The Capillary Index Score Trial: Phase I
Phase: PHASE1
Conditions: Acute Stroke, Brain Ischemia, Ischemic Stroke
Sponsor: Firas Al-Ali

 
 
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Research Protocol 
Title: The CIS Trial 
Principal Investigator: Firas Al-Ali, MD 
Other Investigators: John J. Elias, PhD 
Andrea Jenkins, RN 
Cindy Cole, RN 
Georges Markarian, MD 
Institutional affiliations: Akron General Medical Center 
 
I. 
BACKGROUND AND SIGNIFICANCE 
 
A. Treatment for patients who suffer an ischemic stroke typically depends upon a fixed and 
arbitrary time window. Therapy typically includes intra-venous treatment (IVT) for 
patients who present within 4.5 hours of beginning of symptoms and intra-arterial 
treatment (IAT) for patients who arrive within 8 hours of symptomatic onset as the 
standard of care [1]. During IVT, tissue plasminogen activator (tPA) is injected into a 
vein in the arm. IAT is an endovascular procedure in which a catheter is inserted into an 
artery and directed to the site of the blocked blood vessel in the brain.  The clot is 
removed using a mechanical device with or without an injection of tPA directly at the site 
of the clot.  Several types of mechanical devices are approved for clinical use. Not all 
patients who arrive within this fixed time window receive IVT or IAT, since certain 
defined subgroups of patients do not improve despite complete revascularization (i.e. 
opening of the occluded blood vessel) within the accepted time window. 
 
Patients who should not be treated include those who demonstrate large areas of 
hypodensity (i.e. dark tissue) on head computerized tomography (CT) scan, those with an 
intracranial hemorrhage, and those with other stroke mimics such as herpetic 
encephalitis. [2,3] To further improve the criteria for determining which patients should 
receive therapy, a group of investigators developed the ASPECT Score, an imaging scale 
based on head CT. Patients with an ASPECT Score of < 6 will generally not improve 
with treatment. 
 
B. To further improve patient selection (decrease the number of patients in whom successful 
revascularization is clinically futile) other noninvasive testing methods have been 
applied, including CT perfusion, magnetic resonance imaging (MRI) perfusion, and 
diffusion based images. [4-8] Despite the various forms of noninvasive testing, the good 
clinical outcome (GCO) rate consistently lags behind the rate of good revascularization, 
by at least 30-40%. 
 
C. Despite applying the above selection criteria (time from onset of symptoms and findings 
on CT scan), the percentage of GCO has been consistently lacking behind the 
recanalization rates which has been steadily improving to up to 80-90%. It is clear that a 
significant proportion of good revascularizations are futile due to lack of clinical 
improvement [5-8, 9-12]  
 

 
 
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The investigators believe that focusing only on time and static noninvasive imaging for 
selecting patients suitable for IAT ignores critical physiological factors, i.e. 
differentiating blood-deprived yet viable brain tissue from nonviable tissue.  The 
principal investigator has developed a system referred to as the Capillary Index Score 
(CIS) that helps differentiate between viable and nonviable tissue. The CIS is obtained 
during the diagnostic cerebral angiogram (DCA) performed as a necessary step at the 
time of treatment. The fact that the CIS is obtained just before proceeding with treatment 
differentiates it from all other currently employed neuroimaging-based patient selection 
strategies, which are sometime done an hour or more prior to proceeding with the 
treatment.  Tissue in the ischemic area (tissue blocked from its usual primary blood 
supply), but fed through secondary vessels (pial collaterals) represents tissue that can 
recover if the clot can be removed.  This secondary blood supply is shown by a blush 
surrounding the capillaries on the DCA.  The investigators believe that collateral blood 
flow graded by this system is more accurate than time to treatment in determining the 
patients who should be given endovascular treatment.  The CIS is a 4 point simple system 
(0-3).  The ischemic territory is divided into 3 sections. If a section exhibits a capillary 
blush it is given one point. If the three sections of the ischemic territory have a capillary 
blush the final score is 3. If none exhibit capillary blush the score is zero. Based on the 
1/3 hypodensity rule we considered the CIS to be poor (pCIS) if more than 1/3 of the 
ischemic territory has no capillary blush (CIS=0, 1). A score of 2 or 3 is considered a 
favorable CIS (fCIS). DCA (injecting the ischemic territory only) is a necessary step 
performed prior to clot removal.  Certain operators inject only the occluded vessel instead 
of obtaining more complete imaging which assesses the anatomical and physiological 
status of collateral vessels. It is currently the usual practice of many 
neurointerventionalists to obtain a complete set of DCA films prior to treatment which 
assess collateral circulation. This may increase the time of the intervention by 2-5 
minutes, which most neurointerventionalists believe carries an extremely low risk and 
does not affect outcome.  
 
