Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3
Phase: NA
Conditions: Stroke, Acute, Cerebral Infarction
Sponsor: Gregory W Albers

Endovascular Therapy Following Imaging 
Evaluation for Ischemic Stroke 3 
Study Protocol 
NCT02586415 
April 20, 2017 
Gregory W. Albers, MD, Principal Investigator 
Stanford University 
Stanford, California 94305 

 
 
 
 
 
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PROTOCOL TITLE 
 
 
DEFUSE 3: 
Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 
 
 
 
Protocol Version/Version Date 
 
Version 2.4 
 
April 20, 2017 
 
Protocol Directors 
 
Gregory Albers, MD 
Michael Marks, MD 
Maarten Lansberg, MD, PhD 
 
Stanford University  
Stanford Stroke Center 
780 Welch Rd. Suite CJ350 
Stanford, CA 94304 
 
 
 
Supported by 
 
The National Institute of Neurological 
Disorders and Stroke (NINDS) 
U01 NS092076 
 
 
IDE Number 
 

 
 
 
 
 
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DEFUSE 3 
 
 
AGREEMENT ON THE PROTOCOL 
 
By signing below I confirm that: 
 
1) I have read this protocol and it contains all necessary details for conducting this study 
 
AND 
 
2) I agree to conduct the trial in compliance with this protocol and to adhere to all 
regulations that govern the conduct of the study. 
 
 
 
 
 
________________________________________________________ 
 
 
_______________________ 
Principal Investigator’s Signature  
 
 
 
Date 
 
 
________________________________________________________ 
Principal Investigator’s Name 
 
 
_________________________________________________________ 
Site Name: 
 
 

 
 
 
 
 
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TABLE OF CONTENTS 
 
Table of Contents …………………………………………………………………………………………… 
 
P.1 
1. Summary of Trial               ……….…………………………………………………………… 
 
P.2 
2.   Scientific Background …………………………………………………………………………. 
 
P.2  
 
2.1 State of the Science on Endovascular Stroke Therapy for stroke…….. 
 
P.2 
 
2.2 Prior Studies and rationale for development…………………………………. 
 
P.3 
3. 
Investigational Plan ………………………….……………………………………………….. 
 
P.6 
 
 
3.1 Purpose ………………………………………………………………………….. 
 
P.6 
 
 
3.2 Protocol Design ………………………………………………………………. 
 
P.6 
 
 
3.3 Enrollment Criteria………………………………………………………….. 
 
P.7 
 
 
 
3.3.1 Clinical Inclusion Criteria…………………………………. 
 
P.7 
 
 
 
3.3.2 Clinical Exclusion Criteria………………………………… 
 
P.7 
 
 
 
3.3.3 Neuroimaging Inclusion Criteria………………………. 
 
P.8 
 
 
 
3.3.4 Neuroimaging Exclusion Criteria……………………… 
 
P.8 
 
 
3.4 Enrollment and Randomization……………………………………….. 
 
P.9 
 
 
 
3.4.1 Enrollment………………………………………………………. 
 
P.9 
 
 
 
3.4.2 Randomization………………………………………………… 
 
P.10 
 
 
3.5 Acute Treatment……………………………………………………………… 
 
P.10 
 
 
 
3.5.1 Endovascular Therapy……………………………………… 
 
P.10 
 
 
 
3.5.2 Medical Therapy………………………………………………. 
 
P.11 
 
 
3.6 Clinical and Imaging Evaluations……………………………………… 
 
P.11 
 
 
 
3.6.1 Study assessments and follow‐up visits…………….. 
 
P.12 
 
 
3.7 Site Approval and Monitoring Plan……………………………………. 
 
P.12 
 
 
3.8 Sample size, Adaptive Design and Statistical Analysis………… 
 
P.14 
 
 
3.9 Risk Analysis……………………………………………...……………………. 
 
P. 18 
 
 
3.10 Device Description ………………………………………………………… 
 
P. 21 
 
 
3.11 Monitoring Procedures and Adverse Event Reporting.……. 
 
P. 22 
4.   Investigator’s Agreement & Current Investigators ……..……………………..….. 
 
P. 25 
5.   Executive Committee / Key investigators …………………………………………...... 
 
P. 27 
6.   Institutional Review Board ………………………………………………………………….. 
 
P. 27 
7.   Costs …………………………………………………………………………………………………… 
 
P. 27 
8.   References …………………………………………………………………………………………... 
 
P. 28 
9.   Appendix: Patient Informed Consent Form ...…………………………………………. 
 
P.32  
 
 
 

 
 
 
 
 
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1. SUMMARY OF TRIAL 
DEFUSE 3 is a prospective, randomized, multi‐center, Phase III, adaptive, blinded endpoint, 
controlled trial. A maximum of 476 patients will be randomized and treated between 6 and 
16 hours of symptom onset. Subjects will be randomized 1:1 to endovascular therapy plus 
medical management or medical management alone.  Only the devices listed in this protocol 
are approved for use in DEFUSE 3.  The choice of device or devices employed is at the discretion 
of the clinical investigator.  
 
2. SCIENTIFIC BACKGROUND  
Although stroke is the number one cause of adult disability in the United States1, treatment 
options for stroke are limited.  The only FDA approved treatment for stroke is administration 
of intravenous (iv) tissue plasminogen activator (tPA) within 3 hours after symptom onset.  
Nationwide, only about 4 percent of stroke patients receive this therapy.2  The main reason 
for this low treatment rate is that most patients present to the hospital outside the time‐
window for tPA.3, 4 Even when administered, tPA is often not effective because it either fails 
to recanalize the occluded artery5‐7 or because the brain is already irreversibly injured.8  As a 
result, it is estimated that only 12‐25% of treated patients benefit from tPA.9  Thus, in order 
to improve outcomes from stroke, we need better treatments that are available to a greater 
proportion of stroke patients. 
 
2.1 State of the science on endovascular stroke therapy for acute stroke 
Endovascular stroke therapy, the removal of blood clots with mechanical devices or 
thrombolytic drugs administered intra‐arterially, is the most promising new treatment for 
patients who “fail” treatment with iv tPA or are not eligible for iv tPA. The main advantage of 
endovascular therapy is that it has a high rate of recanalization.10, 11  Blood flow can be 
restored with a success rate of up to 82% with modern thrombectomy devices and 66% for 
intra‐arterial thrombolysis.10, 12, 13 This is approximately twice as effective as iv tPA which 
has a recanalization rate of 10‐50% depending on the location of the blood clot.6, 7  Despite 
higher rates of recanalization with endovascular therapy, two recent randomized controlled 
trials of endovascular therapy, IMS III and MR RESCUE, have failed to demonstrate a clinical 
benefit. Patient and treatment related factors likely both contributed to the neutral results of 
these trials (see below for details).  
Patient‐related factors: A central consideration in the optimization of patient selection for 
acute stroke therapies is the concept of the ischemic penumbra. Ischemic penumbra is 
defined as ischemic tissue that is potentially salvageable and is distinguished from the 
ischemic core that has already sustained irreversible injury.  Clearly, the target of acute 
stroke therapies is salvage of the ischemic penumbra, preventing infarct growth and, most 
importantly, improved functional outcome. Acute stroke trials should therefore ideally be 
limited to patients with an ischemic penumbra. MRI‐based studies, such as DEFUSE 1 and 2, 
indicate that MRI can be used to identify these patients.8, 14, 15 16, 17 
Treatment‐related factors: Recent studies have emphasized the importance of 
recanalization rates, demonstrating the influence on patient outcome of highly effective 
endovascular procedures that lead to complete or near‐complete reperfusion.18, 19  Currently, 
the most common metric for rating the quality of reperfusion is the modified Thrombolysis 

 
 
 
 
 
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In Cerebral Infarction (mTICI) scale, and a clear relationship exists between the degree of 
reperfusion on the mTICI scale and patient outcome.20‐22  Patients with >50% reperfusion 
(mTICI 2B‐3) are much more likely to have a good outcome than patients with <50% 
reperfusion. 
IMS III, the largest endovascular trial to date, did not use advanced imaging criteria to select 
patients.23  Instead it used relatively strict time‐criteria, anticipating that this would yield a 
high proportion of patients with a substantial penumbra.  However, several categories of 
patients who likely did not have substantial penumbra were enrolled.  Nearly one third of the 
patients did not have a vessel occlusion at angiography and 23% had distal MCA occlusions; 
both of these subgroups are unlikely to have substantial penumbral tissue.  In addition, 42% 
of patients had some evidence of irreversible tissue injury (ASPECTS <8) on their baseline CT 
and 14% had evidence of extensive irreversible injury (ASPECTS <5).24 Finally, the 
endovascular devices that were available during IMS III had relatively low rates of early 
reperfusion; mTICI 2B‐3 was only 40% in IMS III. 
 
MR RESCUE, a stroke trial that aimed to demonstrate benefit of endovascular therapy in 
patients with a penumbra based on MRI, had neutral results.25  Several factors likely 
contributed to this.  First, the rate of endovascular reperfusion was extremely low. Only 8 
patients (24%) in the MR RESCUE penumbral group achieved TICI 2B‐3 reperfusion during 
endovascular therapy. Second, patients in the penumbral group in MR RESCUE had larger 
baseline infarct core lesions (median volume 36 ml; IQR 24–51 ml) than the Target Mismatch 
patients in DEFUSE 2 (median volume 13 ml; IQR 5–26 ml). The combination of low rates of 
endovascular reperfusion and relatively large core lesions, both strong predictors of poor 
clinical outcome, likely explains the lack of a treatment effect in “penumbral patients” in MR 
RESCUE.  Moreover, with only 8 endovascular patients in the penumbral cohort achieving 
TICI 2B‐3 reperfusion, MR RESCUE was substantially underpowered. 
 
