard of care),who 
are found by physiologic imaging to have significant viable tissue to warrant 
endovascular recanalization and are able to undergo mechanical thrombectomy within 6-
12 hours of symptom onset or time last seen normal.  Patients will be randomized to 
treatment by endovascular mechanical thrombectomy or best medical therapy (MT). 
 
Indication:  The use of mechanical thrombectomy devices has been shown to be safe and 
effective for the revascularization of occluded cerebral vessels.   However, study results 
to date have only evaluated the treatment of patients within the first eight hours from 
symptom onset.  Pilot data have shown that patients selected with physiologic imaging 
can be treated with endovascular thrombectomy without time restrictions.  
 
Inclusion Criteria:  
1. 
Age 18 and older (i.e., candidates must have had their 18th birthday) 
2. 
NIHSS ≥8 at the time of neuroimaging 
3. 
Presenting or persistent symptoms within 6-12 hours of when groin puncture 
can be obtained 
4. 
Neuroimaging demonstrates large vessel proximal occlusion (distal ICA 
through MCA M1 bifurcation) 
5. 
The operator feels that the stroke can be appropriately treated with traditional 
endovascular techniques (endovascular mechanical thrombectomy without 
adjunctive devices such as stents) 
6. 
Pts are within 6-12 hours of symptom onset, that have received IV-tPA 
without improvement in symptoms are eligible for this study.  Patients 
presenting earlier than 6 hours should be treated according to local standard of 
care. 
7. 
Pre-event Modified Rankin Scale score 0-1 
8. 
Consenting requirements met according to local IRB 
 
 

 
5 
Exclusion Criteria: 
1. 
Patient is less than 6-hours from symptom onset 
2. 
Rapidly improving neurologic examination 
3. 
Absence of large vessel occlusion on non-invasive imaging 
4. 
Known or suspected pre-existing (chronic) large vessel occlusion in the 
symptomatic territory  
5. 
Absence of an associated large penumbra as defined by physiologic imaging 
 according to standard of practice at the participating institution 
6. 
Any intracranial hemorrhage in the last 90 days  
7. 
Known irreversible bleeding disorder  
 
8. 
Known hereditary or acquired hemorrhagic diathesis, coagulation factor 
deficiency, or oral anticoagulant therapy with INR > 2.5 or institutionally 
equivalent prothrombin time of 2.5 times normal  
9. 
Platelet count < 100 x 103 cells/mm3 or known platelet dysfunction  
10. Inability to tolerate, clinically documented evidence in medical history of 
adverse reaction to, or contraindication to medications used in treatment of the 
stroke  
11. Contraindication to CT and MRI (i.e., iodine contrast allergy or other 
condition that prohibits imaging from either CT or MRI) 
12. Known allergy to contrast used in angiography that cannot be medically 
controlled  
13. Relative contraindication to angiography (e.g., serum creatinine > 2.5 mg/dL) 
14. Women who are currently pregnant or breast-feeding (Women of child-
bearing potential must have a negative pregnancy test prior to the study 
procedure (either serum or urine)  
15. Evidence of active infection (indicated by fever at or over 99.9 °F and/or open 
draining wound) at the time of randomization 
16. Current use of cocaine or other vasoactive substance  
17. Any comorbid disease or condition expected to compromise survival or ability 
to complete follow-up assessments through 90 days 
 
18. Patients who lack the necessary mental capacity to participate or are 
unwilling or unable to comply with the protocol’s follow up appointment 
schedule (based on the investigator’s judgment) 
 
Head CT or MRI Scan Exclusion Criteria 
•  Presence of blood on imaging (subarachnoid hemorrhage (SAH), intracerebral 
hemorrhage (ICH), etc.) 
• High density lesion consistent with hemorrhage of any degree 
• Significant mass effect with midline shift 
• Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity 
on the baseline CT scan or ASPECTS of < 7; Sulcal effacement and/or loss of 
grey-white differentiation alone are not contraindications for treatment. 

 
6 
Primary Endpoint:   
The primary objective is to show that AIS patients, ineligible for or refractory to 
treatment with IV-tPA, with appropriate image selection, treated with mechanical 
thrombectomy within 6-12 hours of symptom onset have less stroke related disability and 
improved good functional outcomes as compared to those treated with best MT with 
respect to endpoint defined as: 
 
• 90-day global disability assessed via the modified Rankin score (mRS), analyzed 
using raw mRS scores. Statistical details can be found in section 7.2. 
Secondary Endpoints:   
• 90-day global disability in the 6-12 hr cohort assessed via the overall distribution 
of mRS 
• Proportion of patients with good functional recovery for the 6-12 hr cohort as 
defined by mRS 0-2 at 90 days 
• Mortality at 30 and 90 days  
• Intracranial hemorrhage with neurological deterioration (NIHSS worsening >4) 
within 24 hours of randomization 
• Procedure related serious adverse events (SAE’s)  
• Arterial revascularization measured by TICI 2b or 3 following device use  

 
7 
Table of Contents 
Study Synopsis: ............................................................................................................. 4 
Inclusion Criteria:................................................................................................................. 4 
Exclusion Criteria: ................................................................................................................ 5 
Head CT or MRI Scan Exclusion Criteria................................................................................ 5 
Primary Endpoint: .................................................................................................................. 6 
Secondary Endpoints: ............................................................................................................. 6 
1.  Introduction ........................................................................................................... 9 
1.1  Rationale for study ..................................................................................................... 12 
2.  Purpose and Hypothesis ...................................................................................... 13 
2.1 
Risk Analysis .............................................................................................................. 13 
3.  Objectives ............................................................................................................ 14 
3.1 
Primary Objective ...................................................................................................... 14 
3.2  Secondary Endpoints ................................................................................................. 14 
4.  Trial design .......................................................................................................... 15 
4.1 
Inclusion criteria ........................................................................................................ 15 
4.2 
Exclusion criteria ....................................................................................................... 15 
4.2.1 
Head CT or MRI Scan Exclusion Criteria.............................................................. 16 
4.3 
 Overview of Study Flow ............................................................................................ 17 
4.4  Study VisitsFDA......................................................................................................... 18 
4.5  Recruitment ............................................................................................................... 18 
4.6  Screening .................................................................................................................... 18 
4.7  Informed Consent ...................................................................................................... 18 
4.8   Baseline Evaluation ................................................................................................... 19 
4.9 
 Randomization .......................................................................................................... 20 
5. Study Screening and Treatment Procedure ........................................................ 20 
5.1 
 Imaging Assessment for Eligibility for Trial Participation...................................... 20 
5.3 
Medication during Treatment ................................................................................... 22 
5.4 
Pre-Procedure Angiography ...................................................................................... 22 
5.5 
 Devices and Equipment ............................................................................................ 23 
5.6 
Post-Procedure Care .................................................................................................. 24 
5.7  Recovery and Discharge ............................................................................................ 25 
5.8 
 Hospital Costs ........................................................................................................... 25 
5.9 
 Follow-Up Examination ............................................................................................ 25 
5.9.2 
Angiographic ........................................................................................................ 26 
5.9.3 
Serious Adverse Events ........................................................................................ 28 
6.  Study Primary Endpoints ................................................................................... 28 
6.1 
 Analysis of Primary Endpoint .................................................................................. 29 
6.1.1 
 Definition of Analysis Samples ............................................................................ 29 
7.   General Statistical Considerations .................................................................... 29 
7.1   Sample Size Estimation for the Primary Outcome ................................................... 30 
7.2   Statistical Evaluation of Primary Endpoint .............................................................. 30 
7.3   Missing Data and Imputation Methods .................................................................... 30 
7.4 
Secondary Statistical Analysis ................................................................................... 30 
7.4.1 
Secondary Outcomes ............................................................................................ 30 
7.4.2 
Subgroup Analysis ................................................................................................ 31 

 
8 
7.5   Safety Analysis ........................................................................................................... 32 
7.5.1   Safety Outcomes ................................................................................................... 32 
7.5.2   Interim Safety Monitoring ..................................................................................... 32 
7.6   Blinding ...................................................................................................................... 32 
8. Study Withdrawal ................................................................................................ 33 
8.1 
Unattended Visits ....................................................................................................... 33 
9.  Data Safety Monitoring Board (DSMB) ............................................................. 33 
10.  Trial Operating Committee .............................................................................. 33 
11.  Scientific Advisory Committee (SAC) .............................................................. 33 
12.  Steering Committee (SC) .................................................................................. 34 
12.1. Study Management .................................................................................................... 34 
13.  Investigator Responsibilities ............................................................................. 34 
14.  Required Documents from the Investigator ..................................................... 35 
15.  Investigator Records ......................................................................................... 36 
15.1 Data Collection ........................................................................................................... 36 
15.1.1  Data Management Overview ................................................................................. 36 
15.1.2  Data Acquisition and Central Study Database....................................................... 36 
15.2 Randomization Module.............................................................................................. 36 
15.3 Security, Privacy, and Confidentiality ...................................................................... 37 
16.  Adverse Events .................................................................................................. 37 
16.1  Serious Adverse Events .............................................................................................. 37 
16.2 Reporting and Review of Adverse Events ................................................................. 38 
17.  Ethical Considerations ...................................................................................... 39 
18.   Protection of Patient Confidentiality ............................................................... 39 
19.  Ethics Committee/Institutional Review Board Approval ................................ 40 
20.   Informed consent .............................................................................................. 40 
21.   Quality Assurance ............................................................................................ 41 
22. Protocol Deviations ............................................................................................ 41 
23.  Final Report....................................................................................................... 42 
24.  Information Confidentiality .............................................................................. 42 
25.  Trial Registration .............................................................................................. 42 
26.  Risk Analysis ..................................................................................................... 42 
27.  Publication Policy .............................................................................................. 42 
29.   References ......................................................................................................... 42 
 
 
 
 

 
9 
1.  
Introduction 
Acute ischemic stroke remains a potentially devastating condition and is a leading cause 
of morbidity and mortality affecting estimated 800,000 people per year in the United 
States alone and costing an estimated $41 billion in 2007 [1]. The most devastating 
strokes are generally those caused by proximal occlusions in the cervical and cerebral 
vasculature. The natural history of untreated or unrevascularized large vessel occlusions 
in acute stroke patients results in mortality rates approaching 30% and only 25% of 
patients achieving good neurologic outcomes at 90 days.[2 3] Intravenous (IV) tissue 
plasminogen activator (tPA) administration is approved for use within 3 hours of 
symptom onset, with newer evidence suggesting potential benefit out to 4.5 hours. [1 4-6] 
However, IV tPA does a poor job of effectively revascularizing large vessel occlusions 
[7]. Among patients presenting within the approved time window, close to half are 
ineligible to receive IV tPA due to exclusionary criteria. Moreover, a recent meta-
analysis of 502 patients with a perfusion mismatch treated with IV tPA beyond the 
approved time window failed to show evidence of benefit. [8]   
 
Beyond 4.5 hours patients that present to hospitals that do not offer intra-arterial therapy 
(IAT) are subject to medical therapy (MT).  International Stroke Trial (IST) and Chinese 
Acute Stroke Trial (CAST) evaluated the effect of early aspirin administration in patients 
with acute stroke.[9 10] This data shows that aspirin results in fewer deaths (nine per 
1,000) and more patients with a good functional outcome (seven per 1,000) at 30 days 
after ischemic stroke [11] Best medical therapy also consists of aggressively managing 
blood sugar levels, blood pressure, and hemodynamic status according to the standard of 
practice at each institution.  The medication regimen is primarily centered on anti-
aggregation approach such as aspirin therapy and institution of statins.  Managing these 
patients, especially those with large strokes at presentation, in a stroke unit with available 
neurocritical care has also been shown to improve outcomes.   
 