D. The investigators have retrospectively examined the CIS for patients previously treated 
with IAT for this type of stroke [13-15], initially via large case series analyses and 
subsequently by blinded application of the CIS to patients in three major prospective 
randomized placebo- controlled clinical trials. [9-11] The previous studies indicated that 
patients graded as having a fCIS, indicating good peripheral blood flow, typically have 
good clinical outcomes following successful revascularization.  A good outcome is 
defined as a slight disability and able to carry out daily activities or better.  Good 
outcome rates have been on the order of 70-90% for patients with a favorable CIS and 
good revascularization.  This proportion of good outcomes far exceeds any published rate 
of good outcomes using all other peer- review published patient selection methodologies 
to date. For patients with a pCIS, the maximum rate of good outcomes has been 13% 
despite good and timely revascularization, which is actually well below the success rate 
of approximately 20% for patients who are left untreated, without even tPA [7].  These 
results raise the question if we are not only not helping the patients with pCIS but also 
actually harming them. Clinical trials focused on IAT have had mixed results, with some 
trials showing no benefits compared to IVT with tPA alone [5, 8], and more recent trials 
showing superiority of the IAT plus IVT over IVT alone [3,13-14,16].  The absolute rates 

 
 
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of good outcomes for these recent trials in the IAT arms have varied widely (52-71%).  
The investigators believe that a primary factor explaining differences between studies is 
the portion of people with favorable CIS included in the studies.  Interestingly the ratio 
between the rate of good outcomes in the treatment arm vs. the control arm (no IAT) has 
been stable across the different positive trials showing the effect of IAT at approximately 
1.7 for all of these recent trials, similar to the PROACT II trial more than 15 years ago. 
[3].  The investigators believe the stagnation of this ratio at 1.7 is evidence that the 
selection criteria have not improved despite improvement in the rate of revascularization. 
Based on the existing data, the investigators would like to evaluate the merit of CIS as a 
primary tool for patient selection in IAT, hoping to prove that the rate of treated to 
untreated improvement is on the order of 6 to 7.  We expect that if we select for patients 
with fCIS and obtain good revascularization to obtain around 80% GCO in the treated 
arm.  We also expect successful revascularization to be futile for patients with pCIS. 
 
E. The principal investigator believes that the CIS for each patient is determined genetically. 
In order to explore the genetic link to the CIS, this trial also aims to perform SNP-trait 
association analysis to identify the genetic loci linked to CIS and stroke outcome in 
patients suffering from AIS. Dce1 has recently been found to be responsible for 
approximately 85% of the variation in collateral extent and it is likely that 
polymorphisms of Dce1 are a major determinant of the wide variation in collateral scores 
in humans. If it is shown that Dce1 is correlated to CIS and both are predictive outcomes 
for EVT, then this will further increase confidence in CIS as an assessment of collateral 
status, strengthen patient stratification of patients to define course of treatment for best 
outcome and least risk, and suggest the use of genetic testing in clinical decision making. 
 
II. 
STUDY OBJECTIVE(S); INCLUDING SPECIFIC AIMS AND/OR 
HYPOTHESES 
 
The hypothesis, or idea being tested, is that as long as patients have a favorable CIS they 
can be successfully treated with IAT out to 24 hours. For patients with poor CIS, success 
rates will be relatively low, with no benefit provided by IAT.  The long term objective is 
to: 
a. Lengthen the time window of treatment for patients with fCIS from 6 hours to 24 
hours.  In doing so, we will offer useful treatment to patients who would otherwise be 
denied treatment under current standards. 
b. Encourage focusing on achieving good revascularization rather than limiting time 
during IAT for patients with fCIS. 
c.  Improve the percentage of good outcomes in the treated population  
d. Save patients with pCIS from complications due to brain edema and intra-cranial 
hemorrhage that could potentially result from IAT 
e. Save the health care system the costs of futile treatment of patients with pCIS.   
III. 
METHODS 
 
A. Study Design:  

 
 