New Generation Trials: Recently, a series of positive randomized studies of endovascular 
therapy with treatment initiated within 6 hours of stroke onset in the vast majority of patients 
were reported.  This has prompted new guidelines endorsing endovascular therapy up to 6 
hours after symptom onset.  The American Heart Association is now calling for late window 
studies using advanced imaging for patient selection: “"Further randomized, controlled trials 
should be done to determine whether advanced imaging paradigms using CT perfusion and MRI 
perfusion, CTA, and diffusion imaging, including measures of infarct core, collateral flow status, 
and penumbra, are beneficial for selecting patients for acute reperfusion therapy who are 
beyond 6 hours from symptom onset. (New recommendation, 2015 AHA Guidelines).  
 
DEFUSE 3 will address this new mandate.  Enrollment is limited to patients with salvageable 
tissue (Target Mismatch patients) who are likely to respond favorably to endovascular 
reperfusion in the 6‐16 hour window. Use of the latest generation thrombectomy devices, 
coupled with strict qualification and oversight criteria for the neuro‐interventionalists, will 
result in high rates of reperfusion.  Based on the compelling preliminary data from DEFUSE 2, the 
trial is adequately powered to demonstrate a clear treatment effect.   
 
2.2. Prior studies and rationale for development 

 
 
 
 
 
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This protocol aims to shift the selection of patients for reperfusion therapy from a relatively 
arbitrary decision based on poorly validated clinical characteristics to an objective decision 
based on scientific evidence.  Many factors affect the evolution of the ischemic penumbra into 
the ischemic core, and the rate of progression of irreversible injury is highly variable 
between individuals. This variability is likely mediated by the adequacy of collateral blood 
flow as well as the metabolic milieu of individual stroke patients. The individuality of 
penumbral evolution among stroke patients implies that identifying the extent of the 
ischemic core and penumbra is useful for making treatment decisions. Currently diffusion‐
weighted imaging (DWI) / perfusion‐weighted imaging (PWI) magnetic resonance imaging 
(MRI) affords the best opportunity for approximating the ischemic core and penumbra in 
real time clinical practice.27 
The DWI lesion provides a dependable estimation of the ischemic core and only very rarely 
shows permanent reversal following early reperfusion.28, 29  PWI identifies hypoperfused 
ischemic tissue. Regions defined as abnormal on PWI that do not demonstrate a DWI 
abnormality, often referred to as the DWI/PWI mismatch, can estimate the ischemic 
penumbra.30  It is critical that PWI utilizes an appropriately validated threshold parameter 
that excludes ischemic tissue with modest blood flow reduction (i.e. benign oligemia), 
because this tissue is unlikely to infarct even if reperfusion does not occur. Which PWI 
parameter is optimal, as well as what threshold to use to define critical hypoperfusion, has 
been the focus of multiple research efforts.31 Prior work from our group and others supports 
the use of Tmax, thresholded at >6 seconds, as the optimal PWI parameter to identify 
ischemic tissue destined to become infarcted if timely reperfusion does not occur.32  This 
Tmax threshold correlates well with the penumbral range of cerebral blood flow decline as 
determined by both positron emission tomography and Xenon CT.33, 34 
Using a difference between the volume of the baseline PWI Tmax lesion and the DWI volume 
to identify mismatch, the DEFUSE and EPITHET studies found that most patients with a 
PWI/DWI mismatch responded favorably if reperfusion occurred following iv tPA treatment 
in the 3‐ to 6‐hour time window. However, despite having a mismatch, patients with very 
large baseline DWI lesions (large core infarct volumes) had highly unfavorable outcomes 
following reperfusion. Patients with this MRI pattern, referred to as the Malignant profile, 
had a significantly higher rate of both parenchymal hemorrhage and severe disability/death 
if reperfusion occurred.35  Mismatch patients who do not have the Malignant profile have 
been designated as having a Target Mismatch, and these patents respond extremely 
favorably to reperfusion following iv tPA therapy. In a pooled analysis of DEFUSE and 
EPITHET, Target Mismatch profile patients who experienced reperfusion had a 5‐fold 
increase in favorable clinical response at 90 days and significantly less infarct growth when 
compared to those who did not reperfuse.36  No association between reperfusion and 
favorable outcomes, or a reduction in infarct growth, was apparent for patients without the 
mismatch profile.  
The DEFUSE 2 study utilized an automated mismatch analysis program (RAPID) to 
prospectively establish MRI profiles in a consecutive cohort of patients who then underwent 
endovascular therapy.  DEFUSE 2 confirmed the concepts demonstrated in DEFUSE and 
EPITHET; Target Mismatch patients who achieve early reperfusion therapy have less infarct 
growth and more favorable clinical outcomes (8·8,95% CI 2·7–29·0).37 No association 
between reperfusion and favorable outcomes or infarct growth was present in patients 

 
 
 
 
 
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without Target Mismatch. Furthermore, the positive association between reperfusion, 
favorable clinical response, and attenuation of infarct growth did not diminish in DEFUSE 2 
patients with Target Mismatch who were treated relatively late (6‐12 hours after symptom 
onset, see Figure 1). 
 
Figure 1: The effect of time on the association between reperfusion and good functional outcome (graph on the left) 
and the effect of time to treatment on the probability of good functional outcome patients with reperfusion (graph on 
the right) in Target mismatch patients.  95% CIs are indicated by dashed lines.  Estimates are based on multivariate 
logistic regression, adjusted for age and baseline DWI volume. There is no significant effect of time in either model.38 
This finding contrasts sharply with prior studies that did not use penumbral imaging to 
select patients and suggests that imaging findings may be of equal, or potentially even 
greater, importance than time from symptom onset for identification of optimal patients who 
might benefit from reperfusion therapy. 
How could Target Mismatch patients who are treated late have outcomes that are as favorable 
as those of earlier treated patients? At later time points, the Target Mismatch profile identifies 
patients in whom the infarct is evolving at a relatively slow rate; a DWI lesion that is still 
considerably smaller than the PWI lesion reflects good collateral circulation. These 
collaterals typically allow prolonged, but not permanent, survival of the hypoperfused 
mismatch region. Evidence that the mismatch region is still at considerable risk for infarct 
expansion, even at later time points, was provided by the DEFUSE 2 finding that Target 
Mismatch patients imaged between 6 and 12 hours from symptom onset consistently 
demonstrated substantial infarct growth if reperfusion was not achieved.38 Patients with 
slowly evolving infarct cores are ideal candidates for later time window reperfusion therapy, 
particularly endovascular therapies. One of the drawbacks of the endovascular approach is 
that the time between hospital arrival and achievement of endovascular reperfusion is 
typically at least 90 to 120 minutes. For patients with rapidly growing infarct cores (such as 
patients with the Malignant profile), substantial growth of the infarct core has been reported 
despite endovascular reperfusion. Therefore, removing this population, which represents 
about 20% of eligible patients, from a randomized endovascular trial, has important 
advantages. 
DEFUSE 2 confirmed that early DWI lesions are an excellent surrogate for the ischemic core.  
Despite endovascular therapy, only 2 patients had a final infarct that was smaller than the 
baseline DWI lesion and the size and location of the early DWI lesion was a reliable predictor 
of the final infarct volume in patients with complete reperfusion.39, 40 In DEFUSE 2, younger 
age and smaller DWI volume were significant independent predictors of favorable outcome.  
Subgroup analysis of EPITHET identified DWI lesion size ≤25 ml as a strong predictor of a 

 
 
 
 
 
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favorable response to reperfusion.37, 41 These findings suggest that certain subgroups, in 
particular individuals with Target mismatch and small DWI lesions are most likely to benefit 
from reperfusion.  The adaptive design of DEFUSE 3 (see below) has the potential to focus 
patient enrollment on a subgroup of patients (e.g. those with smaller DWI lesion volumes 
and/or shorter times from symptom onset to randomization) who respond most favorably to 
endovascular therapy. This will allow the study to identify the largest population that has a 
statistically reliable benefit of endovascular therapy. 
New data (presented at the International Stroke Conference, February 2015) suggest that CT 
Perfusion studies, processed with the same software (RAPID) used in the studies described 
above, can identify the ischemic core with accuracy similar to MRI (Cereda, et al ISC 2015) 
and select patients who respond to endovascular reperfusion therapy in early time windows 
(Campbell, et al NEJM 2015, EXTEND‐IA study, Saver, et al NEJM 2015, SWIFT PRIME study).  
Therefore, DEFUSE 3 will allow patient selection with both MRI and CT Perfusion. 
 
3.  INVESTIGATIONAL PLAN 
3.1. Purpose 
DEFUSE 3 is a prospective randomized Phase III multicenter controlled trial of patients with 
acute ischemic anterior circulation strokes due to large artery occlusion treated between 6‐
16 hours of stroke onset with endovascular thrombectomy therapy vs. control.  The primary 
endpoint, the modified Rankin Scale, will be assessed at 3 months.  The patients’ 
participation in the study concludes at that time (3 months from stroke onset).  The study 
will randomize up to 476 patients over 4 years.  The purpose of DEFUSE 3 is to assess the 
safety and efficacy of thrombectomy in carefully selected patients in an extended time 
window.  Only the devices listed in this protocol will be used.  Selection of the specific device 
(or devices) is determined by the individual endovascular therapist.   
 
3.2. Protocol Design 
DEFUSE 3 is a prospective randomized Phase III multicenter controlled trial of patients with 
acute ischemic anterior circulation strokes due to large artery occlusion treated between 6‐
16 hours of stroke onset.  Patients who meet the inclusion criteria will undergo either CT 
Perfusion/CTA or MR DWI/PWI/MRA studies prior to randomization.  Patients who have 
evidence of an ICA or MCA M1 occlusion and a Target Mismatch Profile will be randomized in 
a 1:1 ratio to treatment with endovascular therapy (using one or more DEFUSE 3 approved 
thrombectomy devices) plus standard medical therapy versus standard medical therapy 
alone.  Patients who are consented, but not randomized, will receive standard therapy 
according to local guidelines. Baseline data, and information about early stroke therapies, 
will be captured for this group of patients. 
 