The randomized PROACT II trial demonstrated that stroke patients with MCA occlusions 
undergoing IA fibrinolysis had higher rates of recanalization, 66% with IA thrombolysis 
vs. 18% with placebo (p=0.001), and were more likely to have a 90 day mRS ≤ 2, 40% 
compared with only 25% in the nonrecanalization group (p=0.04). [12] This was further 
supported with subgroup analysis from the multi-center Merci trial where 49% of 
revascularized patients achieved mRS £ 2 as compared to 10% of non-revascularized 
patients (p<0.001).  That study also showed a significant increase in 90-day mortality in 
patients that were not revascularized compared to those that were 52% versus 25% 
(p<0.001). [13] Similarly, the Penumbra POST Trial found that 45% of patients who 
were revascularized achieved a mRS £ 2 compared to 13% of patients who were not 
successfully recanalized.[14] The more recent randomized SWIFT and TREVO studies 
utilized the latest stent retrievers for mechanical thrombectomy to build on the safety and 
efficacy that the Penumbra and MERCI studies have shown. SWIFT showed that 
Solitaire device was able to recanalize 68% of occluded vessels with resultant 36% 
patients with good neurologic outcomes at 90 days.  Similarly, TREVO was able to 
achieve 68% recanalization rates with 40% good clinical outcomes at 90 days.[15 16] 
 
Despite the compelling data from device trials, many stroke practitioners do not consider 

 
10 
IAT standard of care for patients that are not candidates for IV-tPA or where IV-tPA does 
not work. The American College of Chest Physicians recently convened the 
Antithrombotic Therapy and Prevention of Thrombosis Panel to develop evidence based 
medicine recommendations for any disease process requiring antithrombotics.  In regards 
to patients with acute ischemic stroke, they recommended against the use of mechanical 
thrombectomy devices based on current literature, except in select patients who “value 
the uncertain benefit of mechanical thrombectomy higher than the associated risks of 
intervention”. [17] A recent analysis of the National Inpatient Sample found that 4000 
patients over 2 years that underwent endovascular thrombectomy had a 25% mortality 
rate while hospitalized and 50% were discharged to long-term care facilities. [18] 
Another recent publication also concluded that thrombectomy devices were an intriguing 
option but there was little evidence to support their use in routine practice without further 
appropriately designed clinical trials. [19]  
 
Current randomized trials such as the mechanical retrieval and recanalization of stroke 
clots using embolectomy Trial (MR RESCUE), Penumbra THERAPY Trial and the 
efficacy and safety study of desmoteplase to treat acute ischemic stroke Trial (DIAS-3) 
are evaluating the utility of perfusion imaging to select acute stroke patients for 
treatment. The results of these trials are pending.[20 21] More importantly, these trials 
did not utilize the latest generation of endovascular mechanical thrombectomy devices in 
which early results suggest promising results with much faster recanalization times and 
high rates of good neurologic outcome. [22 23]  At the time of this protocol’s initial 
composition there are also two active clinical trials that use perfusion studies as guidance 
in treating patients presenting with stroke symptoms with no clear time of onset. The first 
is the MR WITNESS study which is taking place in NIH stroke center and Massachusetts 
General Hospital (MGH). Secondly, the DAWN trial is being performed by MGH and 
the University of Pittsburgh.[24 25] Our study is unique in that it will utilize perfusion 
imaging to select patients who are not eligible for or refractory to treatment with IV-tPA 
and randomize those patients between best medical therapy and the latest generation 
(FDA approved) mechanical thrombectomy devices.  
 
However, these trials are focusing on patients within the 8-hour time period.  Several 
recent reports have suggested that with image based selection patients may be effectively 
treated beyond these strict time boundaries with good outcomes. [26-29] A five year pilot 
study from our institution utilizing a perfusion imaging based paradigm to select AIS 
patients, irrespective of time, for IAT with mechanical thrombectomy indicates that we 
can treat patients safely (90 day mortality rate 26%, symptomatic bleed rate 7%) and 
effectively (90 day mRS 0-2, 38%) outside of the traditional time windows.  In this 
series, our average time to treat from the last time the patient was seen normal was 11.3 
hours.  Furthermore, the patient outcomes and complications in those treated after 8 hours 
were no different than those treated before 8 hours.[30 31]  We have further combined 
our data with those from 2 other centers and found that in 247 patients there were no 
differences in patient outcomes in those treated beyond 8 hours as opposed to those 
treated less than 8 hours when selected by physiologic imaging.[32] 
 

 
11 
Intra-arterial (IA) thrombolysis within 6 hours and mechanical thrombectomy within 8 
hours have been shown to be feasible methods by which to achieve revascularization and 
there are data which suggest that revascularization improves patient outcomes.[7 12 33-
36]   
 
Until now, there has not been a single trial showing efficacy of intra-arterial 
thrombectomy (IAT) over medical therapy.  The POSITIVE trial was originally designed 
and approved by the FDA to evaluate mechanical thrombectomy to treat acute ischemic 
stroke (AIS) related to a large blood vessel occlusion (LVO). Since the trial began, there 
have recently been data released from four trials that all show overwhelming positive 
outcomes of IAT over medical therapy of patients presenting within 6 hours of AIS 
onset.[37-41] 
 
Due to this recent data, the POSITIVE trial halted enrollment of patients presenting 
within 8 hours of AIS on 11/08/2014, until the published data was available from these 
multiple trials.  The final data from these trials was finally fully available on 2/11/15.  
The POSITIVE steering and executive committees, in discussion with the study 
investigators, decided to permanently halt patients presenting within 6 hours of AIS and 
to change the late time group from 8-12 to 6-12.  The reason to halt enrollment in the 
early time group was due to the overwhelming data across multiple trials. The MR 
CLEAN trial demonstrated an absolute difference of 13.5% in rate of functional 
independence in favor of IAT over medical therapy (32.6% vs 19.1%).  MR CLEAN was 
notable in that it randomized 500 patients in the Netherlands to IV-tPA vs IV tPA and 
IAT presenting within 6 hours of stroke onset.[38]  More robustly, the ESCAPE trial 
favored IAT over medical therapy by an odds ratio of 2.6 with a significant reduction in 
mortality (10.4% vs 19.0%).  The ESCAPE trial was halted after enrolling 316 patients at 
22 centers around the world presenting within 12 hours of stroke onset.  The trial required 
advanced imaging to select patients with LVO and ability to rapidly transition from 
diagnosis to IAT within 30 minutes.[39]  Similarly, the EXTEND IA trial based in 
Australia, was halted after 70 patients were enrolled due to positive results in the MR 
CLEAN trial.  Interim analysis found a marked improvement in ability to achieve 
functional outcome with IAT (71%) over medical therapy (40%).[41] This overwhelming 
data has created an environment where equipoise has been lost in patients presenting 
within 6 hours of AIS onset. 
 
The ESCAPE trial, while overwhelmingly positive and treating patients out to 12 hours, 
unfortunately did not show a significant difference in patients treated between 6-12 
hours.  There was a signal in the direction of intervention (odds ratio 1.7), but this was 
not significant.[39]  It should be noted that only 49 of the 316 patients were in this 6-12 
hour time frame. This perhaps highlights the obvious absence of Level 1 data available in 
treating patients presenting with AIS beyond 6 hours.  The POSITIVE trial is notable in 
that it will continue to evaluate patients out to 12 hours, requiring documentation with 
advanced imaging of LVO and emphasize selecting patients with small or no infarctions 
present at time of triage.   
 

 
12 
All of the recent trials reported data randomizing IAT with or without IV-TPA against 
IV-tPA alone.  Given the overwhelming benefit in patients receiving IAT, it is now 
reasonable to include patients that fail IV-tPA, which also significantly increases the 
potential to enroll POSITIVE Trial candidates.  Many stroke center networks operate 
where small community hospitals or satellite hospitals are enabled to give IV-tPA 
through stroke neurology telemedicine systems.  These hospitals then usually ship the 
patients to larger tertiary hospitals where endovascular interventions can be performed,as 
was frequently done in the MR-CLEAN and ESCAPE trials.  This can often create 
situations where the patient receives IV-tPA at the outside hospital, but by the time they 
arrive at the tertiary hospital they are beyond the recognized 6 hour time window.  Those 
patients within the 6 and 12 hour time from symptom onset would be eligible for this 
trial.  Patients seen within 6 hours of symptom onset will be immediately considered for 
endovascular therapy according to the site’s standard of care. Likewise, patients 
presenting beyond 12 hours will be treated according to the site’s standard of care. 
Similarly, the ESCAPE trial showed that patients over 80 years old significantly 
benefitted from IA therapy just as much as patients younger than 80 years.[39] To better 
reflect this new clinical reality, there will not be any upper age limitations in the 
exclusion criteria of POSITIVE. 
1.1  
Rationale for study 
Intravenous (IV) tissue plasminogen activator (tPA) administration has been shown to be 
safe and effective for treatment of AIS within 3 hours of symptom onset, and newer 
evidence has shown potential benefit out to 4.5 hours.  Mechanical thrombectomy for 
AIS patients has been shown in clinical trials to be safe up to 8 hours after symptom 
onset.  The rapid progression of thrombectomy devices over the last several years has 
resulted in faster recanalization times while maintaining a high degree of safety.  This has 
resulted in improved patient outcomes, similar to prior randomized trial data showing 
improved outcomes over medical therapy or earlier devices.  Data from the MERCI trial 
suggests that patients > 85 as well as those with a baseline NIHSS score > 30 are unlikely 
to benefit from thrombectomy. Patients with rapidly improving neurologic deficits likely 
will have an excellent recovery with conventional care, precluding the ability to detect a 
beneficial treatment effect of thrombectomy. 
 
Pilot data incorporating physiologic imaging has shown that appropriate patients can be 
selected for thrombectomy.  This selection methodology has shown the ability to 
maintain the same level of safety and efficacy as those patients treated in the highly 
selective environment of a clinical trial, despite presenting far beyond accepted time 
based standards.  Vertebrobasilar occlusion patients are excluded to maintain a 
homogenous study population, particularly since no data currently is available addressing 
the comparability of imaging penumbral patterns in the anterior vs. posterior circulation.  
This has also been shown to be reproducible at multiple centers and with different 
imaging modalities. However, all prospective interventional stroke studies performed to 
date have been restricted by the 8-hour time window.   

 
13 
2.  
Purpose and Hypothesis 
The primary aim of acute ischemic stroke treatment is to restore a patient who is severely 
neurologically impaired due to a blockage of a major brain blood vessel back to their 
previous functional status. Identification and selection of appropriate patients is always 
paramount to good clinical outcomes.  Evidence supports the safety of thrombectomy for 
patients presenting with AIS within 8 hours of symptom onset.  Pilot data support 
thrombectomy in some patients after 8 hours based on selection using physiological 
perfusion imaging. 
 
The purpose of this randomized trial is to demonstrate the safety and efficacy of 
mechanical thrombectomy over best medical therapy for treating acute ischemic stroke 
patients ineligible for or refractory to treatment with IV-tPA with persistent symptoms 
within a 6-12 hour time window from symptom onset as selected by physiologic 
perfusion imaging criteria, (patients seen within 6 hours of symptom onset will be 
immediately considered for endovascular therapy according to the site’s standard of care. 
Likewise, patients presenting beyond 12 hours will be treated according to the site’s 
standard of care).     
2.1 
Risk Analysis 
The primary risks to subjects in this study are associated with evolution of large brain 
infarctions or bleeding within the brain, which can cause symptomatic deterioration of 
the subject. Large brain infarctions are much more common when blood vessels are not 
recanalized and recanalization rates are much higher with endovascular therapy.[12 13 
14]  Excessive bleeding from the site of the femoral artery puncture, from other puncture 
sites, or from other body systems is not likely as this trial is evaluating patients ineligible 
for or refractory to treatment with IV-tPA.  The use of Aspirin, as will be standard in the 
medical arm, does not appear to increase the risk of brain bleeding.[9 10 11]  For patients 
undergoing mechanical thrombectomy, the risk of symptomatic bleeding in prior device 
trials has been reported 7-9% of cases.   
 