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The current study focuses on patients with acute ischemic stroke due to a blockage of the 
intracranial internal carotid artery or middle cerebral artery (M1).  The study will be 
performed prospectively in up to 6 stroke centers.  Akron General Medical Center is the 
primary institution for development of the study and data analysis for this multicenter trial. 
To participate in the study, all centers need to meet certain qualified requirements which 
include: 
• 
One neurointerventionalist with 6 years’ experience in performing IAT with 
multiple devices. 
• 
Demonstrate coverage of the comprehensive stroke center 24 hours a day.   
The proposed study will be carried out over a period of 4 years from the initial approval 
date.  Informed consent will be obtained for each patient, as described in section VIII. 
The study will be carried out in 2 phases (Figure 1).   
Phase I will compare outcomes between treated patients with fCIS and pCIS.  All eligible 
patients will be assessed by a full diagnostic cerebral angiogram with dye injection of all 
potential collaterals.  DCA will be used to characterize the CIS.  Treatment will be identical 
for both groups.  All patients will be treated with the combination of IAT and the normal 
standard of care for a patient not receiving IAT (which may include IVT, but not always). 
The sample size will be set to have 60 patients complete the trial.  Distribution of fCIS and 
pCIS patients will not be forced, but the option to balance groups may be employed if the 
percentage for one group reaches 70%. 
In phase II, after confirming the hypothesis that patients with pCIS tend to have poor 
outcomes as compared to the natural history of the disease, only patients with pCIS will be 
enrolled.  30 patients will be randomized into treatment including IAT or without IAT plus 
standard of care based on a simple 1:1 randomization.  All otherwise IV tPA eligible patients 
will be treated with IVT using tPA regardless of the assigned group since this represents 
current standard of care.  Based on previous studies, the results from Phase I should show 
poor results for pCIS patients, on the order of 15% good outcomes, below the published good 
outcomes for patients receiving no treatment.  This phase will provide preliminary data to 
determine if IAT provides any benefit in these patients, or is even potentially harmful, which 
no other clinical trial to date of IAT has formally hypothesized or tested as plausible.  Due to 
the low rate of success the investigators realize this phase will be underpowered to 
definitively show differences between two groups, but the phase will provide preliminary 
safety pilot data on a topic not studied to date to develop plans for a larger and adequately 
powered study. 
 
All eligible patients participating in both phase I and phase II will be given the option to 
donate an additional 8.5 ml blood sample for genetic testing of the Dce1 gene. Blood samples 
will be collected in Paxgene DNA tubes. Collection of this sample will occur during 
regularly scheduled blood work within 48-60 hours of admission. Akron General will store 
all samples until all patients are enrolled after which the samples will be sent to a 
biospecimen processing facility to identify polymorphisms of the Dce1 gene. Results 
obtained from the genetic testing will be analyzed in conjunction with data from phase I and 
II. 
The primary measure of outcome will be the same for both phases.  The outcomes will be 
measured based on the modified Rankin Scale (see appendix) at least 3 months and again at 1 
year following treatment.  Patients will be graded according to this scale by an experienced 

 
 
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neurologist or other mRS scale certified health care provider not involved in the treatment 
and blinded to the treatment for each patient.   
 
B. Study Population:  
The population for the study will be patients with anterior circulation acute ischemic 
stroke due to blockage of the intracranial internal carotid artery or middle cerebral artery 
(M1) within 8 hours of onset of symptoms.  Typically, IAT is only offered to patients up to 6 
hours, with no treatment options directly targeting the clot available after that time.  
Occlusion of one of these vessels will be determined based on CT angiography, magnetic 
resonance angiography, or DCA.  Only patients 18 or over will be considered for the study.  
Other inclusion criteria include a score of 8 or greater on the National Institute of Health 
Stroke Scale (NIHSS, see appendix). Exclusion criteria will include contra-indication for 
IAT found on initial CT, intracranial hemorrhage, stroke mimics (tumor, herpetic 
encephalitis, etc.), more than 1/3 hypodensity on non-enhanced head CT prior to 
intervention, ASPECT Score < 6, and pre-existing disability defined as mRS ≥ 2.  Pregnant 
women will also be excluded. 
 
Figure 1: Study design for Phase I 
 
N = 60 

 
 
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Figure 2: Study design for Phase II 
 
C. Assessment of Resources  
The multicenter study will be carried out at up to 6 stroke centers.  Each center is 
expected to have approximately 1 patient per month eligible for the study.  Enrollment of 
patients will be performed at the end of imaging at each institution.  At Akron General 
Medical Center, consent will be obtained within the DCA imaging suite.  Consent will be 
obtained by a person qualified by the local IRB other than the treating physician.  At Akron 
General, consent will be acquired by one of two neurointerventional lab nurses.  One of these 
two nurses is required to be present for treatment of each patient with acute ischemic stroke, 
regardless of participation in a study.  These nurses are familiar with all aspects of the 
proposed treatment methods and typical outcomes.  The nurses will perform documented 
training on methods for obtaining consent and maintaining confidentiality of data obtained 
from subjects enrolled in research projects. 
 