Randomization of a maximum of 476 patients is planned. At the first interim analysis when 200 
subjects complete follow‐up, if the overall analysis crosses the futility boundary, a novel adaptive 
design will identify, if it exists, a subgroup with the best prospect for showing benefit from 
endovascular treatment, based on baseline ischemic core lesion volumes and the time to 
treatment. The second interim analyses will be conducted at 340 patients at which time the 
study may stop for efficacy/futility, or the inclusion criteria may be adjusted in the case of 
futility. 

 
 
 
 
 
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Approximately 45 sites will be chosen. Individual site selection will be based on a number of 
factors including endovascular volume, MRI and/or CT perfusion access, number of competing 
trials, clinical trial experience, and the diversity of their patient population.  If a site does not 
consent a patient within 4 months of activation, it will be placed on probation. If no patient 
consent occurs in the next 2 months, the site will be replaced with a “back‐up” site. 
 
3.3. Enrollment Criteria 
3.3.1. Clinical Inclusion Criteria: 
1. 
Signs and symptoms consistent with the diagnosis of an acute anterior circulation 
 
ischemic stroke 
2. 
Age 18‐90 years 
3.  
 Baseline NIHSSS is ≥ 6 and remains ≥6 immediately prior to randomization 
4. 
Endovascular treatment can be initiated (femoral puncture) between 6 and 16 
 
hours of stroke onset.  Stroke onset is defined as the time the patient was last known to 
 
be at their neurologic baseline (wake‐up strokes are eligible if they meet the above time 
 
limits).   
5. 
modified Rankin Scale less than or equal to 2 prior to qualifying stroke (functionally 
 
independent for all ADLs) 
6. 
Patient/Legally Authorized Representative has signed the Informed Consent  form. 
  
3.3.2. Clinical Exclusion Criteria: 
1. 
Other serious, advanced, or terminal illness (investigator judgment) or life expectancy 
 
is less than 6 months. 
2. 
Pre‐existing medical, neurological or psychiatric disease that would confound the 
 
neurological or functional evaluations  
3. 
Pregnant 
4. 
Unable to undergo a contrast brain perfusion scan with either MRI or CT 
5. 
Known allergy to iodine that precludes an endovascular procedure  
6. 
Treated with tPA >4.5 hours after time last known well 
7. 
Treated with tPA 3‐4.5 hours after last known well AND any of the following: age 
 
>80, current anticoagulant use, history of diabetes AND prior stroke, NIHSS >25 
8. 
Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; 
 
recent oral anticoagulant therapy with INR > 3 (recent use of one of the new oral 
 
anticoagulants is not an exclusion if estimated GFR > 30 ml/min). 
9. 
Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS  
10. 
Baseline blood glucose of <50mg/dL (2.78 mmol) or >400mg/dL (22.20 mmol) 
11. 
Baseline platelet count < 50,000/uL 
12. 
Severe, sustained hypertension (Systolic Blood Pressure >185 mmHg or Diastolic 
 
Blood Pressure >110 mmHg)  
13. 
Current participation in another investigational drug or device study  
14. 
Presumed septic embolus; suspicion of bacterial endocarditis  
15. 
Clot retrieval attempted using a neurothrombectomy device prior to 6 hours from 
symptom onset 
16.  
Any other condition that, in the opinion of the investigator, precludes an endovascular 
 
procedure or poses a significant hazard to the subject if an endovascular procedure was 
 
performed. 

 
 
 
 
 
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3.3.3. Neuroimaging Inclusion Criteria: 
1. 
ICA or MCA‐M1 occlusion (carotid occlusions can be cervical or intracranial; with or 
without tandem MCA lesions) by MRA or CTA   
AND 
2. 
Target Mismatch Profile on CT perfusion or MRI (ischemic core volume is < 70 ml, 
mismatch ratio is > 1.8 and mismatch volume* is > 15 ml)  
 
Notes: The mismatch volume is determined by the RAPID software in real time based on the 
difference between the ischemic core lesion volume and the Tmax>6s lesion volume.  If both a CT 
perfusion and a multimodal MRI scan are performed prior to enrollment, the later of the 2 scans is 
assessed to determine eligibility. Only an intracranial MRA is required for patients screened with 
MRA; cervical MRA is not required.  Cervical and intracranial CTA are typically obtained 
simultaneously in patients screened with CTA, but only the intracranial CTA is required for 
enrollment. 
 
Alternative neuroimaging inclusion criteria (if perfusion imaging or CTA/MRA is 
technically inadequate): 
A) If CTA (or MRA) is technically inadequate:  
Tmax>6s perfusion deficit consistent with an ICA or MCA‐M1 occlusion  
AND 
Target Mismatch Profile (ischemic core volume is < 70 ml, mismatch ratio is >1.8 and 
mismatch volume is >15 ml as determined by RAPID software) 
  
B) If MRP is technically inadequate: 
ICA or MCA‐M1 occlusion (carotid occlusions can be cervical or intracranial; with or 
without tandem MCA lesions) by MRA (or CTA, if MRA is technically inadequate and a 
CTA was performed within 60 minutes prior to the MRI)  
AND 
DWI lesion volume < 25 ml 
  
C) If CTP is technically inadequate: 
Patient can be screened with MRI and randomized if neuroimaging criteria are met. 
 
3.3.4. Neuroimaging Exclusion Criteria: 
1. 
ASPECT score <6 on non‐contrast CT (if patient is enrolled based on CT perfusion 
criteria) 
2. 
Evidence of intracranial tumor (except small meningioma) acute intracranial 
hemorrhage, neoplasm, or arteriovenous malformation 
3. 
Significant mass effect with midline shift  
4. 
Evidence of internal carotid artery dissection that is flow limiting or aortic dissection  
5. 
Intracranial stent implanted in the same vascular territory that precludes the safe 
deployment/removal of the neurothrombectomy device 
6. 
Acute symptomatic arterial occlusions in more than one vascular territory confirmed on 
CTA/MRA (e.g., bilateral MCA occlusions, or an MCA and a basilar artery occlusion).   
3.4. Enrollment and Randomization 
3.4.1 Enrollment: All patients who meet the clinical criteria listed above are eligible for 

 
 
 
 
 
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enrollment. This includes both patients who are directly admitted to the study site and 
patients who are transferred from an outside hospital. The time of enrollment is the time 
when the informed consent is signed.  After obtaining consent the RAPID output from a CT 
perfusion or multimodal MRI scan will be assessed.  If the patient is confirmed to meet the 
neuroimaging eligibility criteria listed above and not have any of the neuroimaging exclusion 
criteria, then the patient will be randomized.  In general, patients will be consented prior to 
obtaining the RAPID output maps.   In some situations the CT perfusion/ multimodal MRI 
may have been performed as part of standard care prior to the patient being assessed for 
study eligibility. Patients who are consented but do not meet the imaging criteria will not be 
randomized. 
Determination of Target 
Mismatch and Large Artery 
Occlusion: At the conclusion 
of the MRI or CT Perfusion 
scan, the technologist sends 
the sequences from the 
console to RAPID with a 
single mouse click for 
automated processing. The 
RAPID software was 
developed based on data from 
DEFUSE 1 and was 
prospectively validated in 
DEFUSE 2.  The system 
provides fully automated 
processing of brain images. 
The RAPID output maps, which identify the volume and location of ischemic core and 
perfusion lesions, are emailed to investigators (protected health information is automatically 
removed) and auto‐sent to PACS as well as to a secure email system for viewing within 5 
minutes of completion of the scan. Immediately after the images are available, the 
investigator will review the results of the RAPID mismatch map (Figure 2) and the 
MRA/CTA to determine if the patient meets the imaging criteria (listed above).  If a patient 
has undergone multiple imaging evaluations (both MRI and CT or multiple CTs or MRIs), the 
most recent imaging study will be used to determine if the patient meets the imaging criteria.  
The accuracy of the software for identifying the size and location of perfusion and diffusion 
lesions has been established by extensive validation and testing on blood flow phantoms; the 
software received FDA 510K clearance for clinical use in 2013.  The agreement between local 
investigators and the Imaging Core Lab for identification of the mismatch profile in DEFUSE 2 
was 97%, κ 0·92; 95% CI 0·83–1· 
Baseline data will be captured for all consented patients, including for patients who do not 
meet the imaging criteria.  Patients who do not meet the imaging eligibility criteria will 
receive standard care per local hospital practice.  
 
3.4.2 Randomization using a Dynamic Stratification Algorithm:  Once a consented 
patient is determined to meet all Neuroimaging criteria, the patient will immediately be 
Figure 2. The RAPID mismatch summary allows investigators to 
quickly, accurately and easily determine if the patient meets the 
imaging criteria for enrollment.  The patient above meets the Target 
Mismatch criteria: core volume is < 70 ml, mismatch ratio is > 1.8 and 
mismatch volume is > 15 ml. 