Additional risks, approximately 3%, associated with angiography include the risks of 
contrast allergic reactions, kidney dysfunction, vessel perforation and ischemic infarction. 
The CT scans, CT angiography, and cerebral angiography involve exposure to a small 
amount of radiation in addition to the usual x-ray studies done in stroke patients. On 
average, for a complete 2-hour thrombectomy procedure a subject would receive an 
average total dose of 50-100 rads, approximately 9.2 rads for a CTA, and 2.8 rads for a 
head CT scan. There is a small chance of skin or hair damage, but this has yet to happen 
in reported studies for stroke treatments.  
 
Best medical therapy (MT) consists of aggressively managing blood sugar levels, blood 
pressure, and hemodynamic status according to the standard of practice at each 
institution.  The medication regimen is primarily centered on anti-aggregation approach 
such as aspirin therapy and institution of statins.  International Stroke Trial (IST) and 
Chinese Acute Stroke Trial (CAST) evaluated the effect of early aspirin administration in 
patients with acute stroke.[9 10] This data shows that aspirin results in fewer deaths (nine 
per 1,000) and more patients with a good functional outcome (seven per 1,000) at 30 days 

 
14 
after ischemic stroke. [11] Data from device trials using the devices planned for this trial 
suggest a superior functional outcome in patients undergoing mechanical thrombectomy 
ranging from 36-40%. [14 15 16]  Thus, the POSITIVE Investigators feel that subjects 
will likely receive an effective treatment. It has also been shown that the recanalization 
rates associated with mechanical thrombectomy are higher than what has been reported 
for best medical therapy alone. Thus, there is a real possibility that mechanical 
thrombectomy may be more effective than best medical therapy alone. 
 
We do not feel that extending the time parameters beyond the accepted 8-hour indication 
poses a significant risk in appropriately selected patients.  For this reason, we have 
required imaging selection to ensure that we are only including patients with large vessel 
occlusions and also exclude those with a significant underlying infarction and little 
viable/salvageable tissue.  The MUSC experience with this approach over the last five 
years has undergone peer review and been published.  To briefly summarize, the MUSC 
experience with 140 patients treated with perfusion imaging selection, irrespective of 
time from symptom onset, has shown similar rates of good neurologic outcome in those 
treated earlier than the median time (from last normal) of 7 hours as those treated after 7 
hours (30.2% vs 45.5, p=0.1, respectively) with no significant change in mortality (30.2% 
vs 21.2%, p=0.4).  This was similarly shown in a multicenter study where 247 patients 
were treated with a median time of 8 hours and similarly showed near identical rates of 
good neurologic outcome (42.8% vs 41.9%, p=1.0) and similar mortality rates (24.9 vs 
20.3%, p=0.5).  We believe this data shows that extending the time window does not pose 
any increased risk to the patient. 
 
All information concerning subjects will be kept confidential so as to reduce the risk of a 
breach of privacy. Subjects will be assigned study ID #. No personal identifying 
information will be used in presentation or publication of data from this study. 
3.  
Objectives 
3.1 
Primary Objective 
The primary objective is to show that AIS patients, ineligible for or refractory to 
treatment with IV-tPA, (patients seen within 6 hours of symptom onset will be 
immediately considered for endovascular therapy according to the site’s standard of care. 
Likewise, patients presenting beyond 12 hours will be treated according to the site’s 
standard of care), with appropriate image selection, treated with mechanical 
thrombectomy within 6-12 hours of symptom onset have less stroke related disability and 
improved good functional outcomes as compared to those treated with best MT with 
respect to endpoint defined as: 
• 90-day global disability assessed via the modified Rankin score (mRS), analyzed 
using raw mRS scores. Statistical details can be found in section 7.2. 
3.2  
Secondary Endpoints 
• 90-day global disability in the 6-12 hr cohort assessed via the overall distribution 
of mRS 

 
15 
• Proportion of patients with good functional recovery for the 6-12 hr cohort as 
defined by mRS 0-2 at 90 days 
• Mortality at 30 and 90 days  
• Intracranial hemorrhage with neurological deterioration (NIHSS worsening >4) 
within 24 hours of randomization 
• Procedure related serious adverse events (SAE’s)  
• Arterial revascularization measured by TICI 2b or 3 following device use 
4.  
Trial design 
This is a prospective, randomized trial comparing mechanical thrombectomy and best 
MT in AIS patients ineligible for or refractory to treatment with IV-tPA selected with 
perfusion imaging and presenting within 6-12 hours of symptom onset, (patients seen 
within 6 hours of symptom onset will be immediately considered for endovascular 
therapy according to the site’s standard of care. Likewise, patients presenting beyond 12 
hours will be treated according to the site’s standard of care).  Any cleared mechanical 
thrombectomy device that is in common use in the operators region of practice is 
approved for use in the mechanical thrombectomy arm. Best MT will be determined by 
practice standards utilized in the operators region of practice.  Patients will be enrolled 
who meet the inclusion and exclusion criteria and consent to participate will be randomly 
assigned by a central web-based system in a 1:1 manner to treatment with either 
mechanical thrombectomy or MT. Data on each patient will be collected at the time of 
enrollment and treatment, and at subsequent follow-up visits. 
4.1 
Inclusion criteria 
1. 
Age 18 and older (i.e., candidates must have had their 18th birthday) NIHSS 
≥8 at the time of neuroimaging 
2. 
Presenting or persistent symptoms within 6-12 hours of when groin puncture 
can be obtained 
3. 
Neuroimaging demonstrates large vessel proximal occlusion (distal ICA 
through MCA M1 bifurcation) 
4. 
The operator feels that the stroke can be appropriately treated with traditional 
endovascular techniques (endovascular mechanical thrombectomy without 
adjunctive devices such as stents) 
5. 
Pre-event Modified Rankin Scale score 0-1 
6. 
Patients are within 6-12 hours of symptom onset, that have received IV-tPA 
without improvement in symptoms are eligible for this study.  Patients 
presenting outside of this window should be treated according to local 
standard of care. 
7. 
Consenting requirements met according to local IRB 
4.2 
Exclusion criteria 
1. 
Patient is less than 6-hours from symptom onset 
2. 
Rapidly improving neurologic examination 
3. 
Absence of large vessel occlusion on non-invasive imaging 
4. 
Known or suspected pre-existing (chronic) large vessel occlusion in the 
symptomatic territory  

 
16 
5. 
Absence of an associated large penumbra as defined by physiologic imaging 
according to standard of practice at the participating institution 
6. 
Any intracranial hemorrhage in the last 90 days  
7. 
Known irreversible bleeding disorder  
 
8. 
Known hereditary or acquired hemorrhagic diathesis, coagulation factor 
deficiency, or oral anticoagulant therapy with INR > 2.5 or institutionally 
equivalent prothrombin time of 2.5 times normal  
9. 
Platelet count < 100 x 103 cells/mm3 or known platelet dysfunction  
10. 
Inability to tolerate, clinically documented evidence in medical history of 
adverse reaction to, or contraindication to medications used in treatment of the 
stroke  
11. 
Contraindication to CT and MRI (i.e., iodine contrast allergy or other 
condition that prohibits imaging from either CT or MRI) 
12. 
Known allergy to contrast used in angiography that cannot be medically 
controlled  
13. 
Relative contraindication to angiography (e.g., serum creatinine > 2.5 mg/dL) 
14. 
Women who are currently pregnant or breast-feeding (Women of child-
bearing potential must have a negative pregnancy test prior to the study 
procedure (either serum or urine)  
15. 
Evidence of active infection (indicated by fever at or over 99.9 °F and/or open 
draining wound) at the time of randomization 
16. 
Current use of cocaine or other vasoactive substance  
17. 
Any comorbid disease or condition expected to compromise survival or ability 
to complete follow-up assessments through 90 days 
 
18. 
Patients who lack the necessary mental capacity to participate or are 
unwilling or unable to comply with the protocol’s follow up appointment 
schedule (based on the investigator’s judgment) 
4.2.1 Head CT or MRI Scan Exclusion Criteria 
•  Presence of blood on imaging (subarachnoid hemorrhage (SAH), intracerebral 
hemorrhage (ICH), etc.) 
• High density lesion consistent with hemorrhage of any degree 
• Significant mass effect with midline shift 
• Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity 
on the baseline CT scan or ASPECTS of < 7; Sulcal effacement and/or loss of 
grey-white differentiation alone are not contraindications for treatment. 
 
 
 
 
 
 
 
 
 
 

 
17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.3 
 Overview of Study Flow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acute Stroke 
Multimodal CT or MRI reveals ICA/MCA Occlusion 
MR Diffusion-Perfusion or PCT Images 
Acquired 
Randomization 
1:1 

 
18 
 
 
 
 
All sites will keep a screen failure log of all acute stroke patients presenting within 24 
hours of symptom onset but who are not randomized into the study.  Reason(s) for 
exclusion will be recorded. Logs will be data entered by the clinical sites on a monthly 
basis. Recruitment rates will be tracked over time for each hospital. The actual 
recruitment rates as well as potential recruitment rates will be useful for planning further 
clinical trials and determining the widespread impact of the therapy. 
4.4  
Study Visits 
Subjects enrolled in this study will follow the below visit schedule according to their 
institutional standard of care for stroke patient follow-up.  
 
• Baseline 
• Randomization 
• 24 hours (+/-12 hours) Post-Randomization  
• 7 Days Post-Randomization or Discharge (whichever comes first) 
• 30 Days (+/- 14 days) Post-Randomization Follow-up  
• 90 Days (+/- 14 days) Post-Randomization Follow-up  
4.5  
Recruitment 
The target population for the POSITIVE trial is patients greater than 18 years of age who 
have a clinical diagnosis of acute ischemic stroke from a large cerebral vessel occlusion, 
ineligible for or refractory to treatment with IV-tPA, and an identified significant 
penumbral region within 6-12 hours of symptom onset. Patients seen within 6 hours of 
symptom onset will be immediately considered for endovascular therapy according to the 
site’s standard of care. Likewise, patients presenting beyond 12 hours will be treated 
according to the site’s standard of care. 
 
Potential study participants and/or their authorized surrogate will be identified by the 
study team at each site to obtain consent and determine eligibility. Up to 20 sites will be 
included in this study to enroll approximately 200 patients.  
4.6  
Screening 
Consent is obtained, medical history screened, available clinical/neurologic exams 
obtained, and lab work and imaging information per institution standard of care is 
evaluated to determine patient eligibility. Imaging must be performed to confirm 
evidence of a large vessel occlusion. A patient will be considered enrolled upon 
randomization. Randomization will be 1:1 to best MT or a combined best MT and 
mechanical thrombectomy. 
4.7  
Informed Consent 
A member of the research team will explain the study’s objectives to potential 
participants, including a description of standard treatment with the study devices, the 
Medical Therapy 
Mechanical Thrombectomy 

 
19 
requirements of the clinical investigation, and risks and benefits of participating.  All 
informed consent documents used under this study protocol will be consistent with 
applicable elements of ISO14155, Good Clinical Practice Guidelines and 21 CFR Part 50, 
and will be approved by the site’s reviewing IRB/EC prior to study initiation. 
4.8  
 Baseline Evaluation  
Inclusion and exclusion criteria will be confirmed. Once the patient meets all eligibility 
criteria, and the patient or surrogate has provided written informed consent, he/she will 
undergo standard non-study surgical preoperative workup including but not limited to:  
demographic confirmation, medical history, and focused physical examination (see Table 
1 for complete assessment schedule). Baseline imaging may either be CT/CTA/CTP or 
MRI/MRA/MRP prior to the pre-procedure DSA. The baseline neurologic examination 
will be performed by a health care provider or study team member, certified to administer 
the exam and able to give an unbiased neurological and functional assessment (pre-stroke 
mRS and presentation NIHSS).  A pregnancy test will be conducted for applicable 
subjects (females <50 years old and of child bearing potential). Concomitant medications 
will be collected at baseline, 24 hours post-randomization, at discharge, and at follow up 
visits (30 days and 90 days post-randomization).  
 