D. Study Procedures 
Recruitment will occur within the DCA suite or other imaging suite at each site following 
imaging to determine if patients meet enrollment criteria.  Since eligible patients are typically 
mentally impaired by the stroke, consent will be provided by a designated caregiver or family 
member as described in section VIII, unless the patient is found to be competent to give 
informed consent by the treating stroke team neurologist. For all eligible patients, an 8.5 ml 
blood sample will be collected followed by the DCA to assess the CIS. Sample specimens 
will be stored at a temperature of 2ºC to 8ºC at each institution for a maximum of 28 days 

 
 
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before being shipped to Akron General. Akron General will store all samples for long-term at 
temperatures between -70ºC and -80ºC until the samples are sent for genetic analysis. 
The initial phase of treatment for patients treated with IAT typically takes 2-3 hours in 
the angio suite to try to remove the clot from the blood vessel.  To remove the clot, Trevo 
stent retriever (Stryker Neurovascular) will be used as the first pass. Patients are then 
transferred to the neuroscience intensive care unit (routine). The length of stay in the unit 
varies from patient to patient and will be determined by the local treating team.  Patients can 
be discharged to home care or to a rehabilitation facility depending on their condition, based 
on the current standard of care.  All medications and rehabilitation techniques prescribed for 
patients following the procedure will be based on the normal standard of care for the treating 
physician, regardless of the treatment group or classification of the CIS. 
For follow-up, patients will be seen by the participating neurologist at intervals typical of 
the standard of care.  The primary outcome measure will be acquired at the 90 day follow up.  
At this appointment, a mRS score will be ascribed for the patient by a modified Rankin Scale 
certified health care provider blinded to the CIS categorization (phase I) or the treatment 
(phase II).  Assessment based on the mRS is standard for follow up appointments, regardless 
of inclusion in the study.  A standard follow up visit typically takes 15-30 minutes.  For 
patients who cannot make it to the neurologist for a follow-up visit due to persistent 
significant handicap or limited access to transportation, mRS will be categorized over the 
phone by discussing the condition of the patient with a caregiver or nurse at the home or 
rehabilitation facility and the patient.   
A secondary follow-up, patients will be seen by the participating neurologist at intervals 
typical of the standard of care.  The primary outcome measure will be acquired at the 1 year 
follow up.  At this appointment, a mRS score will be ascribed for the patient by a modified 
Rankin Scale certified health care provider blinded to the CIS categorization (phase I) or the 
treatment (phase II).  Assessment based on the mRS is standard for follow up appointments, 
regardless of inclusion in the study.  A standard follow up visit typically takes 15-30 minutes.  
For patients who cannot make it to the neurologist for a follow-up visit due to persistent 
significant handicap or limited access to transportation, mRS will be categorized over the 
phone by discussing the condition of the patient with a caregiver or nurse at the home or 
rehabilitation facility and the patient.   
Pre-operative condition and patients outcomes will be assessed using standardized and 
validated measures.  The primary endpoint of a mRS score will be obtained at least 90 days 
following treatment and again at 1 year following treatment.  NIHSS score will be obtained 
in the emergency room before the treatment, within 24 h of treatment, and before discharge. 
The person who will obtain the NIHSS will be certified to obtain it.  Adequacy of 
revascularization will be assessed at the end of treatment by the treating physician according 
the modified thrombolysis in cerebral infarction (mTICI) scale (see Appendix).  All of these 
measures are standards for care and trials of acute ischemic stroke. [8-10] All case report 
forms will be maintained by the primary investigator at the local site, and stored within 
locked cabinets.  The personal identifying information on the case report forms will be de-
identified and assigned a code before being transferred to Akron General Medical Center for 
transfer of the data to a de-identified database which will be used for analysis. 
 
IV. 
DATA COLLECTION 
 

 
 
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A. How and what data will be collected  
Data related to patient demographics, stroke risk factors, condition prior to treatment, 
time of treatment, and outcomes will be collected for each patient.  Data on demographics 
will include sex, age, and race.  Data on stroke risk factors will include history of 
hypertension, blood pressure, prior heart attack, arrhythmias, diabetes, glucose (sugar) level 
at admission, and obesity.  Data on condition prior to treatment will include NIHSS score 
determined in the emergency room.  Data on time of treatment will include time from 
symptoms to arrival at emergency room, time to start of DCA, and time to end of the 
procedure.  Data on outcomes will include mRS at 3 months, mRS at 1 year, NIHSS score 
within 24 hours and at discharge, and complications brain edema and intra-cranial 
hemorrhage. Other parameters within these categories could be acquired as deemed 
necessary for analysis of the data. 
 