 
 
 
 
 
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randomized on the WebDCUTM website.   A dynamic stratification system will ensure well‐
balanced subgroups. The randomization algorithm, which will be programmed into the data 
capture system, will employ biased‐coin minimization and the variance method with 
stratification weights.44  The strategy is to balance treatment assignment along the marginal 
distribution of each stratification factor. The stratification factors used will be: 1) age, 2) core 
lesion volume, 3) time from symptom onset to enrollment, 4) baseline NIHSS, and 5) study 
site.  When a new patient is enrolled, the site will enter the stratification factor values into 
the eCRF (electronic case report form) on WebDCUTM.  The dynamic randomization 
algorithm will determine an imbalance measure for each treatment group. The treatment 
group associated with the smallest imbalance measure will receive the largest probability of 
assignment in the biased‐coin randomization. The biased‐coin acceptance region and 
stratification weights are specified in the Randomization Plan.  The superior balancing 
characteristics of dynamic randomization over blocked randomization have been well 
established. 
Patients will be assigned to either endovascular therapy plus medical therapy or to medical 
therapy alone (1:1 randomization).  Crossover from medical to endovascular therapy is 
strictly prohibited; endovascular to medical therapy crossover is defined as a patient who is 
assigned to endovascular therapy but does not have a conventional angiogram performed.  
Endovascular to medical therapy crossover is only allowed if an endovascular 
contraindication arises after randomization. Sites will be closely monitored for crossovers 
(see site monitoring plan below).  
3.5 Acute Treatment   
3.5.1 Endovascular Therapy: In patients randomized to endovascular therapy, the goal for 
femoral artery puncture will be within 45 minutes of randomization; femoral artery 
puncture must occur within 90 minutes of the completion of the qualifying imaging.  Patients 
will be treated with thrombectomy devices (stent‐retrievers) and/or suction thrombectomy 
systems currently cleared by the FDA for thrombus removal in patients experiencing an 
acute stroke within 8 hours of symptom onset following the published instructions for use 
for these devices. These devices will be used up to 16 hours following symptom onset in 
DEFUSE 3 based on an FDA IDE. The devices which will be used are the Trevo Retriever, the 
Solitaire Revascularization Device, Covidien MindFrame Capture Revascularization Device 
and the Penumbra thrombectomy system. 
Standard medical therapy, based on current AHA guidelines, will also be provided for all 
patients. Individual investigators may use any of these devices or any combination of these 
devices to remove thrombus from the ICA, MCA M1 segment or, if needed, from M2 segments 
of the intracranial circulation.  These are all approved anatomic locations for these devices.  
The use of thrombectomy devices should be performed in accordance with the indications 
for use.  If there is a severe stenosis of the common carotid artery or the proximal internal 
carotid artery, investigators may also use other FDA devices approved for angioplasty or FDA 
devices approved for stenting of the carotid artery as deemed appropriate.  The use of 
adjuvant intra‐arterial (IA) thrombolytic medication is not currently approved by the FDA 
for stroke treatment and cannot be used in DEFUSE 3.  
Sites will use local protocols for femoral access, sedation, heparin infusion, monitoring, etc. 
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angiogram.  At the conclusion of the procedure, a post‐treatment angiogram as a cervical 
injection of the involved carotid circulation will also be obtained.   Imaging will cover the full 
region of the normal circulation in AP and lateral projections at 2‐3 films per second through 
the entire venous phase.  All brain imaging from stroke onset through hospital discharge, 
including the baseline MRI and CT, as well as angiographic images obtained for the diagnostic 
and therapeutic portions of the procedure, will be transmitted to the core lab.  
3.5.2 Medical Therapy: Patients randomized to medical therapy will receive standard 
medical therapy based on current AHA guidelines.  Based on the time window for DEFUSE 3, 
it is anticipated that very few of the patients enrolled in DEFUSE 3 will have received iv tPA 
prior to randomization (“tPA failures”).  For these patients, the sites’ post‐tPA protocol will 
be followed.  Non‐tPA treated patients randomized to medical therapy will be treated with 
aspirin, 325 mg on Day 1, and 81‐325 mg/day (investigator’s preference) on day 2‐5, unless 
an indication for early anticoagulation is present (as determined by the patient’s attending 
physician).  All patients will receive standard DVT prevention therapy.  Intravenous 
anticoagulants are prohibited (unless a clear indication for early anticoagulation is 
documented); dual antiplatelet therapy is prohibited unless carotid stenting was performed 
during the endovascular procedure or a clear indication for dual antiplatelet therapy is 
documented.  Subsequent antithrombotic therapy will be determined by the patient’s 
attending physician. 
3.6 Clinical and Imaging Evaluations 
Follow‐up (imaging and clinical): Randomized patients will be followed clinically for 90 
days and will have an MRI/MRA/MR perfusion at 24 hours (range 18‐30 hours) to assess 
infarct volume, recanalization, hemorrhage and reperfusion (Table 1 below). 
Table 1 Schedule of Events  
  
Screening Enrollment 
Baseline / 
Randomization
Endovascular
Procedure 
24 hours 
(+/‐6 hrs)
Hospital 
Discharge
Day 30 
(+/‐ 7 days)
Day 90 
 (+/‐ 14 days)
Screen Failure Log
X
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
Subject Enrollment 
 
X 
 
 
 
 
 
 
Inclusion and Exclusion Criteria
 
 
X
 
 
 
 
 
MRI or CTP 
 
 
X 
 
X++ 
 
 
 
Randomization
 
 
X
 
 
 
 
 
Medical History
 
 
X
 
 
 
 
 
Vital Signs
 
 
X
 
 
 
 
 
NIH Stroke Scale
 
 
X
 
X
X
X
X
Modified Rankin Scale
 
 
X+
 
 
X
X
X
Baseline ASPECTS Score
 
 
X
 
 
 
 
 
Baseline Labs*
 
 
X 
 
 
 
 
 
Endovascular Therapy 
 
 
X 
  
  
  
24 Hour Labs
 
 
 
 
X
 
 
 
Hospital Discharge
 
 
 
 
 
X
 
 
Adverse Event Assessment 
 
 
 
X 
X 
X 
X 
X 
NeuroQOL
 
 
 
 
 
 
X
 
 
 
 
 
 
 
 
 
*Laboratory Evaluation includes CBC with Platelets, Creatinine, Glucose, INR, activated PTT, and Pregnancy test (if 
applicable).  At 24 hour follow‐up only creatinine is required. + Historical mRS at baseline, mRS/NIHSS to be 
performed by an NIHSS/mRS certified member of the research team who is blinded to treatment allocation at 30 and 
90 days. ++ Patients will preferably undergo an MRI with MRA AND MR Perfusion at 24 hours; if an MR cannot be 
performed, a CT with CTA AND CTP can be substituted.  For patients who are consented but not randomized, the 
schedule of events is limited to a summary of stroke therapies received within 24‐hrs of stroke onset.  

 
 
 
 
 
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3.6.1 Assessments and follow‐up visits 
Baseline visit:  All items in Table 1 above listed under “baseline” are to be performed prior 
to randomization.   The MRI or CT scan should be performed with the DEFUSE 3 (baseline) 
protocol, which will be installed at all study sites.  In addition, the inclusion/exclusion page 
of the case report form must be completed to determine if the patient meets the eligibility 
requirements for the study. If the patient is eligible and the consent form is signed by the 
patient or authorized representative, then the randomization procedure should occur 
immediately.  
24 hour visit (+/‐ 6 hours):  The items listed for this visit in Table 1 should be performed 
between 18 and 30 hours from the time of randomization.  The only laboratory value 
required at the 24 hour visit is a serum creatinine.  If possible, the 24 hour follow‐up imaging 
study should be performed with multimodal MRI, rather than CT perfusion.  The MRI or CT 
scan performed at this time should be performed with the DEFUSE 3 protocol.   
Discharge visit: The items listed for this visit in Table 1 should be performed on the day of 
hospital discharge  
30 and 90 day visits: The items listed for this visit in Table 1 should be performed on Day 
30 (+/‐ 7) days and Day 90 (+/‐ 14) days.   The mRS score must be performed by an mRS 
certified investigator who is blinded to treatment allocation at both the 30 and 90 day visits.  
If an in person visit is not possible, then the mRS should be performed by phone by an mRS 
certified investigator who is blinded to treatment allocation.  If an in person visit is not 
possible, then the NIHSS score will be marked “not available” in the case report form.  
Neurological worsening: If clinical worsening (defined as a >4 point increase on the NIHSS 
score) occurs prior to discharge, a CT scan or MRI should be obtained as soon as possible.  
Neurological worsening is a reportable adverse event. 
 
3.6.2 Sources of Materials 
Information on the clinical status of patients will be obtained from the patient’s medical 
record. Study coordinators at the site will complete the DEFUSE 3 case report forms to 
collect basic demographic and medical information about the patients.  Data will 
subsequently be entered into the StrokeNet’s WebDCU electronic data capture system. 
Imaging data will be electronically transmitted to the coordinating center at Stanford via 
RAPID (all patient identifiers are removed by the software prior to exporting the data 
outside of the site’s firewall). All study sites will complete a stroke screening log that 
documents all patients treated in the cath lab beyond 6 hours at their center, and reason for 
exclusion of patients not enrolled, in the StrokeNet’s WebDCU electronic data capture 
system. Serious adverse events (SAEs) will be reported within 24 hours of the event in the 
StrokeNet’s WebDCU electronic data capture system. The data collection process will include 
patient demographics, medical history, vital signs, laboratory assessments, NIHSS and mRS 
scores, and results of diagnostic studies performed to clarify stroke etiology.  
 
3.7. Site Approval and Monitoring Plan 
Site approval: Individual sites approved for participation in the study will be high‐volume 
sites.   Selected sites will have access to emergent CT perfusion and/or MR imaging 24/7. 
Prior to activating a site, we will verify that RAPID is functional at the site. Together with the 

 
 
 
 
 
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site’s CT and/or MR technologists, we will install the DEFUSE 3 scan protocol on the local 
scanners and perform a dummy‐run to assess image quality and train the technologists in 
software handling and data sending. A site will be activated for enrollment after test cases 
processed with RAPID have ensured good quality maps.   
Monitoring for imaging quality: The Imaging Core Lab will monitor image quality 
throughout the study.  If significant inadequacies or protocol errors are noted at a site, 
enrollment will be halted.  Enrollment will resume after all imaging problems have been 
resolved and repeat dummy runs have been obtained that demonstrate adequate image 
quality. 
 