Table 1: Schedule of Events 
Activity 
Baseline 
Randomization/Procedure 
24hrs Post-Randomization 
7days Post-Randomization or 
Discharge 
30d Post-Randomization 
90d Post-Randomization 
Neurological Deterioration 
Any Add’ l FU (if needed) 
Study Closure 
Evaluation of Criteria 
 
 
 
 
 
 
 
 
 
Eligibility Labs1 
X 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Past Medical History 
X 
 
 
 
 
 
 
 
 
Clinical Evaluation 
X 
 
X 
X 
X 
X 
X 
X 
 
Modified Rankin Scale 
X4 
 
X5 
X5 
X5 
X5 
 
X 
 
NIH Stroke Scale 
X4 
 
X5 
X5 
X5 
X5 
X 
X 
 
Glasgow Outcome Scale 
 
 
X5 
X5 
X5 
X5 
 
X 
 
Stroke Impact Scale 
 
 
 
 
 
X 
 
 
 
CT/CTA or MRI/MRA2 
X 
 
X 
 
 
 
X 
 
 
Angiogram, TIMI/TICI scores3 
 
X 
 
 
 
 
 
 
 
Mechanical Thrombectomy Procedure3 
 
X 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1Eligibility Labs are those required to be within a certain range as part of the inclusion/exclusion criteria list, including: 
pregnancy test (if applicable), INR, platelets, and creatinine. 

 
20 
2CT/CTA or MRI/MRA are required at baseline and 24hrs post-randomization, and any time there is a neurological 
deterioration (a change in NIHSS of 4 points or more) or hemorrhage. 
3Only applicable to those patients randomized to receive mechanical thrombectomy. 
4Must be completed by an unbiased healthcare provider. 
5Must be completed by a BLINDED stroke study team member. 
4.9 
 Randomization 
A stratified randomization will take place centrally within REDCap (Research Electronic 
Data CaptureTM), the database system that will be used for this study.  Randomization 
occurs in a 1:1 ratio to either the mechanical thrombectomy procedure or the best MT 
treatment group. The treatment assignment will be based on stratification by NIHSS (<20 
vs. ≥20) within each center. The randomization table will be prepared by the study 
statistician, which will be uploaded to REDCap before the study begins. Once a patient is 
determined to meet all study eligibility criteria, immediately prior to the procedure, the 
Investigator (or authorized team member) will log on to REDCap to randomize the 
subject. The Investigator will not be blinded to treatment assignment. Once a patient is 
randomized, the patient is considered enrolled in the study and must be followed through 
the end of study. 
5. 
Study Screening and Treatment Procedure 
The screening and treatment procedures are described briefly below. The study procedure 
will take place after clinical baseline assessment and immediately following 
randomization to the thrombectomy arm in order to minimize time between initial 
evaluation and stroke treatment. Groin puncture must occur within one (1) hour of 
randomization.  
5.1 
 Imaging Assessment for Eligibility for Trial Participation 
The subject should be clinically evaluated in the same manner as any routine acute 
ischemic stroke patient.  Clinical assessment documenting NIHSS and significant past 
medical history should be obtained.  Imaging with CT or MR per the institution standard 
of care is required to exclude acute intracranial hemorrhage.  Additional anatomic and 
physiologic imaging with CT or MR perfusion imaging per the institution standard of 
care should then be performed on patients that do not have evidence of significant 
ischemia on initial scans.  Anatomic imaging can utilize CT angiography (CTA) with 
contrast bolus imaging to visualize the vessels of the head as well as presence of 
collateral circulation.  Similar anatomic cerebral imaging can be performed with MR 
angiography (MRA).  The studies must demonstrate an acute major vessel intracranial 
anterior circulation occlusion (ICA or MCA).   
 
All MRIs will be performed on MR scanners equipped with echo-planar imaging 
capability to allow rapid acquisition of diffusion and perfusion scans. Patients with 
contraindications to MRI (metal implants such as pacemakers, claustrophobia, etc.) are 
not eligible for inclusion in the trial using MRI but may be eligible for inclusion using 
CT.  The following sequences will be obtained: DWI, FLAIR (optional but recommended 
for baseline study), PWI, T2* GRE, and intracranial time-of-flight MRA (total 15 minute 
acquisition time), and contrast-enhanced neck MRA. For the baseline study, the 
sequences must be performed in the following order: DWI, GRE, intracranial MRA, 

 
21 
contrast enhanced neck MRA, PWI, FLAIR. All MRIs will be performed on 1.5-3.0 T 
scanners equipped with echo-planar imaging capability. The GRE sequence will be used 
to rule out hemorrhage and a pretreatment head CT scan will not be required in order to 
minimize any delay to therapy. A standard DWI sequence (b=0, 1000 s/mm2 applied in 
each of three principal gradient directions, with ADC map calculation) will be used. MRI 
perfusion measurements will be made using sequential T2*-weighted (gradient echo) EPI 
time sequence scanning. Early in the time series, a bolus (0.1 mmol/kg) of MRI contrast 
material will be rapidly infused (5 ml/sec through an 18 or larger gauge angiocatheter) 
using a power injector. Alternative approaches to contrast dosing will be discussed as 
needed on a site by site basis.  
 
Physiologic imaging should also be performed utilizing contrast bolus tracking technique 
with either MR or CT technologies.  Post processing will be as per the institution routine 
perfusion evaluation, with deconvolution algorithms preferred.  Patient selection will be 
based on the presence of a significant mismatch between the region of infarction depicted 
on the routine brain imaging scan (extent of CT low attenuation or DWI hyperintensity) 
and/or low CBV on perfusion maps as per institution standard of care.  The viable 
ischemic penumbra will be determined as the region of tissue at risk as determined on the 
CBF and MTT (or Tmax) maps minus the region of infarction previously identified.   
Site-specific perfusion thresholds are to be chosen to include only significant 
prolongation in transit times or reduction in blood flow, such that minor perfusion 
changes reflecting benign oligemia are not included in ‘at risk’ tissue estimates.  The 
qualitative presence of at least 2 color change difference from the normal is considered 
significant on the color rainbow scale perfusion maps or if quantitative measures are used 
then an absolute CBV <2 ml/100g reflected the infarct core and relative MTT >145% (or 
absolute value of >6 seconds) of the contralateral hemisphere most accurately reflected 
the penumbra.  There must be at least 50% volume tissue at risk or an identified eloquent 
region at risk.  The presence of greater than 1/3 territory MCA infarction, ASPECTS <7 
or acute infarction greater than 35 cc (from recent data from MR RESCUE trial) volume 
is considered a boundary for exclusion.  Acute volumes will be estimated at the site using 
AxBxC/2 calculations. 
5.2  
Preparation for Treatment 
Patients randomized to the control group will receive best conventional MT for acute 
stroke as determined by the attending stroke physician. All attending stroke physicians 
will follow current AHA guidelines for the treatment of acute ischemic stroke. Patients 
randomized to thrombectomy will receive ASA 325 mg x1 during the first 24 hours 
following the procedure. Other anti-thrombotic regimens may be initiated or resumed 
after 24 hours. Clopidogrel may be employed in patients intolerant of aspirin.  
Endovascular intervention can be performed under either general anesthesia or conscious 
sedation based on best practices as determined by treating physician.  Attempt should be 
made to expedite the transition from imaging to treatment in as rapid a fashion as 
possible.   The subject should be prepared for the planned interventional procedure 
according to standard hospital procedures.   Mechanical trombectomy should be 
performed with the operator’s standard thrombectomy technique using aspiration or a 
stent retriever, separately or in combination.  

 
22 
5.3 
Medication during Treatment 
 
Subjects will undergo the index study treatment procedure as per the standard anesthetic 
protocol at the individual clinical site. Concomitant medications and therapies will be 
administered using standard hospital practice.  The use of IA Verapamil will be allowed 
as per clinical standard for the treatment or prophylaxis of vasospasm encountered in the 
access to the intracranial vessels.  IA or IV abciximab will be allowed to treat fresh 
platelet aggregation on deployed devices.  Low dose IV heparin will be allowed per 
clinical practice to prevent acute thrombus formation.  Administration and dosage of 
these medications will be captured in the study CRF. 
 
Table 2: Recommended Medical Therapy Prior to and After Procedure 
During procedure: 
IA verapamil or nitroglycerine 
IA or IV abciximab 
IV heparin 
After procedure: 
Aspirin 
IV heparin 
5.4 
Pre-Procedure Angiography 
If the patient is randomized to mechanical thrombectomy, the groin puncture to initiate 
the procedure should occur within 1 hour. An introducer sheath will be placed in the 
femoral artery. Diagnostic angiography is initially performed via the transfemoral 
approach with catheterization of the carotid artery appropriate to the patient’s presenting 
symptoms. Once thrombus in the appropriate vessel is identified, the thrombectomy 
procedure will be initiated. If at the time of diagnostic angiography, the vascular lesion is 
deemed to not be an appropriate candidate for treatment with a clot retriever device or if 
no clot is visualized in the appropriate vessels, endovascular thrombectomy will not be 
pursued. Vascular lesions that are not appropriate candidates for clot retrieval are: the 
presence of dissection that precludes safe passage of the microcatheter or significant 
(>67%) proximal cervical common or internal carotid artery atherosclerotic stenosis that 
will obstruct retrograde extraction of a distal thrombus. Please note: angioplasty of the 
proximal cervical common or internal carotid artery to achieve < 67% stenosis for 
enrollment in the trial is prohibited. 
 
Per local standard of care and prior to the thrombectomy, a Digital Subtraction 
Angiography (DSA) will be performed to define the angio-architecture of the occluded 
vascular segment. When possible, an assessment of collateral blood flow by DSA should 
be done per institutional standard of care, particularly in cases of terminal internal carotid 
artery occlusion. Prior to mechanical thrombectomy by the thrombectomy device, 
baseline Thrombolysis in Myocardial Infarction/Thrombolysis in Cerebral Infarction 
(TIMI/mTICI) scores by DSA (see Tables 3 and 4) will be obtained. CTA or MRA is not 
an acceptable substitute for this assessment. The investigator shall make an initial 
assessment of TIMI/mTICI flow in the target vessel territory. 
  
Immediate post-treatment angiograms in the AP, lateral, and working positions will be 
obtained, and de-identified DICOM images will be submitted to the Independent Core 
Lab (ICL). The site Investigator will take necessary steps to ensure that pre- and post- 

 
23 
placement angiograms are performed using similar views, magnifications, and contrast 
amount so as to ensure valid “before-after” comparisons.  TIMI/mTICI scores are to be 
assessed after completion of the procedure.  Note should be made of any complicating 
factors such as vessel dissection or perforation.  Pre-procedure and post-procedure 
angiograms shall be sent to an independent Core Laboratory to make a final 
determination on TIMI/mTICI flow. 
 