V. 
DATA ANALYSIS 
 
A. Sample Size Considerations 
Phase I 
A power analysis has been performed based on the previous retrospective analyses of the 
relationship between outcomes and the CIS for phase I.  The sample size was calculated for 
the influence of the combination of CIS and revascularization on good outcomes (mRS ≤ 2) 
based on the following assumptions.  
 
The percentage of patients with fCIS will be 60% 
 
The percentage of patients with good revascularization will be 50% 
 
The rate of good outcomes for the combination of fCIS and good revascularization 
is assumed to be 70% 
 
The rate of good outcomes for the combination of fCIS and poor revascularization 
is assumed to be 20% 
 
The rate of good outcomes for the combination of pCIS and good revascularization 
is assumed to be 20% 
 
The rate of good outcomes for the combination of pCIS and poor revascularization 
is assumed to be 10% 
The assumptions provide the following power analysis: 
 
𝛼 = 0.05 for overall analysis and set to 0.025 for subgroup analysis comparing fCIS 
and good revascularization to all other groups due to multiple comparisons 
 
power = 0.90 
 
Needed Sample size = 54 patients 
 
An additional 6 patients completing the trial are budgeted due to risk of errors in 
estimated outcomes.  An additional 15-20 patients are expected to be enrolled due 
to patients lost to the 90 day follow up and/or deviations from the protocol.  
Phase II 
Phase II will be an exploratory study evaluating the rates for good outcomes for patients 
with pCIS treated with IVT plus IAT vs. IVT (or other standard of care) only.  The rate of 
good outcomes is expected to be approximately 13% for the IAT group with 
revascularization.  The investigators have no prior data on expected rates of good outcomes 
for patients with pCIS treated with IVT only.  The best possible outcome rate would be on 

 
 
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the order of 25% noted previously for untreated acute ischemic stroke.  Due to the low levels 
of good outcomes, the investigators acknowledge the study will be underpowered to detect a 
difference between the two treatment groups for a total sample size of 30.  Phase II will serve 
as a pilot study to initially establish estimates of rates of good outcomes for pCIS patients 
treated with IVT only for design of a larger prospective study. 
Genetic Analysis 
Genetic analysis will be performed based on the following: 
 Genetic and expression analysis for the two groups based on their collateral score 
 Adjust groups for cardiovascular/stroke risk factor presence and other known 
confounding conditions 
 High density SNP array analysis will be performed for common and rare alleles 
against known collateral-related genes that have been identified in mice. These 
include human RABEP2 and its isoform RABEP1 and related gene pathways; 
VEGFA, FLK1 and their related gene pathways; NOTCH, DLL4, ADAM10, 
ADAM17, CNX37 and their related gene pathways. 
 Subgroup analysis will be performed for ethnicities. 
 Taqman assays and/or exome sequencing of significantly associated SNPs and/or 
genes. 
 Pending results, a future validation study will follow this discovery study by 
increasing the sample size.   
B. Statistical Methodology 
 
Data for the proposed study will be analyzed using comparison of proportions and 
multivariable logistic regression.  Analysis of proportions based on Fisher exact tests will be 
used to compare rates of good outcomes between the fCIS and pCIS groups as the primary 
end point for phase I.  The influence of successful revascularization on outcomes for patients 
with fCIS or pCIS will also be analyzed using Fisher exact tests as the secondary end point. 
Binary and/or ordinal multiple logistic regression analyses will be used to evaluate the 
influence of multiple parameters on the likelihood of a good outcome.  These parameters will 
include CIS, mTICI score, NIHSS score, time to revascularization, age, sex, history of 
diabetes mellitus, history of high blood pressure, history of coronary artery disease.  The 
same analyses will be performed for phase II, instead focusing on the treatment groups rather 
than the CIS classification. 
 
VI. 
DATA AND SAFETY MONITORING PLAN 
 
A. Describe any provisions for monitoring the data for safety 
 
A safety committee will monitor the data.  The safety committee will be composed of at 
least 3 voting members.  At least two members will be neurologists, neuroradiologists or 
neurointerventionalists with experience treating acute ischemic stroke who are not 
investigators at any of the sites.  These members will not be affiliated with the institution of 
the principal investigator, any sub- investigator, or Akron General Medical Center.  At least 
one member with a background in biostatistics who is not an investigator or affiliated with 
Akron General Medical Center will also be on the committee.   
For phase I, the only deviations in normal standards of care are: 

 
 