Table 2. Example Imaging Sequences for DEFUSE 3 scans 
Sequence 
Scan Parameters (3T) 
Time 
MRI 
 
   6 min 
 
Localizer 
128X256; 28 FOV;5/5mm, GRE 
24 sec 
 
Calibration 
 
5 sec 
 
DWI 
128x128, 24 FOV, 5/0mm, 30 slices, 1 NEX, R=2; b=0 and 1000 s/mm2 
over 3 axes, TE/TR=min/7000ms. 
25 sec 
 
GRE 
256x192; 24 FOV; 5/0 mm, 30 slices, TE/TR= 25/800ms, flip 20, 
interleaved EPI, 16 shots 
27 sec 
 
MRA 
intracranial 
256x192, 1 mm; 4 slabs, 26 phase-encodes; 6 overlap, 22 FOV, 0.8 rFOV, 
fractional echo, ZIPx2, ZIPx512, minTE, flowcomp, TR=18ms, flip=18, 
inferior->superior ramppulse, R=2; 19 MIPS 
143 sec 
 
PWI 
128x128; 24 FOV; 5/0 mm, 17 slices, TE/TR=35ms/1800ms, R=2 using 
0.1mmol/kg Gadolinium @ 4ml/sec. 
108 sec 
CT (example below for GE VCT; comparable protocols will be used for other scanner 
models) 
5-6 min 
 
Non-con head 
2.5 – 5mm, 40 slices, 120-140kV, 265-290mA 
120-180 
sec 
 
CTA 
0.625mm, 0.984:1/39.37cm, 120kV, 550mA , inject and observe for 15 
sec until contrast concentration in ascending aorta reaches 80HU (smart 
prep) then the CT gantry moves along with the bolus of the contrast 
material from the aortic arch up to the apex of the brain in 5sec. 
      90 sec 
 
CTP 
22 FOV, 40mm, 8x5mm, 1.8sec time interval, 45 cycles, 80kV, 125mA; 2 
runs 
90 sec 
 
Monitoring for bias: A detailed site‐monitoring plan has been developed to detect bias. This 
plan will protect the study from enrollment, randomization, and treatment bias. The first 
component involves monitoring the percentage of each site’s endovascular volume (within 6‐16 
hrs) that is enrolled in DEFUSE 3.  Sites will report their volume of endovascular stroke 
procedures (within 6‐16 hrs) each month on a screening log.  If a DEFUSE 3 eligible patient is 
treated with endovascular therapy outside the DEFUSE 3 study, an explanation will be required 
detailing why the patient was not enrolled. The second component of the plan involves tracking 
of patients who are consented but not randomized. These patients will require an entry in the 
WebDCU with an explanation why the patient was not randomized as well as documentation 
whether endovascular therapy was performed outside of the study. A third component involves 
monitoring of crossover after randomization. The Executive Committee will review the data 
described above for each site every 6 months. If evidence of enrollment bias is suspected, it will 
be investigated. If confirmed, the site will be placed on probation. If additional incidents of 

 
 
 
 
 
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suspected bias are confirmed, the site will be withdrawn. Routine monitoring of the clinical sites 
for source to database verification will be performed by the StrokeNet Data Management Center. 
 
3.8. Sample Size, Adaptive Design and Statistical Analysis 
DEFUSE 3 will feature a novel adaptive trial design that will allow the study to focus on a 
subpopulation if interim or final analyses indicate futility in the overall population.59  The 
adaptive design was developed specifically for DEFUSE 3. It is based on closed testing theory and 
the group sequential methods for the Generalized Likelihood Ratio (GLR) statistic developed by 
Lai and Shih.60  The adaptive design was chosen because there is strong preliminary data that 
suggests that the effect of endovascular treatment is modified by two baseline variables: core 
lesion size and time‐to‐treatment.  The way the adaptive design takes advantage of these 
biological assumptions (when they are true) is by reallocation of future accrual to the subgroup 
with the best prospects for showing efficacy. Specifically, if a subgroup is chosen at an interim 
analysis, subsequent enrollment is limited to patients in that subgroup.  As a result, this 
subgroup will become larger than it would have been in the absence of the adaptive design. 
The criterion for deciding which subgroup has the best chance of showing a benefit from 
endovascular therapy combines both the estimated size of the effect in the subgroup and the 
sample size of the subgroup.  The GLR statistic (Kullback‐Leibler criterion) is used to identify this 
subgroup because it optimally balances those two criteria. It selects the subgroup that has the 
best chance of showing an effect because it has an apparently large effect and is also of 
substantial size (note there are 5 subgroups of increasingly larger size, figure 3). The adaptive 
design employs two biologically‐based assumptions to limit the inflation of sample size; a 
monotonicity/contiguity assumption and an a prior assumption that the effect is largest in the 
patients with the smallest DWI lesions and the shortest 
time to randomization (cell C11 in figure 3).  The 
boundaries of the categories (cells) will be determined just 
prior to the 1st interim analysis based on the distribution of 
patients across these two dimensions (lesion volume and 
time‐to‐treatment). 
Primary analysis:  The primary endpoint is the 
distribution of scores on the modified Rankin Scale (mRS) 
at day 90.  We will test the null hypothesis at the interim 
and final analysis using a normal approximation of the 
Wilcoxon‐Mann‐Whitney test (the generalized likelihood 
ratio [GLR] test). The primary analysis will be intention to 
treat, adjusted for design and not adjusted for covariates. 
For each analysis, an efficacy bound will be set to control 
the overall (one‐sided) Type I error rate at 2.5%.  At each 
interim analysis a futility bound will be set to decide if the 
study should continue recruitment in the overall group, 
shift accrual and testing to a subgroup, or stop in its 
entirety.  The futility boundary adapts when a subgroup is 
selected to the fact that the maximum analyzed sample size 
is a random variable that is no larger than the fixed 
maximum number of patients randomized (n=476).  Because subgroup selection reduces the 
Figure 3.  The cohort is stratified 
according to core lesion volume and 
time to randomization.  Exact 
boundaries of the stratification will be 
determined based on the distribution of 
patients just prior to the first interim 
analysis.  Depending on the results of 
the 1st interim analysis, subsequent 
enrollment will continue in all 6 cells or 
will be limited to one of 5 sub-groups 
(C11, C11+21, C11+21+12, C11+21+12+22, or 
C11+21+12+22+13).

 
 
 
 
 
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maximum number of patients available for analysis at completion of the study, this method 
effectively allows an easier futility stop after subgroup selection. This setup replaces conditional 
power analyses with an automatic and more powerful adjustment of boundaries.   
First interim analysis (n=200 randomized and completed 90 day follow‐up): The null 
hypothesis is tested in the entire patient population: 
1. If neither efficacy nor futility bound is crossed, the trial continues enrollment to the 2nd 
interim analysis. 
2. If the efficacy bound is crossed, the trial stops and efficacy is declared in the overall 
population. 
3. If the futility bound is crossed, the optimal subgroup is selected based on the Kullback‐
Leibler criterion and the null is tested in that subgroup.  The futility bound is relaxed as 
described above, based on the expected maximum number of patients in the trial at 
completion (ie 476 minus the number of patients already enrolled in cells that will no longer 
be open for enrollment). 
3.1. If neither bound is crossed, the trial will continue with enrollment limited to the 
selected subgroup 
3.2. If the efficacy bound is crossed, the trial stops and efficacy is declared in the selected 
subgroup 
3.3. If the futility bound is crossed, the trial stops for futility. 
 
Second interim analysis (n=340 randomized and completed 90 day follow‐up): If, after the 
first interim analysis, the study proceeds with enrollment in the overall population (option 1 
above), the testing at the 2nd interim analysis is identical to the first interim.  If enrollment is 
limited to a selected subgroup (option 3.1), the null is tested in that subgroup: 
1. If neither bound is crossed, the trial continues to the final analysis with enrollment of 136 
additional patients limited to the selected subgroup 
2. If the efficacy bound is crossed, the trial stops and efficacy is declared in the selected 
subgroup 
3. If the futility bound is crossed, the trial stops for futility. 
 
Final analysis (n=476 randomized and completed 90 day follow‐up): If, after the second 
interim analysis, the study proceeds with enrollment in the overall population, the null is tested 
in the overall population: 
1. If the efficacy bound is crossed, endovascular therapy is declared efficacious in the overall 
population. 
2. If the efficacy bound is not crossed, the optimal subgroup is selected and the null is tested in 
that group: 
2.1. If the efficacy bound is crossed, endovascular therapy is declared efficacious in that 
subgroup 
2.2. If the efficacy bound is not crossed, endovascular therapy will be declared of no benefit. 