Table 3: Thrombolysis in Myocardial Infarction (TIMI) Flow Classification 
TIMI Score 
Classification of Blood Flow 
TIMI 0 
No Perfusion 
TIMI 1 
Penetration without perfusion.  Penetration past the 
initial occlusion, but no distal branch filling 
TIMI 2 
Partial perfusion of the artery with incomplete or slow 
distal branch filling 
TIMI 3 
Complete perfusion of the artery 
 
* From Chesebro et al. Circulation 1987;76:142-154 and Khatri et al. Stroke 
2005;36:2400-2403 
 
Table 4: Modified Thrombolysis in Cerebral Infarction (mTICI) Perfusion Categories 
Grade 0: 
No Perfusion. No antegrade flow beyond the point of occlusion. 
 
Grade 1: 
Penetration With Minimal Perfusion. The contrast material passes beyond 
the area of obstruction but fails to opacify the entire cerebral bed distal to 
the obstruction for the duration of the angiographic run. 
 
Grade 2: 
Partial Perfusion. The contrast material passes beyond the obstruction and 
opacifies the arterial bed distal to the obstruction. However, the rate of entry of 
contrast into the vessel distal to the obstruction and/or its rate of clearance 
from the distal bed are perceptibly slower than its entry into and/or clearance 
from comparable areas not perfused by the previously occluded vessel, e.g, the 
opposite cerebral artery or the arterial bed proximal to the obstruction. 
Grade 2a: 
Partial filling with <50% of the entire vascular territory is visualized. 
 
Grade 2b: 
Partial filling with ≥50% of the entire vascular territory is visualized. If 
complete filling of all of the expected vascular territory is visualized, the 
filling is slower than normal. 
 
Grade 3: 
Complete Perfusion. Antegrade flow into the bed distal to the obstruction 
occurs as promptly as into the obstruction and clearance of contrast material 
from the involved bed is as rapid as from an uninvolved other bed of the 
same vessel or the opposite cerebral artery. 
** From Higashida et al. Stroke2003;34:e109-37and Tomsick et al. AJNR 2008;29:582-
587 
5.5 
 Devices and Equipment 
 
In addition to the thrombectomy device, devices that may be required for the study 
procedure include, but are not limited to, those shown in Table 5. All devices required to 

 
24 
perform the procedure are to be provided by the site and are available commercially for 
the indications for which they are proposed in this study.   
 
Table 5: Devices that may be used during the Thrombectomy Procedure 
Access devices:   
Guiding catheter and sheath 
Thrombectomy devices:   
All FDA cleared cerebral mechanical aspiration 
and stent retriever thrombectomy devices are 
allowed. 
 
Note: The Merci retrieval device will NOT be 
allowed in the trial. 
Non-ionic contrast: 
Institutional standard of care 
Guidewires: 
Investigator preference from FDA approved 
devices and standard of care 
Additional: 
Any other adjunctive, approved/cleared device 
for IA stroke treatment 
 
Device Instructions: 
 
All thrombectomy devices are to be used in accordance with directions for use in the 
package insert approved by the FDA with the exception of the 8-hour from symptom 
onset use limit. 
 
First generation thrombectomy devices such as Merci retrieval device will NOT be 
allowed in the trial. 
 
It is recommended that all medical therapy decisions are made in accordance with 
guidelines from the AHA/ASA or critical care guidelines. 
5.6 
Post-Procedure Care 
Patients randomized to the medical therapy group will receive best conventional MT for 
acute ischemic stroke as determined by the attending stroke physician. Standardization of 
medical management in both arms will occur according to the following: 
 
• General medical management according to AHA/ASA guidelines  
• Admission to monitored or intensive care unit for at least 24 hours 
• Aggressive hypertensive-hypervolemic therapy should be used only in the 
case of symptomatic blood pressure fluctuations or if blood pressure drops 
below the normal range for the patient 
• Antithrombotics: ASA 325 mg PO qd X 7 days (clopidogrel may be used as 
adjunctive therapy if indicated for cardiac disease) then per discretion of 
treating physician 
• Close monitoring of BP and glucose with treatment according to AHA/ASA 
guidelines  
• Follow-up imaging study required in any patient with neurologic deterioration 

 
25 
 
Neurological and functional exams will be conducted (NIHSS and mRS at a minimum) 
within 24 (+/-12) hours of randomization by a dedicated, pre-specified Blinded Study 
Stroke team member with NIHSS certification and expertise with a back up person 
named for cases in which the blinded team member was involved. Follow-up imaging 
(i.e., non-contrast CT scan) will be performed at 24 (+/-12) hours after randomization, 
and will be reviewed to assess hemorrhagic transformation based on ECASS definitions: 
 
HI 1: 
Small petechiae along the margins of the infarcted area 
without space-occupying effect 
HI 2: 
More confluent petechiae within the infarcted area but 
without space-occupying effect 
 
PH 1: 
Hematoma in <30% of the infarcted area with some slight 
space occupying effect 
PH 2: 
Hematoma in >30% of infarcted area with substantial space 
occupying effect 
 
Based on previous work, only PH 2 will be defined as a clinically significant 
hemorrhage. 
 
In addition, any neurological deterioration should be evaluated by urgent CT scan 
and other evaluations as indicated according to investigator/hospital best practice. 
A symptomatic intracranial hemorrhage will be defined as 24 hour CT evidence 
of an ECASS defined intracerebral and a 4-point or more worsening of the NIHSS score. 
5.7  
Recovery and Discharge 
The subject will be recovered from the treatment and discharged from the hospital as per 
standard practices.  
 
At 7 Days Post-Randomization or Discharge the following will be completed by a 
dedicated, pre-specified Blinded Study Stroke team member not involved in the patient’s 
treatment: neurological exams (including NIHSS, mRS, and GOS), a review of any 
adverse events, and a review of current medications.  
5.8 
 Hospital Costs 
For each subject, device costs (the market price for each device) will be collected for the 
hospitalization during which the index procedure took place. These costs will include 
device costs, materials used to treat the occlusion, and number of days spent in the 
hospital (ICU and non-ICU length of stay). 
5.9 
 Follow-Up Examination 
 
5.9.1 Clinical 
Several clinical outcome measures were selected for this study. These were chosen on the 
basis of their reliability, familiarity to the neurologic community, adaptability for use in 

 
26 
patients who have had a stroke, and comparability to end points used in other trials of 
thrombolytic therapy. The modified Rankin Scale (mRS) is an overall assessment of 
global handicap. In the original Rankin Scale, a score of zero indicates the absence of 
symptoms and a score of 5, severe disability. The modified Rankin Scale adds a score of 
6 for fatal outcomes. The Glasgow Outcome Scale (GOS) is a global assessment of 
function.[42] A score of zero on the GOS indicates a good recovery; a score of 2 
moderate disability; a score of 3 severe disability; a score of 4 survival but in a vegetative 
state; and a score of 5, death. It has been used in previous trials assessing outcome in 
hemorrhagic and ischemic stroke patients. [43][43] [43] [43] [43] [43] [43] [42] [42] [38] 
[36][36, 35] The National Institutes of Health Stroke Scale (NIHSS) is a 42 point scale 
that quantifies neurologic deficits in 11 categories. Normal function without neurologic 
deficit is given a score of zero.  
 
Additionally a quality of life scale outcome measure will be utilized in this study.  
Quality of life scales are designed to be sensitive to changes in outcome from mild and 
moderate stroke undetected by other outcome measures. Important parameters not fully 
interrogated by conventional outcome scales can be assessed by quality of life scales, 
including emotion, communication, cognition, and social role function. Standard 
measures, such as the mRS, primarily evaluate physical aspects of stroke outcome, not 
addressing more relevant quality of life measures. The Stroke Impact Scale (SIS) is a 
validated assessment of quality of life specifically in patients with stroke. [44] [39] 
[37][37, 36] 
 
All 24hr Post-Randomization (mRS, GOS, NIHSS), Day 7/Discharge (mRS, GOS, 
NIHSS), Day 30 (mRS, GOS, NIHSS), and Day 90 (mRS, GOS, NIHSS, SIS) clinical 
outcome measures will be assessed by a dedicated, pre-specified Blinded Study Stroke 
team member with NIHSS certification and expertise with a back up person named for 
cases in which the blinded team member was involved in the case during the acute 
hospitalization. Nursing staff, patients, and their family members will be instructed not to 
unblind the investigators performing these assessments.  
 
5.9.2 Angiographic 
All angiograms will be assessed by a central core lab neuroradiologist who is blinded to 
treatment assignment and clinical status. The extent of angiographic reperfusion after 
treatment will be classified in the primary analysis according to Thrombolysis in 
Myocardial Infarction (TIMI) grades.[37,38,40, 44,45] Recanalization is graded 
according to the TIMI scale shown in Table 3 above. A TIMI Score will be recorded for 
all affected vessel segments. Additionally, mTICI classification will also be documented.   
5.9.2.1 Neuroimaging Outcome Measures 
• Ischemic Core Lesion Volumes 
The initial ischemic core lesion volume will be defined using the model equations 
noted above respectively for MRI and CT. Final infarct volume will be defined as 
hyperintense regions on the day 7 FLAIR sequence (or hypodense region on day 7 

 
27 
CT). Lesion volumes will be quantified employing an interactive semi-automated 
program. For each patient, “percent lesion change” will be defined as:  
 
 
 
 
•  Perfusion Lesion Volume 
Regions of abnormal perfusion will be identified by visual inspection and outlined 
by hand using an interactive semi-automated image analysis program. 
• Percent Salvaged Penumbral Tissue 
The percent salvaged tissue will be defined as: 
 
Number of Penumbral Voxels on Pretreatment Imaging Not Designated as Final 
Infarct Abnormality on D7 X 100 
 
• Hemorrhagic Transformation 
Hypointense regions consistent with acute hemorrhage will be identified by visual 
inspection on the noncontrast CT or GRE sequences and outlined by hand to 
provide lesion volumes. Regions of hemorrhagic transformation will be 
categorized as petechial hemorrhage or hematoma according to the Berger 
classification scheme: 
 
 
 
 
 
 
 
 
 
 
• Vessel Stenosis or Occlusions 
For the pretreatment studies, the intracranial vessels will be evaluated for the 
presence of flow voids or signal loss suggestive of vessel occlusions or stenoses. 
The lesion location and severity of narrowing will be recorded for each 
abnormality. CTA or MRA will be considered positive for stenosis of a major 
vessel (ICA, MCA, ACA, PCA, basilar, vertebral) if the measured percent 
stenosis is ³ 67% or if a flow gap is present. Percent stenosis will be measured 
using WASID trial criteria adapted for the intracranial circulation from the 
NASCET method: 
(Day 7 Final Infarct Volume – Pretreatment Core Lesion Volume) 
 X 100 
Day 7 Final Infarct Volume 
HI (hemorrhagic infarction) 
Type 1: 
Small petechiae along the margins of the infarct 
Type 2: 
More confluent petechiae within the infarcted area, but 
without space-occupying effect 
 
PH (parenchymal hemorrhage) 
Type 1: 
Hematoma < 30% of the infarcted area with some slight 
space-occupying effect 
Type 2: 
Dense hematoma >30% of the infarcted area with substantial 
space-occupying effect, or as any hemorrhagic lesion 
outside of the infarcted area 