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1- 
the extra few minutes for full DCA for some centers as opposed to injecting only the 
occluded vessel  
2- 
Adding IAT to treatment of patients seen between 6 and 24 hours of onset of 
symptoms.  
The safety committee will be looking at known potential complications for IAT in both fCIS 
and pCIS groups.  These include:  
A. parenchymal hemorrhage type 2 symptomatic or asymptomatic hemorrhagic 
transformation within the vascular territory of the index ischemic stroke within 24 hours 
of treatment  
B. Any neurological worsening (NIHSS increase of 4 points or more) within 24 hours of 
treatment. 
The rate of complications will be assessed by the safety committee after evaluation of 20, 
30 and 40 patients.  The trial will be stopped for safety if the rate of brain edema and intra-
cranial hemorrhage is significantly larger for the pCIS group than the fCIS group. 
The safety committee will meet at the end of phase I and give its recommendation to 
launch phase two or not depending on their review.  The primary reason not to launch phase 
II would be higher than expected good outcomes for the pCIS patients treated with EVT plus 
standard of care, giving the indication that IAT should not be withheld from patients during 
phase II.  During phase II, the safety committee will review the data on complications as 
noted above and percentage of good outcomes after 10 and 20 subjects are evaluated for 
comparisons between the two treatment groups. 
 
VII. 
STUDY LIMITATIONS 
 
A. Potential Limitations of Procedures  
 
The primary limitation for phase II is the small sample size.  Due to the expected 
relatively low rates of good outcomes for pCIS patients regardless of type of treatment, the 
power will not be sufficient to establish whether or not treatment with IAT is beneficial for 
patients with pCIS.  The study will, however, provide the preliminary data needed to plan for 
a future, larger prospective clinical trial. Potential limitations for the genetic component of 
this study include DNA damage due to improper handling or storage of blood samples. The 
Paxgene DNA tubes are designed to stabilize DNA in the blood. However, the tubes will 
only function properly if the instructions for inverting the tube multiple times and prompt 
shipment for storage at Akron General are followed. 
 
VIII. 
ETHICAL CONSIDERATIONS 
 
A. Informed Consent  
Enrollment of patients will be performed in an imaging suite at each institution.  Once 
eligibility is determined by the treating physician based on imaging, the consent process will 
be initiated by a study research coordinator or study nurse.  These investigators are familiar 
with all aspects of the proposed treatment methods and typical outcomes and maintaining 
confidentiality of data obtained from subjects enrolled in research projects.   
Consent will be obtained using IRB-approved consent forms.  The consent process will 
emphasize oral presentation with brief summaries of the relevant information due to the time 

 
 
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sensitive nature of treatment of stroke.  The consent process will include visual illustrations 
and simple consent forms.  The presentation will include an explanation of the 
diagnosis/proposed treatment with a focus on risks, benefits and alternative treatments.  Best 
available rates on outcomes for the proposed treatment methods will be provided.   
 
Due to the influence of stroke on mental function, a capacity assessment will be 
performed for each eligible subject.  The capacity assessment will include the following 
elements: 
 Indication that the patient is being asked to make a treatment choice and the patient’s 
ability to assess current health situation and make the choice is being evaluated 
 Inquiries into the patient’s self-assessed ability to make a treatment choice and 
assessment of the patient’s ability to paraphrase disclosed information 
 Ability of the patients to express a stable choice, with treatment decision expressed 
immediately after disclosure and at the close of the interview  
 Careful documentation of the encounter 
Alternative measures of consent will be employed for patients who do not demonstrate 
acceptable mental capacity.  The alternative process will include: 
 Attempting to establish whether patient has drafted an advance directive (i.e. living 
will, power of attorney) 
 In the absence of an advance directive, seeking substituted judgment of a proxy 
authorized by state law 
For the cases with patients who do not demonstrate acceptable mental capacity and whose 
proxy (i.e. power of attorney, family member) is not immediately present, telephone consent 
will be used. A study research coordinator or study nurse will fully explain the diagnosis and 
proposed treatment, with a focus on risks, benefits and alternative treatments in the same 
manner as the normal consent process. The telephone consent process will include the 
following steps: 
 Two witnesses will listen to the statements made by the person authorized to give 
consent on the phone. 
 One of those witnesses will indicate, "Phone consent by," print the consenting 
individual's name followed by their own initials. 
 Both persons will date and sign the consent form as witnesses. 
 The proxy will provide written consent, using the normal trial consent forms, upon 
arrival at the hospital. 
 