 
 
 
 
 
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If enrollment after one of the interim analyses is limited to a selected subgroup, the null will be 
tested in that subgroup only and efficacy or lack thereof will be declared as per options 2.1 and 
2.2 above. 
Power and sample size considerations: The projected overall effect of endovascular therapy is 
based on 1) the observed 90‐day modified Rankin Scale outcomes in DEFUSE 2 of target 
mismatch patients treated >6hrs after symptom onset and 2) the assumption that early 
reperfusion will be achieved in 75% of the endovascular arm vs. 20% of the medical therapy 
arm.20, 21, 61 Using these data, we projected the distributions on the mRS at 90 days in the 
endovascular and control arms of DEFUSE 3:  
 
mRS at day 90 
 
0 
1 
2 
3 
4 
5 
6 
Total 
Endovascular group 
18.0% 
11.5% 
19.6% 
11.5% 
16.4% 
11.5% 
11.5% 
100% 
Medical group 
9.7% 
7.9% 
15.0% 
17.7% 
14.4% 
17.7% 
17.7% 
100% 
 
This distribution corresponds to a standardized effect of 0.36 for the primary analysis.  Based on 
these data, the fixed sample size for a non‐adaptive design requires a total of 376 patients 
(188/arm) to have 90% power at an alpha of 5% (Wilcoxon‐Mann‐Whitney test); 100 additional 
patients are added for the adaptive design to reach a maximum sample size of 476 for DEFUSE 3.   
We ran simulations (n=5000) to compare the performance of a traditional fixed sample‐size 
design (fixed n=476) to the adaptive design (max n=476) under various scenarios (see Table 3, 
below).  For the simulations the effect size is expressed as a standardized effect, where a 
standardized effect of 0.3 corresponds to a conservative projected effect of endovascular therapy 
(anticipated effect 0.36; see above). 
Imaging outcomes: We hypothesize that endovascular treatment improves radiological 
outcomes in stroke patients with favorable clinical and imaging characteristics.  DEFUSE 2 
demonstrated a substantial reduction in infarct growth among Target mismatch patients treated 
in the 6‐12 hour time‐window who achieved early reperfusion: median growth 0.5 ml (IQR: ‐2 – 
10) with reperfusion (n=23) vs. 39 ml (IQR: 18‐121) without reperfusion (n=13), p<0.001. These 
data have been extrapolated to DEFUSE 3 using the same assumptions described above; 
anticipated an early reperfusion rate of 75% in the endovascular arm vs. 20% in the medical 
arm.  This yields a sample size of 42 per group for 90% power.  Therefore, DEFUSE 3 is highly 
powered to demonstrate differences in lesion growth.  Infarct volumes, ischemic lesion growth, 
and reperfusion rates at 24 hours will be compared between groups with the Mann‐Whitney U 
test. The 24 hour endpoint is based on data demonstrating that assessment of infarct volume at 
24 hours captures the effect of reperfusion therapies on infarct growth and predicts outcomes 
similarly to day 90 infarct volumes.29, 62  RAPID‐assessed ischemic core volume at baseline will 
be correlated with 24h infarct volume (DWI volume) in subjects who achieve reperfusion 
without PH1 or PH2 intracranial hemorrhage.  Pearson’s correlation coefficient will be calculated 
and the median absolute error (ml) will be reported.  Similarly, correlation of the baseline Tmax 
>6 volume and the 24h infarct volume in patients without PH1 or PH2 intracranial hemorrhage 
who have <10% reperfusion will be performed. Correlation of RAPID predicted infarct volume 
(coregistered baseline ischemic core and 24h Tmax >6 volume) with the actual 24h infarct 
volume will also be performed.  

 
 
 
 
 
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Scenario 
Standardized effect in cells  
C11, C12, C21, C22, C31, C32 
Average 
standar
d. effect 
Adaptive Design 
Fixed Design 
Average 
No. 
randomized 
Power 
Number 
randomized 
Power 
#0 
0 
0 
0 
0 
0 
0 
0 
361 
2.2% 
476 
2.5% 
#1 
0.3 
0.3 
0.3 
0.3 
0.3 
0.3 
0.3 
354 
80% 
476 
89% 
#2 
0.5  0.4 
0.3 
0 
0 
0 
0.2 
400 
86% 
476 
55% 
#3 
0.5  0.5 
0 
0 
0 
0 
0.17 
403 
87% 
476 
41% 
Table 3. Under the null (Scenario #0), the adaptive design controls the total Type 1 error below 2.5%, stops 
early for futility 63% of the time, and the average number of randomizations is 361. If the effect is uniform across 
cells (scenario #1), the fixed-sample design is optimal, but the adaptive design results in only a small loss of 
power (from 89 to 80%). The adaptive design performs much better (higher power and smaller expected sample 
size) than the fixed sample, conventional trial when the effect size distribution across the subgroups is in accord 
with the biological assumptions (scenarios #2 and 3). If the effect is concentrated in two cells with small core 
volumes (scenario #3), the adaptive design maintains power (87%) while the conventional design collapses (41% 
power). The adaptive design also performs well compared to a non-adaptive, fixed sample that includes efficient 
multiple comparisons-adjusted testing for effect in subgroups at the end of the study. (see Lai et al59) 
Secondary analysis: Our secondary endpoint is the proportion of patients with mR S 0‐2 at day 
90 (indicating functional independence).  The difference in the proportions of patients with mRS 
0‐2 between treatment arms will be assessed using logistic regression. 
Subgroup analyses: Subgroup analyses of the effect of endovascular therapy on the primary and 
secondary endpoints will be performed.  Subgroups will be defined based on the stratification 
variables, key demographic factors (such as race and ethnicity), tPA vs. no tPA, CTP vs. MRI 
selection, and witnessed vs. unwitnessed symptom onset, wake‐up vs non‐wake‐up stroke, and 
TICI 0‐2a vs. TICI 2b/3 results in cath lab.   
Missing data/lost to follow‐up (LTFU):  
All effort is put forth to ensure near complete follow‐up, in particular with the assessment of the 
primary outcome (mRS at 90 days), death (mRS=6), and stroke recurrence.  If the primary 
outcome (mRS at 90 days) cannot be assessed in the clinic, it will instead be obtained by phone 
using a structured interview.  If the subject’s mRS cannot be obtained in clinic or by phone within 
the window of 60 to 120 days from randomization, then for primary analyses the day 30 mRS 
score will be used as the primary outcome (ie day 30 mRS carried forward).  If neither the 30‐
day nor the 90‐day mRS is available, then the mRS will be imputed. We do not expect this to alter 
the main study results given our estimated very low LTFU rate (<2%). 
DEFUSE 3 Timetable 
 
 
 
 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
 Install RAPID at 
all sites 
 Begin 
enrollment 
(anticipated to 
begin mid‐
year) 
 Pt 
enrollment 
continues 
for a total of 
4 yrs 
1st interim 
analysis 
Potential 
modification of 
enrollment criteria  
based on adaptive 
design 
2nd interim 
analysis 
Potential 
modification of 
enrollment 
criteria  based on 
adaptive design 
 Finish 
enrollment 
 Data Analyses 
 Publication of 
results 

 
 
 
 
 
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3.9. Risk analysis  
Description and analysis of all increased risks to the research subjects: 
 
Potential complications of MRI scan include localized twitching sensation due to the 
magnetic field changes during the scan, anxiety due to claustrophobia and allergic reaction to 
the contrast agent.  The allergic reaction may include headache, nausea, rash, hives, nasal 
congestion, sneezing, itching or swelling. If a severe reaction occurs, swelling of the throat, 
chest tightness, or a marked drop in blood pressure may occur.  In addition, pain, bleeding, 
bruising, coldness or inflammation at the injection site may occur. Precautions will be taken 
for early detection and rapid treatment if such reactions occur.  
 
Potential complications of CT scan include radiation exposure and allergic reaction to CT 
contrast agents. 
 
Radiation doses: 
Combined scanning with comprehensive stroke imaging, which includes a noncontrast head 
CT scan, perfusion imaging, and CT angiography of the cervicocranial vessels starting at the 
aortic arch results in a dose of approximately 7‐10 mSv. (AJNR 2010 31: 1003‐1009). 
According to the National Council on Radiation Protection and Measurement, the average 
annual radiation dose per person in the U.S. is 620 millirem (6.2 milliSieverts). 
 
Reactions to contrast agents: 
 Mild 
Nausea, Vomiting, Headache, Cough, Nasal stuffiness, Altered taste, Flushing, Itching, 
Rash, Hives, Sweats, Swelling of eyes or face 
 Moderate 
Mild hypotension, Tachycardia or Bradycardia, Bronchospasm, Wheezing, Dyspnea, 
Laryngeal edema, Generalized or diffuse erythema 
 Severe 
Cardiopulmonary arrest, Clinically manifested arrhythmias, Profound hypotension, 
Convulsions, Unresponsiveness, Respiratory failure, Laryngeal edema  
The rate of major reactions (e.g., anaphylaxis, death) is very low, estimated at one in 
170,000 administrations. 
 
Potential complications of endovascular therapy include stroke; new clot in an artery; 
total blockage of an artery; infection and pain in the region of insertion site; lack of blood 
flow to the brain; rupture or puncture of an artery; significant tearing of the vessel wall; 
bleeding requiring blood transfusion; allergic reaction to contrast dye; abnormal low blood 
pressure requiring treatment; temporary closing of the artery (vessel spasm); formation of 
or dislodgments of clots which block the arteries (embolism).  In rare circumstances, the 
procedure could result in death. At the puncture site in the groin, a blood clot or other blood 
vessel injury may occur and require blood transfusion or surgical repair. Infection may occur 
at the puncture site; this could cause pain and require additional medications.  There is some 
chance of an allergic reaction to the x‐ray contrast (dye) used during the angiogram 
procedure.  Minor allergic reactions may include a rash or hives.  There is also the possibility 
of a serious allergic reaction that could include shortness of breath and swelling, drop in 

 
 
 
 
 
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blood pressure, and even death.  Patients will be closely monitored for these reactions and 
receive prompt treatment to reverse any allergic reactions. 
 
Safety of endovascular therapy beyond 8 hours 
Mechanical thrombectomy devices have been used beyond 8 hours of stoke onset in a 
number of clinical trials and registries.  No safety concerns have been associated with late 
window therapy.  In DEFUSE 2 37, patients were treated up to 12 hours after symptom onset, 
and no safety concerns were identified in any time window.  Based on both favorable safety 
data and encouraging efficacy data, Stryker Neurovascular has initiated the DAWN Study 
with a 24 hour treatment window.  No safely issues have been identified to date in DAWN.  
The DAWN study is being run under an FDA IDE. 
 