 
28 
% stenosis  = (  1 - 
Dstenosis 
)  X 100 
Dnormal 
(Selecting Dnormal: distal for ICA; proximal for intracranial vessels) 
5.9.3 Serious Adverse Events 
All serious adverse events (SAE’s) occurring during the 90 days of study participation 
will be recorded. Adverse events and serious adverse events are critical endpoints and 
will be assessed as they occur and at the scheduled clinic visits. A serious adverse event 
is one that is fatal or life-threatening, is permanently or substantially disabling, requires 
or prolongs hospitalization, or any event that the treating clinician judges to be a 
significant hazard, contraindication, side effect, or precaution. For each recorded adverse 
event, the patient’s attending physician will be asked to classify the causal relationship of 
the event to the study treatment as definitely related, probably related, possibly related, 
unlikely related, or not related. Especially detailed form and narrative reports of the 
following specific adverse events will be obtained: 
• Neurologic Deterioration: Increase of 4 or more points in the NIHSS  
• Symptomatic Hemorrhagic Event: an ECASS defined ICH visualized on 
follow-up imaging study and associated with a 4 or more point worsening on 
the NIHSS score*  
• Angiographic or thrombectomy procedural complications: Groin hematoma 
requiring transfusion or surgery, vessel dissection, vessel perforation, 
presence of emboli in a previously uninvolved territory, or other unanticipated 
procedure-related event, device fracture 
• Malignant cerebral edema: Edema associated with neurologic impairment or 
requiring medical or surgical intervention 
• Subarachnoid Hemorrhage (SAH): Both symptomatic and asymptomatic SAH 
visualized on follow-up imaging study. 
*Asymptomatic hemorrhage events are not considered serious adverse events 
 
An unblinded Safety Monitor will review all serious adverse events individually on a 
continuous basis as they occur and aggregate unblinded data on adverse events quarterly. 
This individual will report independently to the appointed DSMB at regularly scheduled 
DSMB meetings. This individual also has the authority to alert the DSMB at any time if a 
potential safety issue arises. If at any point, these reviews raise any safety concerns, the 
DSMB will be empowered to suggest that the trial be placed on hold and request 
additional analyses of the trial dataset. 
6. 
 Study Primary Endpoints 
The primary objective is to show that AIS patients, ineligible for or refractory to 
treatment with IV-tPA, Patients seen within 6 hours of symptom onset will be 
immediately considered for endovascular therapy according to the site’s standard of care. 
Likewise, patients presenting beyond 12 hours will be treated according to the site’s 
standard of care. with appropriate image selection, treated within 6-12 hours with 
mechanical thrombectomy have superior rates of good functional outcomes as compared 
to those treated with best MT with respect to endpoint defined as: 
 

 
29 
• 90-day global disability assessed via the modified Rankin score (mRS), analyzed 
using raw mRS scores. Statistical details can be found in section 7.2. 
6.1 
 Analysis of Primary Endpoint 
6.1.1  Definition of Analysis Samples 
• Target Population 
The target population for the POSITIVE trial is patients who are at least 18 who 
have a clinical diagnosis of Acute Ischemic Stroke who are ineligible for or 
refractory to treatment with IV-tPA and able to begin the thrombectomy 
procedure within a 6-12 hour time window of symptom onset or time last seen 
normal and as selected by physiologic imaging criteria. 
 
• Intent to Treat Sample 
As the primary analysis, all efficacy and safety outcome measures will be 
analyzed under the intent-to-treat (ITT) principle.  Under this principle, the 
evaluable sample includes all subjects who are randomized.  Each subject will be 
analyzed according to the treatment group to which they were assigned at 
randomization. 
 
• Per Protocol Sample 
In addition to the defined ITT analysis sample, a per-protocol sample is defined as 
a subset of the ITT sample.  This sample will be used for secondary sensitivity 
analyses of the primary and secondary outcomes.  The per-protocol sample will 
include all randomized subjects that do not have the following protocol violations 
or deviations: 
a. Eligibility violation 
b. Treatment crossover 
c. Missing 90 day primary outcome (not including missing due to death prior 
to the 90 days) 
7.   
General Statistical Considerations 
The POSITIVE Trial is a multicenter, randomized, Phase III clinical trial investigating 
the safety and efficacy of endovascular mechanical thrombectomy administration in acute 
ischemic stroke patients ineligible for or refractory to treatment with IV-tPA presenting 
within a 6-12 hour time window as selected by physiologic imaging criteria compared to 
best MT. The primary hypothesis to be tested is that treatment with endovascular 
mechanical thrombectomy will improve outcomes at 90 days as compared to the best MT 
group. Each eligible subject will be randomized in a 1:1 ratio to either the endovascular 
mechanical thrombectomy or the best MT treatment group with a stratified randomization 
by NIHSS (<20 vs. ≥20) within each center to balance randomization. This variable was 
chosen because of the known association with outcome.  Randomization will take place 
centrally through the web-based REDCap database system.  The centrally controlled 
randomization will help ensure the treatment balance at any interim analysis as well as in 
the final analysis.   

 
30 
7.1   
Sample Size Estimation for the Primary Outcome 
For this study design, power and sample size are computed by assuming that the true 
proportions of subjects with various mRS outcomes at the 90-day follow-up visit are 
consistent with the observed OR across all three recently published positive mechanical 
thrombectomy trials (EXTEND IA = 2.0, ESCAPE = 2.6, MR CLEAN = 1.67), which 
yields an average OR across all three of 2.1[37-39]These data were used for the sample 
size calculation under the proportional odds ordinal logistic model. With the 
hypothesized OR of 2.1, a total sample size of 180 was estimated to achieve at least 80% 
power to detect the difference in mRS scores between the control and treatment groups. 
After accounting a loss of follow-up rate of 10%, the revised POSITIVE trial with a total 
of 200 patients would provide adequate power with moderate effect size.  
7.2   
Statistical Evaluation of Primary Endpoint 
 
90-day global disability assessed via the modified Rankin score (mRS), analyzed using 
raw mRS scores. 
Statistical analysis of the primary endpoint will be conducted with a proportional odds 
ordinal logistic model using raw Rankin scores 0 to 6 (with 5 and 6 collapsed). The 
stratification variables used in the randomization (NIHSS and center) along with pre-
specified potential confounding (prognostic) variables will be adjusted in the analyses. 
The potential confounding (prognostic) variables include race, age, previous stroke, 
smoking history, DM, hypertension, and hypercholesterolemia. As a sensitivity analysis, 
unadjusted analyses will be also performed. 
7.3  
 Missing Data and Imputation Methods 
Under the ITT principle, all patients who are randomized are included in the analysis.  
Therefore, missing data, especially in the outcome measures, can be problematic.  Every 
effort is to be made to keep all missing data, particularly the Day 90 outcomes, to a 
minimum. Despite the clinical sites’ best efforts, some missing data may be inevitable 
mainly due to lost-to-follow-up (LTFU).  The number and proportion of subjects eligible 
for and compliant with each follow-up examination will be presented.  Subjects who 
withdraw from the study will be tabulated with reasons for withdrawal.  Since the 
primary endpoint is defined using mRS, subjects deceased during study follow-up will be 
scored as mRS 6.  Other subjects not completing the 90-day follow-up visit will be 
categorized for the primary endpoint using the mRS as of the last available follow-up 
visit or discharge (whichever is later).  As a sensitivity analysis, we will also perform 
analysis after excluding subjects without 90-day follow-up evaluations. Additional details 
will be provided in the Statistical Analysis Plan (SAP). 
7.4 
Secondary Statistical Analysis 
7.4.1 Secondary Outcomes 
• 90-day global disability in the 6-12 hr cohort assessed via the proportion of 
patients achieving a mRS of 0-2 
• Proportion of patients with good functional recovery for the 6-12 hr cohort as 
defined by mRS 0-2 at 90 days 

 
31 
• Mortality at 30 and 90 days  
• Intracranial hemorrhage with neurological deterioration (NIHSS worsening >4) 
within 24 hours of randomization 
• Procedure related serious adverse events (SAE’s)  
• Arterial revascularization measured by TICI 2b or 3 following device use 
 
Secondary outcome endpoints will be compared between randomized groups in an 
ITT fashion; with overall Type I error controlled using hierarchical testing.  That is, if 
statistical significance is observed on the primary effectiveness endpoint, the 
secondary clinical efficacy endpoints will then be tested in sequential fashion each at 
a two-sided alpha level of 0.05, with testing ceasing once a null hypothesis cannot be 
rejected.  The statistical tests will be performed in the order specified above.   
7.4.2 Subgroup Analysis 
7.4.2.1 Clinical Efficacy 
• Maximum documented change in NIHSS  
• Percentage of patients achieving NIHSS ≥10 point improvement or NISSS ≤4  
• NIHSS at Discharge/Day 7 post-randomization of thromectomy versus MT arms 
• Functional independence (mRS 0-2) according to MR vs CT based selection 
methodology   
• Functional independence (mRS 0-2) according to involved hemisphere   
• Functional independence (mRS 0-2) correlated with location of vascular 
occlusion, vascular collateral score, NIHSS, and age 
• Time at which functional independence (mRS 0-2) was achieved (Discharge/7 
day, 30 day, and 90 day) 
• Percentage of patients receiving hemicraniectomy 
7.4.2.2 Technical Efficacy: 
• Volume of cerebral infarction as measured by a CT or MRI scan at 24(+/-12)hrs 
post randomization 
• Correlation of core infarct volume predicted by initial CT Perfusion imaging with 
24(+/-12)hrs post randomization stroke infarction in subjects who achieved TICI 
2b-3 reperfusion 
• Correlation of at risk penumbral volume predicted by initial CT Perfusion 
imaging with 24(+/-12)hrs post randomization stroke infarction in subjects who 
were randomized to MT 
• mRS (at 90 days) of patients successfully revascularized (TICI 2b and 3 versus 
TICI 1 and 2a; TICI 1 and 2a/b versus TICI 3)  
 
Subgroup analysis will be compared between randomized groups in an ITT fashion, with 
adjustment for multiple comparisons such that each will be evaluated at a two-sided alpha 
level of 0.01. Subgroup analyses are prospectively defined ancillary endpoints and will be 
presented descriptively. Additional details for these subgroup analyses will be provided 
in the Statistical Analysis Plan (SAP). 
 

 
32 
This is a multi-device clinical study where various devices may be used to treat vessel 
occlusion.  The study is conducted with standardization of subject enrollment, data entry 
and adverse event reporting.  All investigational sites will follow the requirements of a 
common protocol, data collection procedures and forms, and will utilize approved 
mechanical thrombectomy devices in accordance with product labeling.  
7.5   
Safety Analysis 
7.5.1   Safety Outcomes 
Several specific adverse events will be monitored throughout the study.  However the 
primary safety outcomes to be assessed at completion of the trial are: 
• Symptomatic intracranial hemorrhage at 24 hours post-randomization 
• Asymptomatic intracranial hemorrhage at 24 hours post-randomization 
• Intracranial hemorrhage within 90 days of hospital discharge 
• Clinically significant complications (pneumonia, sepsis, UTI, etc.) at time of 
discharge or 7 days post randomization, whichever comes first. 
• Mortality rates at 30 days post-hospital discharge 
• Mortality rates at 90 days post-hospital discharge 
• Treatment-related SAEs up to 48 hours post-randomization 
7.5.2   Interim Safety Monitoring 
7.5.2.1 Stopping the Trial Based on Interim Safety Data 
The DSMB will receive periodic safety reports of all AEs and SAEs. In addition, the 
treatment-related SAE’s occurring within 48 hours of randomization will be monitored as 
a safety outcome along with the following: 
• Symptomatic intracranial hemorrhage within 24 hours of randomization 
• Asymptomatic intracranial hemorrhage within 24 hours of randomization 
• Mortality rates at 30 days post-hospital discharge 
• Mortality rates at 90 days post-hospital discharge 
• Treatment-related SAEs during the study 
• All SAE’s during the study 
• Major non- intracranial hemorrhage bleeding complications during hospitalization 
• Recurrent stroke within 90 days of hospital discharge 
 
Additional details of the monitoring plan will be included in the study SAP and 
Monitoring Plan. 
7.6   
Blinding 
This study is not blinded. Blinding is difficult, if not impossible, from a clinical 
perspective. It is not possible to blind the Investigator who treats the patient, nor is it 
possible to blind the internal review committee (IRC) members. Additionally, physicians 
treating subjects who experience an adverse event after must know how the stroke was 
treated in order to effectively report the adverse event and plan further treatment.  
Blinding the study is not required for interpretation of study outcomes. However to avoid 
bias in study results, the person performing the primary outcome assessment at 90 days 