B. Risks and Side Effects  
Acute anterior circulation large vessel occlusion ischemic stroke is a serious and 
potentially fatal condition. Severe disability and death can result regardless of the type of 
treatment performed.  For the proposed study, risk is minimized by treating all patients in 
phase I with the combination of IAT and standard of care.  Randomization of treatment 
between IAT plus standard of care or standard of care alone is only used for the patients 
with pCIS in phase II, after establishing a poor rate of good outcomes (< 15%) for those 
patients with pCIS treated with the combination of IAT and IVT.  Patients not enrolled in 
the study will be treated with the normal standard of care for the participating institution.  
At Akron General Medical Center the normal standard of care is supportive treatment.  
The investigators believe there is a risk to treating patients with pCIS with IAT.  Opening 

 
 
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up the blood supply to ischemic tissue could potentially increase the risk of vasogenic 
edema and/or hemorrhagic transformation, as well as possible herniation. 
It is theoretically possible that results from the genetic analysis could be used to 
obtain information that could lead to patient discrimination by possible employers and 
insurance providers. However, given the de-identification at the contributing institution 
followed by off-site genetic analysis on the de-identified samples, coupled with the 
genetic data for any individual not being returned to the contributing site, the risk is felt 
to be negligible.  
No compensation to patients for poor outcomes is available for participating in this 
study.  Akron General Medical Center will continue to provide standard care to all 
enrolled subjects following the initial stroke care, and submit charges for all usual care to 
the patient’s insurance.  The patient will be responsible for any charges not covered by 
insurance.  In case of emergency following treatment, patients should follow standard 
practices to seek urgent medical treatment.  Adverse events should also be reported to the 
principal investigator (Dr. Al-Ali) at 330-780-3406. 
 
C. Adverse events 
Adverse events may include: 
1. New clot formation due to placement of guiding catheter 
2. Intra-cranial hemorrhage due to perforation of the treated vessel 
3. Symptomatic intra-parenchymal hemorrhage 
4. Extension of clot to a previously patent vessel 
5. Interval developing of significant vasogenic edema causing herniation 
and/or other sign of mass effect 
6. Arterial access complications such as retroperitoneal hematoma, rectus 
muscle hematoma, or large groin hematoma more than 25 cm 
7. Arterial venous fistula in the groin confirmed by ultrasound 
8. Allergic reaction to dye 
Each complication will be treated following the standard of care. Since the 
complications above are reported with these types of intervention, but there is no firm 
data to determine the accepted rate per operator, any center that has two or more events 
will be scrutinized and their technique will be evaluated by the principal investigator and 
safety committee.  If a shortcoming is identified, guidelines will be provided for the 
center specific to the complications or the center could be dropped.  
 
D. Benefits to Subjects  
For phase I, patients who can be treated between 6 and 24 hours following onset of 
symptoms for acute ischemic stroke will be treated with IAT plus standard of care.  
Currently those patients are not offered IAT due to the belief that too much time has 
passed to restore tissue that has been deprived of the primary source of circulation. 
However, the new Extend IA trial proved that these patients could be treated. [4] The 
investigators believe that successful treatment beyond 6 hours with IAT is possible for 
patients with fCIS. In doing so we are offering a potentially useful treatment to patients 
who would otherwise not have the option.  
 
E. Costs to Subject  

 
 
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Costs to the subjects will be standard costs for the treatment performed for acute 
ischemic stroke.  Usual, customary, and reasonable treatment costs will be initially billed 
to the patients insurance, if applicable, with the patient responsible for any portion not 
paid by insurance in accordance with usual institutional policies.  The protocol is based 
on standard techniques for treating acute ischemic stroke that can be applied to an 
individual patient based on the discretion of the treating physician. 
 
F. Compensation to Subject  
All patients who participate in the 90 day follow up visit will be compensated for 
parking and mileage expense up to a maximum of $25. All patients who participate in the 
1 year follow up visit will be compensated for parking and mileage expense up to a 
maximum of $25. 
 
F.  Provisions for vulnerable subjects  
Vulnerable subjects, children, pregnant women, and prisoners, will not be enrolled in 
the study. 
 
G. Subject Privacy and Data Confidentiality  
Measures will be taken to protect the privacy of the subjects and confidentiality of 
their personal information from the enrolled subjects.  The enrollment process will take 
place within the imaging suite or emergency department, in a manner to maximize the 
probability that only the caregivers will be aware that a subject is eligible for a trial.  The 
only other person at each site who will be aware that a subject is enrolled will be a 
research coordinator at each site tasked with collecting data and reviewing procedures.   
The protected health information will be collected for each enrolled subject at each 
site.  The paper files will be stored within locked filing cabinets within the office of the 
primary investigator or research coordinator.  The data will be de-identified before being 
provided to the primary institution for analysis (honest broker).  Patients will be 
identified based on a code including an identifier for the site and the patient number at the 
site.  Any electronic files relating the patient name to the code will be kept at the home 
institution.  The files will be password protected and stored on a single desktop computer.  
The files may be backed up on a password-protected portable drive.  When data is used 
for presentations at professional organizations or submissions to journals, no patient 
identifiers will be disclosed.  All data will be maintained at each site for a minimum of 3 
years.  After the principal investigator has determined that the data has been fully 
analyzed and presented, the paper data from individual patients will be shredded, while 
electronic data will be deleted and overwritten. 
 