Methods to mitigate risks to subjects in the trial 
Methods to mitigate risks to subjects in the trial include exclusion of subjects with bleeding 
disorders and selection of subjects via neuroimaging (infarct core lesions less than 70 ml) to 
minimize the risk of symptomatic intracranial hemorrhage. Computed Tomography (CT) scans 
will be performed for neurological deterioration (≥ 4 point increase in National Institutes of 
Health Stroke Scale (NIHSS) score) to identify new strokes, hemorrhage, or edema.  Hospitals 
will follow their local standard of care safety procedures in order to reduce the risk of kidney 
dysfunction caused by contrast agents.   Only investigators who are trained and experienced 
with use of the devices allowed within the trial are eligible to participate (see Site Approval 
and Monitoring Plan) above. The adaptive design will eliminate subgroups with an 
unfavorable therapeutic response. 
 
Patients will be carefully screened for CT, MRI and endovascular treatment contraindications 
according to the inclusion/exclusion criteria and excluded from enrollment if any are present. 
 
Radiation exposure: Radiation exposure during all tests will be minimized by optimizing the 
imaging protocols and by limiting fluoroscopy‐time during the endovascular procedure.  All 
CT sequences, including the CTP sequence, meet all FDA guidelines for radiation exposure.   
 
Stopping rules or safety triggers for the study 
Symptomatic ICH or death rates that exceed pre‐specified thresholds will trigger a meeting of 
the DSMB to discuss the events and make a determination on the continuation of the trial.   
Below are the pre‐specified triggers: 
 
The DEFUSE 3 has established the following automatic stopping rules, based on identifying with 
95% probability:  
 
1) the rate of symptomatic ICH (NIHSS worsening of 4 or more points associated with ICH) in 
the endovascular group is exceeding 10%  
2) the rate of 90 day mortality in the endovascular group is exceeding 20%. 
 
If either threshold is crossed, the study will be automatically placed on hold until the 
investigators and the DSMB can conduct a review of events. 
 

 
 
 
 
 
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Adverse events (AEs) will be collected, recorded, and analyzed in accordance with Section 
3.11 below.  
 
Safety oversight for this study will be provided by both the DSMB and an independent 
Medical Safety Monitor.  Please see Section 3.11 for details. 
 
Patient Population:  Four hundred and seventy six acute stroke patients meeting the pre‐
defined inclusion criteria will be enrolled in the trial.  The mean age is anticipated to be 69 
years of age.  Our targeted planned enrollment breakdown is as follows:  
 
Racial Categories 
Ethnic Categories 
Total 
Not hispanic or 
Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/Alaska Native 
2 
2 
1 
1 
6 
Asian 
13 
13 
1 
1 
28 
Native Hawaiian or Other Pacific 
Islander 
2 
3 
0 
0 
5 
Black or African American 
32 
32 
1 
1 
66 
White 
175 
174 
11 
11 
371 
Racial Categories: Total of All 
Subjects  
224 
224 
14 
14 
476 
 
Imaging core lab: The Stanford imaging core lab has 15 years of experience with MR image 
storage and processing. It will perform the organization, archiving and blinded analysis of all 
imaging data collected in DEFUSE 3.  They will be responsible for MRI and CT Perfusion 
image processing and artifact removal and will generate final lesion volumes for all MRI 
scans performed in the study. 
DSA Angiograms sent to the core lab will include a baseline (pre‐treatment) and a final 
angiogram for the territory of treatment.  In addition, angiographic images from MRA or CTA 
will be sent to the core lab.  The MRA or CTA will be used to assign a primary arterial lesion 
(AOL) from non‐invasive imaging.  The baseline DSA angiogram will also be used to assign a 
primary arterial occlusive lesion (AOL) and a pre‐treatment mTICI score.  The final 
angiogram will have a post‐treatment mTICI score assigned.22,52  This scoring system defines 
TICI 2A as partial perfusion of < 50% of the vascular distribution of the occluded artery and 
2B as partial perfusion of > 50% of the vascular distribution. The scoring system will use 
these previously described definitions22:  
 Grade 0 No perfusion 
 Grade 1 Antegrade reperfusion past the initial occlusion, but limited distal branch 
filling with little or slow distal reperfusion 
 Grade 2a Antegrade reperfusion of less than half of the occluded target artery 
previously ischemic territory (eg, in 1 major division of the MCA and its territory) 
 Grade 2b Antegrade reperfusion of more than half of the previously occluded target 
artery ischemic territory (eg, in 2 major divisions of the MCA and their territories) 

 
 
 
 
 
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 Grade 3 Complete antegrade reperfusion of the previously occluded target artery 
ischemic territory, with absence of visualized occlusion in all distal branches 
Two senior neurointerventionalists will perform the angiographic analysis, blinded to the 
clinical data, MR imaging and CT Perfusion results, and the analysis of the other core lab 
reader.  Any disagreements in the AOL interpretation or the mTICI scores will be adjudicated 
by common review of those cases and a consensus reading will be applied.    
National Data Management Center: Data management and site monitoring will be 
performed by the StrokeNet National Data Management Center (NDMC) at Medical 
University of South Carolina (Director, 
, PhD, see letter of support).  The 
NDMC will create the database and set up the interface on the website (WebDCU™) where 
clinical site personnel will enter the data into the electronic CRF. Data quality assurance 
processes include: (1) logic and rule checks built into the database; (2) monitoring by the 
Data Manager at the NDMC; (3) central monitoring by the statistical programmer at the 
NDMC; and (4) risk‐based source verification monitoring by the Clinical Research Associates.  
DEFUSE 3 data, including neuroimaging, will be shared in accordance with the StrokeNet 
data sharing policies. Anonymized neuroimaging will be stored on secure servers at the 
Stanford Stroke Center with nightly back‐up. NINDS Common Data Elements will be used for 
both clinical and imaging data.   
 
3.10. Description of devices 
The following FDA approved thrombectomy devices will be included: 
1) Trevo Retriever 
2) Solitaire™  Revascularization Device 
3) Covidien MindFrame Capture Revascularization Device 
4) Penumbra thrombectomy system including the following devices and pumps: 
 
 
 
Penumbra Aspiration Pump (1115V) 
Penumbra System [026, 032, 041]  
Penumbra System 054 
Penumbra System Separator Flex [026, 032, 041, 054]  
Penumbra System MAX 
Penumbra Pump MAX 
Penumbra System 110 Aspiration Tubing 
Penumbra System Reperfusion Catheter ACE64 & ACE68 
 
3.11. Monitoring procedures 
The coordination of the DEFUSE 3 Trial operations will be centralized through the following: 
NIH StrokeNet National Coordinating Center (NCC)/ PI: 
, MD 
University of Cincinnati 
 
Cincinnati, Ohio 
 
 
Leading the NCC team will be the Project Manager, who will be assigned to coordinate the 
following study oversight: trial communication required training activities, site assessment 
and/or initiation visits, collection of trial related regulatory documents, recruitment 
performance tracking, site monitoring, and performance analysis.  Study oversight will be 
handled according to the Data Monitoring Standard Operating Procedure (SOP Number ADM 
19).   
 

 
 
 
 
 
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DEFUSE 3 will have an independent Data and Safety Monitoring Board (DSMB) appointed by 
the NIH to oversee study safety.  Patients in both study arms will be assessed for the 
incidence of stroke‐related mortality at 90 days, the incidence of symptomatic intracranial 
hemorrhage at 36 hours from symptom onset (defined as a ≥ 4 point worsening of immediate 
pre‐deterioration NIHSS neurological status vs. post deterioration and associated with brain 
hemorrhage), and the incidence of significant neurologic deterioration prior to discharge 
(defined as ≥ 4 point worsening of the immediate pre‐deterioration NIHSS neurological 
status vs. post deterioration and not attributed to sedation).  In the endovascular arm 
patients will be assessed for intra‐procedural complications including: intra‐procedural 
mortality, vessel perforation, arterial dissection, access site complication requiring surgical 
repair or blood transfusion, embolization and device failure. SAEs will be reported within 24 
hours of awareness of the event.  
 
The DSMB will meet in person or by teleconference, on a semi‐annual basis, to monitor the 
cumulative safety data during participant follow‐up.  In no instance will more than 12 
months elapse between DSMB reviews of cumulative safety data after the first participant 
has been randomized.  The DSMB will monitor the study according to the guidelines specified 
in the study protocol and the operating procedures established at the initial meeting, unless 
the DSMB determines during the course of the trial that modification of the guidelines is in 
the best interest of the study and its participants. 
    
Independent Medical Safety Monitor:  
In addition to the DSMB, Dr. 
 has been appointed as the independent 
Medical Safety Monitor (MSM) for DEFUSE 3.  Dr. 
 is not involved in the study and 
has no conflict of interest.  He will be responsible for ongoing monitoring of reports of SAEs 
submitted by the clinical centers in real time to ensure good clinical practice and to identify 
safety concerns quickly.  Dr. 
 may suggest protocol modifications to prevent the 
occurrence of particular AEs, e.g., modifying the protocol to require frequent measurement of 
laboratory values predictive of the event or to improve expeditious identification of SAEs. In 
the event of unexpected SAEs or an unduly high rate of SAEs, Dr. 
 will promptly 
contact the DSMB Liaison who will notify the DSMB Chair.  In the event that he is unavailable 
for an extended period of time (i.e., extended vacation, sabbatical, illness, etc.), a back‐up 
MSM will be nominated by the study PI and approved by the DSMB.  
 