 
33 
must be blinded to the subject’s treatment assignment and have not been associated with 
the care of the subject during the acute treatment phase. 
8. 
Study Withdrawal 
Subjects may be terminated or withdrawn from the study for the following reasons: 
• Voluntary withdrawal of consent–– meaning that a subject voluntarily chooses not 
to participate further in the study.  All data collected up to the withdrawal of 
consent will be maintained in the study database. 
• Lost to follow-up –– defined as a subject who is more than one month late to a 
study visit and for whom 5 documented telephone attempts to contact the subject 
and at least one certified letter were unsuccessful. 
• Subjects may also be withdrawn at the investigator’s discretion if within their best 
interest.  
8.1 
Unattended Visits 
Any study subject who does not attend a scheduled follow-up visit should be contacted 
by site personnel to determine the reason for the missed appointment(s). If the missed 
visit was due to a serious adverse event, (e.g., re-hospitalization) an Adverse Event report 
must be completed in the study database and any reporting requirements met. 
9. 
 Data Safety Monitoring Board (DSMB) 
A DSMB will be comprised of 4 members not participating in the trial and will include a 
neuroradiologist, neurologist, neurosurgeon and statistician.  The DSMB will exercise 
review of the overall safety of the trial, periodically review all adverse events occurring 
in the trial, and make recommendations to adjustments in the study protocol, should any 
be considered necessary for safety or other related reasons.  
10. 
 Trial Operating Committee 
This study will have a trial operating committee (TOC) whose goal is to oversee trial 
operations. The TOC will consist of the study PI, statistical PI, project managers, data 
managers, and others deemed necessary in overseeing the day to day operations of the 
trial.  The TOC will review study progress, study conduct at individual clinical sites, 
other clinical site performance measures, and blinded DSMB reports.   
11. 
 Scientific Advisory Committee (SAC) 
This committee will be comprised of prominent investigators who are not part of this 
study. The SAC will function as an independent group that is charged with critically 
reviewing all aspects of the trial and advising the TOC on new scientific developments 
that may affect the design or conduct of this trial. Removed from the day-to-day 
operation of the trial, this committee is charged with providing a frank appraisal of the 
overall success of the TOC in achieving its operational objectives related to recruitment, 
data quality, and safety. This committee will be available to the Principal Investigators 
and TOC to consult on any problems that occur during the trial. 
 
Unlike the Data Safety Monitoring Board, however, the SAC will not review data on 
overall rates of outcome or interim effectiveness data. The SAC does not have authority 

 
34 
to change the research protocol; it may recommend changes, but these would have to be 
approved by the Data Safety Monitoring Board before implementation. 
 
The SAC will meet once prior to the start of enrollment to review the final protocol and 
procedure manual. Thereafter, it will meet as often as it deems necessary. At least one 
week before each meeting, the Principal Investigator will provide a progress report to the 
SAC to include all information requested by its Chair. It is anticipated that this report will 
require contributions from the respective centers in this study. 
12.  
Steering Committee (SC) 
The Steering Committee will be comprised of the trial PI’s, principal investigators from 
the 5 top enrolling centers, statistician, and a representative from each corporate 
sponsor.  The SC will be responsible for overall supervision and execution of the trial 
including adherence to protocol, progress of enrollment, patient safety, and consideration 
of new information.  While daily trial management is the responsibility of the TOC, the 
TOC will provide key input to the SC for study planning, execution and data 
presentation. 
12.1. Study Management 
As the study Principal Investigator, Aquilla Turk, DO has overall responsibility for the 
conduct of the study according to 21 CFR 812, 21 CFR Part 50, Good Clinical Practice 
(GCP) Guidelines (Guidance for Industry, E6 Good Clinical Practice Consolidated 
Guidance, ICH, April 1996), ISO 14155: Part 1 and 2, the Declaration of Helsinki, 
Medical Device Directive, Annex X, FDA and all applicable regulatory requirements. For 
this study, Dr. Turk will have certain direct responsibilities and will delegate other duties 
to appropriately qualified individuals.   All personnel participating in the conduct of this 
clinical trial will be qualified by training, education, and experience to perform his or her 
respective tasks. 
 
*NOTE: A complete list of participating investigators will be maintained and will be 
available upon request. 
13. 
 Investigator Responsibilities 
The Investigator(s) shall be responsible for the day-to-day conduct of the investigation as 
well as for ensuring that the investigation is conducted according to all signed 
agreements, applicable elements of ISO 14155, the Clinical Investigational Plan, 
applicable FDA regulations, and the principles that have their origin in the Declaration of 
Helsinki.  
 
The investigator is also responsible for having control of the device under investigation, 
for protecting the rights, safety and welfare of subject’s under the investigator’s care and 
for obtaining informed consent in accordance with 21 CFR Part 50. Each Investigator 
must sign the Investigator Agreement (or an equivalent and a Financial Disclosure) prior 
to becoming eligible to enroll subjects in this trial.  
 
Responsibilities of the Investigator include, but are not limited to: 

 
35 
• Ensuring that IRB approval is obtained prior to undertaking the trial at a clinical 
site 
• Ensuring that participation of a subject in a clinical trial includes obtaining written 
informed consent prior to randomization and/or other non-standard of care study-
related assessments  
• Providing the study sponsor with accurate and complete financial information per 
21 CFR Part 54 
• Ensuring that all personnel assisting with the clinical trial are adequately informed 
and understand their trial-related duties and functions 
 
It is recommended that each site identify a study coordinator for this study. Working with 
and under the authority of the clinical site Principal Investigator, the study coordinator 
assures that all study requirements are fulfilled and serves as the contact person at the site 
for all aspects of study administration. 
 
The Investigator will allow direct access to source data/documents for trial related 
monitoring, auditing, IRB/EC review, and regulatory inspection. Also, the investigator 
will allow auditing of their clinical investigational procedure(s). 
14. 
 Required Documents from the Investigator 
At a minimum, the investigational site will provide the following documents to the study 
sponsor: 
• Signed Investigator Agreement  
• Written and dated IRB/EC approval  
• Written and dated IRB/EC approval for ICF document  
• IRB/EC approval for any other written documents to be provided to the study 
subject (e.g., advertising)  
• HIPAA documentation (if applicable) 
• Investigator and Co-Investigators’ current Curriculum Vitae*  
• Current medical licenses  
• Any other relevant documents requested by the study sponsor or the reviewing 
IRB/EC or other regulatory authorities, 
• FDA Form 3454 or 3455 (or equivalent) regarding financial interests 
• Fully executed contract 
• Ongoing IRB approval documents 
• Source Documents for data verification 
• Site Delegation of Authority Log 
 
* With regard to the Sub-Investigators current CVs, the study may begin once the CV of 
the site PI, IRB approval and IRB approved consent and privacy statement, the 
investigator’s agreement, Medical License, and financial disclosures, fully-executed 
contract, and others listed above, have been received. No additional Investigators may 
participate in the study, however, until a copy of their CV and all other required 
documents have been provided to the study sponsor. 

 
36 
15. 
 Investigator Records 
The Investigator must ensure that all study subject records are stored for at least 6 years 
after the end of the clinical study. To avoid error, the study site should contact Aquilla 
Turk, DO prior to the destruction of study records to ensure that they no longer need to be 
retained. In addition, Aquilla Turk, DO should be contacted if the Investigator plans to 
leave the investigational site so that arrangements can be made for the handling or 
transferring of study records. 
 
The Investigator will also maintain original source documents from which study-related 
data are derived, which include, but are not limited to: 
 
• Clinic progress notes recording subject’s medical history and medications 
• Medical charts with operative reports and subject condition upon discharge 
• Medical records regarding AE’s/SAE’s, including treatment and clinical outcome  
• Results of diagnostic examinations, imaging (such as x-rays, MRIs), as well as the 
report of the radiologist’s reading/interpretation of diagnostic imaging 
• Signed notes of phone calls and/or correspondence indicating investigational 
site’s attempts to follow study subjects at the required follow-up visits until 
subject’s participation in the study is complete or terminated  
• Records relating to patient death (e.g., death certificate, autopsy report, if 
available, or terminal medical records) 
15.1 
Data Collection 
15.1.1  Data Management Overview 
Data management will be handled by the VUMC Cerebrovascular Clinical Research 
group, which is housed in the Department of Neurological Surgery at the Vanderbilt 
University Medical Center (VUMC). All activities will be conducted in coordination with 
the study PI, the sites, and the TOC. The data validation procedure will be implemented 
on two levels: first, automated checks will display warnings for invalid data, and second, 
the Project Manager will verify individual data fields and query discrepancies. More 
information can be found in the Monitoring Plan. 
15.1.2  Data Acquisition and Central Study Database 
The entire study will be conducted using an electronic data acquisition method where all 
clinical data on enrolled subjects will be data entered (single-keyed) by the site personnel 
into a web-based data management system entitled Research Electronic Data Capture 
(REDCap) system that provides a user-friendly and easy-to-navigate interface, The latest 
version of each eCRF and source document worksheets will be available as a PDF file on 
the REDCap website for use by study personnel.  
15.2 
Randomization Module 
The web-based Randomization Module will be used by authorized site personnel for the 
purpose of randomizing eligible patients. The Study Coordinator (or other appropriate 
study team member) will log onto the REDCap system using a unique username and 
confidential password. When a subject is deemed eligible, a unique subject ID and record 

 
37 
will be generated in REDCap. Once the Study Coordinator has entered the required 
subject information and clicked “Randomize”, the computer program will display the 
treatment assignment for the subject.  The subject is considered randomized and enrolled 
at the time the REDCap system generates the treatment assignment.  
15.3 
Security, Privacy, and Confidentiality 
VUMC employs several layers of data protection to ensure data security. The first part of 
security is physical protection of the hardware systems, access to which is limited to 
authorized personnel. By limiting access, ensuring only authorized personnel have 
access, and tracking all entry, we can ensure this risk is minimal. Additionally, REDCap 
has a built-in audit trail that tracks all user activity and changes made to the data entry 
fields with a date-time stampe.  
16. 
 Adverse Events 
Adverse events (AE’s) may occur at any time after randomization.  Pre-existing 
conditions (existing prior to randomization) will be documented in the subject’s medical 
record as part of prior medical history but will not count as an AE unless it worsens 
during the study.  Adverse events (serious and non-serious) will be documented on an 
Adverse Event form. Non-serious adverse events will be recorded from randomization 
through hospital discharge or 7 days post-randomization (whichever is earlier). Serious 
adverse events will be recorded from randomization through the end of study (i.e., 90 day 
post-randomization follow-up). 
 
Investigators will record characteristics of each adverse event on an Adverse Event form. 
Each adverse event will be judged by the Investigator as to its level of relatedness to the 
investigational devices and investigational procedure.  In addition, the Investigator will 
identify the date of onset, severity and duration. Severity will be judged using the scale 
noted in Table 10. All adverse events will be monitored until they are adequately 
resolved or explained or until the subject reaches the end of the study. 
 