IX.  PLANS FOR DISSEMINATION OF FINDINGS 
Data acquired for the study will be prepared for publication in journals focused on treatment 
of acute ischemic stroke.  The study will also be registered on clinicaltrials.gov to allow the 
general public to access the results of the study.  
 
X.  REFERENCES 
 

 
 
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1. Powers, William J., et al. 2015 AHA/ASA focused update of the 2013 guidelines for the 
early management of patients with acute ischemic stroke regarding endovascular 
treatment. Stroke. (2015): STR-0000000000000074. 
2. von Kummer R, Allen KL, Holle R, Bozzao L, Bastianello S, Manelfe C, Bluhmki E, 
Ringleb P, Meier DH, Hacke W. Acute stroke: usefulness of early CT findings before 
thrombolytic therapy. Radiology. 1997 Nov;205(2):327-33. 
3. del Zoppo G, Higashida R, Furlan A, Pessin M, Rowley H, Gent M. PROACT: A Phase II 
Randomized Trial of Recombinant Pro-Urokinase by Direct Arterial Delivery in Acute 
Middle Cerebral Artery Stroke. Stroke. 1998;29(1):4-11. 
4. Wisco D, Uchino K, Saqqur M, Gebel JM, Aoki J, Alam S, George P, Newey CR, Man S, 
Tateishi Y, McNeil J, Winfield M, Cheng-Ching E, Hui FK, Toth G, Bain M, Rasmussen 
PA, Masaryk T, Ruggieri P, Hussain MS. Addition of hyperacute MRI AIDS in patient 
selection, decreasing the use of endovascular stroke therapy. Stroke. 2014 45(2):467-72.  
5. Campbell BCV, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N et al. 
Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 
2015;372(11):1009-18. 
6. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ et al. A 
randomized trial of intra-arterial treatment for acute ischemic stroke. N Engl J Med. 
2015;372(1):11-20. 
7. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J et al. Randomized 
assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 
2015;372(11):1019-30. 
8. Saver J, Goyal M, Bonafe A, Diener H, Levy E, Medes-Pereira V et al. Solitaire FR With the 
Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke. 
Abstract presented at: International Stroke Conference 2015. 2015 Feb 11-13; Nashville, 
Tennessee, USA. 
9. Combined Intravenous and Intra-Arterial Recanalization for Acute Ischemic Stroke: The 
Interventional Management of Stroke Study. Stroke. 2004;35(4):904-911. 
10. The Interventional Management of Stroke (IMS) II Study. Stroke. 2007;38(7):2127-2135. 
11. Broderick J, Palesch Y, Demchuk A, Yeatts S, Khatri P, Hill M et al. Endovascular Therapy 
after Intravenous t-PA versus t-PA Alone for Stroke. New England Journal of Medicine. 
2013;368(10):893-903. 
12. Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, et al. SYNTHESIS 
trial: Endovascular Treatment for Acute Ischemic Stroke. N Engl J Med. 2013; 368:904-913. 
13. Al-Ali F, Jefferson A, Barrow T, Cree T, Louis S, Luke K et al. The capillary index score: 
rethinking the acute ischemic stroke treatment algorithm. Results from the Borgess Medical 
Center Acute Ischemic Stroke Registry. Journal of NeuroInterventional Surgery. 
2012;5(2):139-143. 
14. Al-Ali F, Tomsick T, Connors J, Gebel J, Elias J, Markarian G et al. Capillary Index Score in 
the Interventional Management of Stroke Trials I and II. Stroke. 2014;45(7):1999-2003. 
15. Al-Ali F, Elias JJ, Tomsick, TA, Liebeskind DS, Broderick JP. Relative Influence of the 
Capillary Index Score, Revascularization and Time on Stroke Outcomes from the IMS III 
Trial. Submitted to Stroke March 2015. 
16. Khatri P, Yeatts SD, Mazighi M, Broderick JP, Liebeskind DS, Demchuk AM, et al. Time to 
angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of 

 
 
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data from the Interventional Management of Stroke (IMS III) phase 3 trial.  The Lancet 
Neurology. 2014; 13:567-74. 

 
 
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XI.  APPENDICES  
 
 
 
 
Modified thrombolysis in cerebral infarction (mTICI) scale 
 
 
 

 
 
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