Adverse Event Reporting 
Consideration of adverse events will hereafter consist of adverse events, serious adverse 
events, and adverse device effects, including anticipated adverse device effects and 
unanticipated adverse device effects. 
• Adverse event (AE) is defined as any untoward/undesirable clinical occurrence in a 
clinical investigation of a subject which does not necessarily have a causal 
relationship with the treatment under investigation. An Adverse Event can therefore be 
any unfavorable and/or unintended sign, symptom, or disease temporally associated 
with the use of a device product, whether or not considered related to the device 
product. Only abnormal laboratory values that are deemed clinically significant by the 
investigator will be classified as adverse events. 
 

 
 
 
 
 
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• Serious adverse event (SAE) is defined as any untoward/undesirable adverse 
experience that results in any of the following outcomes: 1) death; 2) a life‐
threatening adverse experience; 3) inpatient hospitalization or prolongation of 
existing hospitalization; 4) a permanent/persistent or significant 
disability/incapacity or a congenital anomaly/birth defect; 5) important medical 
events 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, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. This category 
includes the use of intra‐arterial thrombolytics and/or intracranial stents. 
 
• Anticipated adverse device effect (AADE) is defined as any adverse effect related to 
the device or procedure, which is identified in the protocol or the IFU for the device. 
 
• Unanticipated Adverse Device Effects (UADEs) is defined as any serious adverse 
effect on health or safety or any life‐threatening problem or death caused by, or 
associated with a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application, or 
any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects. 
 
Reports of UADEs will be made to the FDA within 10 days of receiving notification of the UADE 
(as required in 21 CFR 812 18p (b)(1)). 
 
Safety Monitoring 
The MSM will monitor all AE reports to identify and trend all events that would require 
temporary discontinuation of study enrollment, to fully characterize device safety, to modify 
the study protocol, or to terminate the study. 
 
Reporting Procedures for All Adverse Events 
All Adverse Events, whether or not attributed to the study and/or the devices, observed by the 
investigator or reported by the subject, will be recorded from the time of randomization 
through Day 5 or discharge, whichever is earlier.  All SAEs will be recorded through Day 90. 
 
The following attributes w i l l  be assigned by the reporting investigator: 
 
1. Description of event 
2. Date of onset 
3. Date of resolution (if applicable) 
4. Seriousness 
5. Relationship to the study device and/or procedure(s) 
6. Severity 
7. Action(s) taken 
8. Outcome(s) 
  

 
 
 
 
 
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Severity is defined as a measure of the intensity of a reaction, effect or experience. The 
measurement(s) are described as mild, moderate, severe, life threatening or death. The event 
itself, however, may be of relative minor medical significance. The severity of Adverse Events 
is assessed according to the following index scale: 
 
 Mild 
asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated  
 Moderate 
minimal, local or noninvasive intervention indicated; limiting age‐appropriate 
instrumental Activities of Daily Living.  
 Severe 
medically significant but not immediately life‐threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care Activities of Daily 
Living.  
 Life‐threatening consequences;  
urgent intervention indicated 
 Death related to AE 
 
The relationship of an AE to the study device or procedure will be graded as follows: 
 Unrelated 
 Unlikely  
 Reasonable possibility 
 Definitely 
 
Serious Adverse Events All Serious Adverse Events including deaths will be reported to 
the MSM, the Central Institutional Review Board (IRB) and the FDA, as required. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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4. 
INVESTIGATOR’S AGREEMENT 
As this study will be carried out by the NIH StrokeNet, the names of the specific sites and 
investigators are not yet available.  Investigator’s agreements for key investigators at the 
coordinating site are included.  
 
All investigators will be required to sign the following agreement: 
 
INVESTIGATOR AGREEMENT 
FOR THE CLINICAL INVESTIGATION OF THE DEFUSE 3 TRIAL 
 
I___________________________________________________ agree to participate as an Investigator on the 
DEFUSE 3 trial. 
 
I have been provided a copy of the following Food and Drug Administration (FDA) regulations: 
21 CFR Part 812, Investigational Device Exemptions; 21 CFR Part 50, Protection of Human 
Subjects; and 21 CFR Part 54, Financial Disclosure by Clinical Investigators. 
 
I agree and/or certify that: 
 
1. I will conduct the clinical investigation in accordance with this agreement, all requirements 
of the investigational plan, IDE regulations, other applicable regulations of the FDA, and 
any conditions of approval imposed by my reviewing Institutional Review Board (IRB) or 
FDA.  I agree to abide by all of the responsibilities of Investigators addressed under 21 CFR 
Part 812, Subpart E and Subpart G, including but not limited to the following: 
 
2. I will obtain written approval from the authorized IRB for the institution at which this 
investigation will be conducted.  
 
3. I will ensure that Informed Consent is obtained from each subject participating in this 
clinical investigation in accordance with the informed consent regulation found in 21 CFR 
Part 50, and that a signed copy of the informed consent is available to the sponsor 
(sponsor-investigator) and the sponsor’s (sponsor- investigator’s) designated monitor. 
 
4. I will ensure the accurate completion of protocol case report forms and, if I am not also the 
sponsor- investigator of the corresponding IDE application, I will submit completed 
protocol case report forms to the sponsor (sponsor-investigator) at the time frames 
specified in the Protocol and/or FDA regulations. 
 
5. I have the appropriate, relevant qualification to conduct and to oversee the conduct of the 
clinical investigation as documented by the following: (initial applicable statement) 
____ My relevant qualifications, including dates, location, extent and type of experience are 
listed in my most recent curriculum vitae (CV), which is attached to the Agreement and 
which will be maintained by the sponsor (sponsor-investigator) of the corresponding IDE 
application. 
____ My curriculum vitae (CV) does not reflect my relevant qualifications, therefore 
attached to this Agreement is a statement of my relevant experience (including dates, 

 
 
 
 
 
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location(s), extent and type of experience) which will be maintained by the sponsor 
(sponsor-investigator) of the corresponding IDE application. 
 
6. There are no reasons to question my ability to oversee the appropriate conduct of this 
clinical investigation.  (Initial applicable statement) 
____ I have never participated in an investigation or other research activity which was 
terminated (disqualified) by the FDA, IRB (or equivalent), or sponsor of a study due to 
non-compliance issue. 
____ I have participated in an investigation or other research activity which was terminated 
(disqualified) by the FDA, IRB (or equivalent), or sponsor of a study due to non-
compliance issue.  The specific circumstances leading to this termination and my role in 
the respective problems or issues and the resolution of these problems or issues are 
summarized in an attachment to this Agreement. 
 
I further certify that I have not been debarred under the Generic Drug Enforcement Act of 1992, 21 
USC §§ 335a and 335b.  In the event that I become debarred or receive notice of an action or threat of action 
with respect to my debarment during the term of this Agreement, I agree to immediately notify the sponsor 
(sponsor-investigator) and the authorized IRB for my study site.  If I am the sponsor-investigator of the 
corresponding IDE application I will notify the authorized IRB and the FDA. 
 
As required by 21 CFR Part 54, Financial Disclosure by Clinical Investigator, I will disclose sufficient and 
accurate financial information to the sponsor (sponsor-investigator) by completing the Certification of 
Financial Interest Form (attached) and if applicable, the Disclosure of Financial Interest Form (attached).  I 
will also notify the sponsor (sponsor-investigator) if my disclosed financial information changes at any time 
during the clinical investigation or up to one year following the closure of the study. 
 
 
Site Name and Address: 
__________________________________________ 
__________________________________________ 
__________________________________________ 
                                                             ________________________________________           __________ 
                                                                      Investigator Signature                              Date 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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5. EXECUTIVE COMMITTEE / KEY PARTICIPATING INVESTIGATORS 
The Executive committee, composed of experts in vascular neurology, endovascular therapy 
and neuroimaging, will provide the overall scientific guidance for the study.  The committee will 
typically meet monthly by phone (1 hour/month) for the full duration of the study.  
Responsibilities include oversight of the overall conduct of the study with regard to protocol 
compliance and modifications/amendments, study progress, and problem‐solving. Dr. Albers 
will chair the executive committee. 
 
Key Participating Investigators at Coordinating Site 
 
Gregory W. Albers, MD
Principal Investigator 
Stanford Stroke Center 
780 Welch Rd.  Suite 350 
Palo Alto, CA 94305 
650‐723‐4448 
galbers@stanfordmed.org 
Michael Marks, MD
Co‐Principal Investigator 
Stanford University Medical 
Center 
300 Pasteur Dr. 
Stanford, CA 94305‐5105 
650‐723‐6767 
mmarks@stanford.edu  
Maarten Lansberg, MD, PhD
Protocol Director 
Stanford Stroke Center 
780 Welch Rd.  Suite 350 
Palo Alto, CA 94305 
650‐723‐4448 
lansberg@stanford.edu 
 
 
6. 
INSTITUTIONAL REVIEW BOARD 
The University of Cincinnati Institutional Review Board will serve as the National Central 
Institutional Review Board for all participating sites.  The Central Institutional Review 
Board (CIRB) for multicenter protocols is the single IRB of record. It has regulatory 
responsibility for assuring the protection of the rights and welfare of research participants in 
accordance with Standard Operating Procedure ADM 12; Central Institutional Review Board 
Reporting. The National Institute of Neurological Disorders and Stroke (NINDS) selected the 
University of Cincinnati Institutional Review Board (IRB) to serve as the CIRB for the NIH 
StrokeNet (StrokeNet). 
 
University of Cincinnati IRB Registration # 00000180 FWA #: 00003152 Expiration Date: 
6/27/2016 
 
, PhD, CIP 
Chairman CIRB 
 
 
  
 
 
 
 
7. COSTS 
All of the eligible devices that will be used in this study are currently on the market. There 
will be no charges beyond the typical standard of care for use of these approved devices.  
These devices will be used and billed according to the standard of care for each institution. 
 
 
 
 

 
 
 
 
 
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APPENDIX 
 
I. 
DEFUSE 3 Patient Informed Consent Form