Table 10. Definition of event severity for judgment by Investigator. 
Term 
Definition 
Mild 
Patient is aware of a sign or symptom, but that sign or symptom does not 
interfere with normal activity  or  symptom is both transient and resolved 
Moderate 
Symptoms interfere with the subject’s usual activity or symptoms 
require treatment 
Severe 
Symptom(s) cause either severe discomfort or have a significant impact 
of the subject’s usual activity and symptoms require treatment 
16.1  Serious Adverse Events 
 
An adverse event is considered serious if it: 
• Resulted in death 
• Resulted in permanent impairment or damage 
• Required inpatient hospitalization or prolongation of existing hospitalization 
• Required medical or surgical intervention to prevent any of the above outcomes 
 

 
38 
As the last above bullet point references, an important medical event that may not result 
in death, be life-threatening, or require hospitalization may be considered a serious 
adverse event when, based upon appropriate medical judgment, the event may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include (but are not 
limited to): allergic bronchospasm requiring intensive treatment in an emergency room or 
at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; or, 
the development of drug dependency or drug abuse.  Serious adverse events should not 
be reported for hospitalization or prolonged hospitalization in the following scenarios: for 
a diagnostic or elective surgical procedure related to a pre-existing condition; to allow for 
an efficacy measure for the study; or, for a planned surgical procedure that was not the 
result of a condition worsening due to participation in the study. 
 
An assessment should be made regarding the seriousness, severity and relationship to the 
investigational devices and investigational procedure.   The following factors should be 
considered when evaluating causality of adverse events: 1) the temporal sequence from 
the study procedure; 2) patient's response after discontinuation or re-introduction; and, 3) 
severity of the event.  The investigators, on the basis of their clinical judgment and 
guided by the following definitions, should determine the relationship of an adverse event 
to the administration of the investigational device, and/or study procedure(s) as: 
definitely related, i.e. following in a reasonable temporal sequence, known to be a 
complication, and having no other explanation; probably related, i.e. following in a 
reasonable temporal sequence and not reasonably explained by the patient’s clinical state 
or other therapies; possibly related, i.e. could have been explained by other therapies or 
patient’s clinical state; or not related. 
16.2 
Reporting and Review of Adverse Events 
To provide for consistent reporting of adverse events, serious and non-serious adverse 
events will be recorded on the Adverse Event form in the database.  Non-serious adverse 
events will be recorded from randomization through Day 7 or hospital discharge 
(whichever occurs first). Serious adverse events will be recorded from randomization 
through the end of study (i.e., 90 day final follow-up visit, death, or withdrawal of 
consent). 
 
In order to ensure prompt reporting of adverse events, we require that all adverse events 
(as well as all related study data) be entered into the REDCap database within five 
working days of the study team becoming aware of the event for the following 
timepoints: Procedure and 7 Days Post-Randomization/Discharge (whichever occurs 
first). For all serious adverse events (SAEs), we require that they be reported in the 
REDCap within 24 hours of the study site staff first being made aware of the occurrence 
of the SAE. The 24 hour reporting requirement for SAEs applies to all study timepoints.   
 
Reports of serious or life-threatening adverse events will be provided to appropriate 
members of the TOC and the Medical Safety Monitor (MSM). The MSM will conduct an 
independent review of each SAE. If the MSM believes the adverse event is serious, 
unexpected and either definitely, probably, or possibly related to the investigational 

 
39 
device(s) and/or study procedures, the TOC staff forward a Safety Report (pre-filled with 
as much data as possible) to the clinical site Investigator to be completed with any 
additional information that may be relevant to the SAE. The Safety Reports will be 
included in the reports prepared for the DSMB. The principal investigator at each clinical 
site will be responsible for reporting to his/her own IRB/EC according to individual 
IRB/EC policies. After the submission of the initial Safety Report, the principal 
investigator at the corresponding clinical site will be responsible for obtaining follow-up 
information about the event and reporting it to the TOC.  
 
If it is determined that an unanticipated adverse device effect presents an unreasonable 
risk to subjects, the Principal Investigator will recommend the termination of all 
investigations or parts of investigations presenting that risk as soon as possible. The PI 
and SC shall make a determination regarding termination not later than 15 working days 
after the sponsor first receives notice of the effect. Termination of all investigations or the 
parts of investigations that have been deemed to present the risk(s) shall occur not later 
than 5 working days after the PI and SC makes this determination. 
 
The trial will resume only after determining there is sufficient evidence to reinstate the 
trial, and after each clinical site obtains IRB/EC approval. 
 
17. 
 Ethical Considerations 
The rights, safety, and well-being of clinical investigation subjects shall be protected 
consistent with the ethical principles laid down in the Declaration of Helsinki. This shall 
be understood, observed and applied at every step in this clinical investigation. 
It is expected that all parties will share in the responsibility for ethical conduct in 
accordance with their respective roles in the investigation. The Sponsor and the 
Investigator(s) shall avoid improper influence or inducement of the subject, monitor, the 
clinical investigator(s) or other parties participating in or contributing to the clinical 
investigation. 
18.   
Protection of Patient Confidentiality 
At all times throughout the clinical investigation, confidentiality will be observed by all 
parties involved. All data shall be secured against unauthorized access. Privacy and 
confidentiality of information about each subject shall be preserved in study reports and 
in any publication. Each subject participating in this study will be assigned a unique 
identifier.  
 
Monitors and auditors will have access to the study subject list and other information that 
personally identifies study subjects to ensure that data reported in the database 
corresponds to the person who signed the ICF and the information contained in the 
original source documents. Such personal identifying information may include, but is not 
limited to the subject’s name, address, date of birth, and medical record number. 

 
40 
19. 
 Ethics Committee/Institutional Review Board Approval 
Institutional Review Board (IRB) / Ethics Committee (EC) approval is required prior to 
study commencement. The Investigator must also obtain renewal of IRB/EC approval as 
dictated by local requirements (but at least annually) during the entire duration of the 
study. The Investigator is responsible for fulfilling any conditions of approval imposed 
by the reviewing IRB/EC, such as regular reporting, study timing, etc. Study data 
required to be included in IRB/EC reports (e.g., Continuing Reviews) must be obtained 
from the SDMC; in order to ensure that accurate and consistent data are presented. 
The Investigator will provide the Project Management (PM) team with copies of such 
approvals and reports. Withdrawal of IRB/EC approval must be reported to the PM team 
immediately following the investigator’s knowledge of the withdrawal. 
 
The reviewing Independent Review Board (IRB) / Ethics Committee (EC) must review 
and approve an Informed Consent Form (ICF) specific to this study. Prior to the start of 
the trial, the PM team will provide each study center with a sample ICF. The study 
center, to meet specific requirements, may modify this sample ICF; however, the ICF 
must contain all of the elements required by the protocol, regulations, and GCP. Each 
investigational site will submit a copy of their ICF to the Sponsor prior to submission to 
their IRB; and, the IRB/EC approved ICF and renewal approvals to the PM team as 
required for the duration of the study. The original signed and dated ICF should be 
retained by the investigational site for monitoring, and a copy provided to the subject. 
 
20.   
Informed consent 
 
Upon confirmation of patient’s eligibility, a written informed consent document must be 
obtained prior to any study-specific evaluations being conducted.  In accordance with US 
FDA regulations (21 CFR 50) and ICH-GCP Consolidated Guidelines (Federal Register, 
May 9, 1997, Vol. 62, Number 90), a witnessed, IRB-approved, informed consent will be 
required from all subjects or their appropriate surrogate, as defined in 21 CFR 50.3(m), 
prior to participating in this trial.  At the time of initial contact with a potential candidate, 
the investigator(s) will provide an adequate explanation of the purpose, procedures, 
possible risks/benefits, and participant responsibilities, as well as the fact that his/her 
participation is voluntary, that he/she may withdraw from the study at any time, and that 
the decision not to participate or to withdraw will not affect subject’s care in any way.  
Potential participants or their surrogate will be given ample opportunity to ask questions 
and to consider their decision.  If the subject expresses a sustained interest, a signed and 
dated written informed consent will be obtained. A copy of the consent form will be 
given to the participant or surrogate, and another copy will be placed in his/her medical 
record. The informed consent must be obtained by either the clinical site PI or other 
members of the study team who have been delegated the authority to obtain informed 
consent. Each of the study team members with this delegation must be qualified in terms 
of education, experience, and training to obtain informed consent. 
 
The written informed consent document (and any other written information to be 
provided to the study subject) should be updated whenever new information becomes 
available that may require significant revisions to the informed consent document 

 
41 
previously signed by a subject. Any such revision or update must be approved by the 
reviewing IRB/EC before being provided to the study subject. Previously consented 
subjects will be made aware of the changes and depending on the extent and/or severity 
of the new information a subject may be asked to “re-consent” to continued participation 
in the trial. 
21.   
Quality Assurance 
To ensure monitoring responsibilities are performed to the fullest extent possible on a 
real-time basis through REDCap, the VUMC Cerebrovascular Clinical Research group 
will perform on-site and centralized monitoring for the trial. In addition to on-site 
monitoring, centralized monitoring (per the FDA’s most recent monitoring guidance 
developed in August 2011) reflects a modern, risk-based approach and will include 
uploading of all non-de-identified source documents to the REDCap system.  Centralized 
monitoring focuses on critical study parameters and relies on a combination of 
monitoring activities.  In this recent guidance, the FDA has encouraged the 
implementation of centralized monitoring due to its ability to ensure quality and integrity 
of data.  Centralized monitoring is also very effective at identifying data fraud, data 
fabrication, and data errors.  
 
For the first subject enrolled at any site, 100% of the data will be verified against source 
documents.  For subsequent subjects, a checklist of key outcome and safety data variables 
requiring source document verification (SDV) has been developed based on the trial’s 
safety and efficacy endpoints.  Sites will be evaluated in an ongoing manner to determine 
if there is a need to monitor more frequently or more thoroughly or via on-site evaluation. 
All documents and data shall be produced and maintained in such a way to assure control 
of documents and data to protect the subject’s privacy as far as reasonably practicable. 
Only users with password-protected REDCap access will have the ability to view study 
data within the secure REDCap database.  The Primary Investigator, Sponsor and 
representatives of regulatory authorities are permitted to inspect the study documents as 
needed. All attempts will be made to preserve subject confidentiality. 
22. 
Protocol Deviations 
A protocol deviation is defined as any study action taken by the clinical Investigator or 
site personnel in conflict with the Study Protocol. All protocol deviations will be entered 
into REDCap within 48 hours of the deviation.  These will be tracked within the REDCap 
system and queries will be made and recorded through REDCap. 
 
Deviations must be reported regardless of whether medically justifiable, or taken to 
protect the subject in an emergency. Investigators will also adhere to procedures for 
reporting study deviations to their IRB/EC in accordance with their specific IRB/EC 
reporting policies and procedures. 
 
Good Clinical Practice Guidelines require that Investigators maintain accurate, complete 
and current records, including documents showing the dates of and reasons for each 
deviation from the protocol.  

 
42 
23. 
 Final Report 
A final report will be completed, even if the study is prematurely terminated. At the 
conclusion of the trial, a multi-center abstract reporting the results will be prepared and 
may be presented at a major meeting(s). A multi-center publication may also be prepared 
for publication in a reputable scientific journal. The publication of results from any single 
center experience within the trial is not allowed until the aggregate study results have 
been published, unless there is written consent from the study PI. 
24. 
 Information Confidentiality 
All information and data generated in association with this study will be held in strict 
confidence and remain the sole property of Principal Investigator. The Investigator agrees 
to use this information for the sole purpose of completing this study and for no other 
purpose without written consent from the Trial Operating Committee. 
25. 
 Trial Registration 
The study will be registered in a publicly accessible trial database (e.g., clinicaltrials.gov) 
prior to study initiation. 
 
26. 
 Risk Analysis 
A thorough risk analysis was performed as part of design control recommendations of the 
Quality System Regulation (21 CFR 820).  
27. 
 Publication Policy 
Publication of the results of this trial will be governed by the policies and procedures 
developed by the Trial Operations Committee.  The Publication Policy will be fully 
compliant with the voluntary NIH Public Access Policy mandated by the 
Consolidated Appropriations Act of 2008 (Division G, Title II, Section 218 of PL 
110-161). 
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