Conditions: Cognition Disorder Stroke Occlusion Carotid
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
Complete occlusion of the Internal carotid artery (ICA) by atherosclerotic disease (COICA) causes approximately 15%-25% of ischemic strokes in the carotid artery distribution. Patients treated with medical therapy have a 7%-10% risk of recurrent stroke per year for any stroke and a 5%-8% risk per year for ipsilateral ischemic stroke during the first 2 years after ICA occlusion. Internal carotid artery occlusion causes an estimated 61,000 first-ever strokes per year in the US an incidence more than twice the annual occurrence of ruptured intracranial aneurysms Additionally, 40% of subjects with COICA who present with transient ischemic attack (TIA) and 70% of COICA who present with stroke have cognitive decline with increased risk of vascular dementia and Alzheimer's' disease (AD) with time (2,3).

Symptomatic COICA subjects are at increased risk of developing cognitive impairment and progressive development of vascular dementia and AD with time. Our proposal leverages several compelling retrospective and prospective preliminary data from human to perform this exploratory trial with go/no-go criteria to proceed to a phase 3 based on the data generated

Detailed description:
Study Design:

Prospective randomized open blinded end-point (PROBE) study

This is a phase 2 randomized single-center open label clinical trial with randomization of 1:1 to either best medical management vs. best medical management and endovascular revascularization of COICA.

Screening, Enrolling, \& Randomization:

All subjects who presents to our tertiary hospital with a diagnosis of COICA will undergo full evaluation including 1) documenting previous history of transient ischemic attack (TIA) and/or stroke; 2) cervical and brain CT angiography (CTA) to document complete occlusion; 3) CT perfusion (CTP) to assess for presence of penumbra evident by increased mean transient time (MTT) in the ipsilateral side of COICA; and 4) Montreal cognitive assessment (MoCA) score. If any subject is found to have complete occlusion of COICA, evident of abnormal/prolongation of MTT on CTP, previous history of TIA and or stroke, and MoCA \<26 or abnormal response on another neuropsychological assessment preformed in the screening battery, then further evaluation is obtained including: MRI spectroscopy to assess for presence/absence of lactate in the ipsilateral watershed area (centrum semiovale), and size of ipsilateral hippocampus and amygdala, additional cognitive testing battery, and digital subtraction angiography (DSA) to document adequately the type of COICA the subject have (type A-D).

If a subject meets all inclusion criteria (complete occlusion, MoCA \<26 and/or abnormal other neuropsychological test result, abnormal CTP) they will be randomized, after consent is obtained. If all inclusion criteria are met other than the CTP, they will be enrolled but not randomized. These subjects will only be eligible for best medical management- not surgical intervention.

If any subject does not have complete occlusion or abnormal MoCA \>26 or other neuropsychological assessment, then the subject is excluded and no further testing needed (see exclusion criteria).

If the subject meets all inclusion criteria, then a baseline of complete neurological testing, full demographics, CTA or MRA, CTP, MoCA, additional neurological testing, MRI spectroscopy and DSA are obtained and subject is randomized 1:1 to either best medical management or best medical management + endovascular balloon angioplasty and stenting. Follow up clinic visits are arranged at 6 and 12 months. Repeat testing of MoCA and additional cognitive testing battery are done at these clinical follow-up visits (6 and 12 months). MRI of the brain and is done at 6 and 12 months. DSA is performed at 1 year follow-up for intervention subjects to assess brain bio-markers and revascularization respectively.

Arms:
arm 1: Subjects meet all inclusion criteria and were randomized to intervention arm 2: Subjects meet all inclusion criteria and were randomized to best medical management arm 3: Subject meets all inclusion criteria EXCEPT abnormal CTP. Subjects are not randomized and are eligible for only best medical management

Interventions: intervention 1: Endovascular intervention intervention 2: Aspirin and Clopidogrel (maximal medical Therapy)
Intervention descriptions: intervention 1: Endovascular angioplasty of the occluded carotid using balloon angioplasty and reconstruction with stents: coronary stents distally (Rebel, Boston Scientific; Vision, Abbott Vascular) and carotid stents proximal (Acculink and Xcat, Abbott Vascular) Patients will stay on their aspirin 325 mg and clopidogrel 75 mg intervention 2: Best Medical Management: daily dual antiplatelet therapy (aspirin: 325 mg p.o. qd and Clopidogrel: 75 mg p.o. qd), optimization of systolic blood pressure (120 -140 mmHg), and smoking cessation.

Protocol document:
Prot_SAP_001.pdf: 
Neurocognitive Impairment Assessment in Symptomatic 
Carotid Occlusion Recanalized Endovascularly 
Protocol Number: 01 
National Clinical Trial (NCT) Identified Number:  NCT03176420 
Co-Principal Investigator: David Hasan 
Co-Principal Investigator: Colin Derdeyn 
Funded by: NIA 
Version Number:  v.6.1 
October 12, 2021 
 
NCT04219774 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.2 
Wording changes for medical management 
Promoting clarity and consistency  
1.3 
Defined Visit windows 
Promoting clarity and consistency  


  
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Table of Contents 
STATEMENT OF COMPLIANCE ......................................................................................................................... 1 
1 
PROTOCOL SUMMARY .......................................................................................................................... 1 
1.1 
Synopsis ........................................................................................................................................... 1 
1.2 
Schema ............................................................................................................................................ 3 
1.3 
Schedule of Activities (SoA) ........................................................................................................... 6 
2 
INTRODUCTION ....................................................................................................................................... 7 
2.1 
Study Rationale ............................................................................................................................... 7 
2.2 
Background ...................................................................................................................................... 7 
2.3 
Risk/Benefit Assessment ................................................................................................................ 9 
2.3.1 
Known Potential Risks ................................................................................................. 9 
2.3.2 
Known Potential Benefits........................................................................................... 10 
2.3.3 
Assessment of Potential Risks and Benefits ........................................................... 10 
3 
OBJECTIVES AND ENDPOINTS .......................................................................................................... 13 
4 
STUDY DESIGN ...................................................................................................................................... 14 
4.1 
Overall Design ............................................................................................................................... 14 
4.2 
Scientific Rationale for Study Design .......................................................................................... 20 
4.3 
Justification for Dose ..................................................................................................................... 20 
4.4 
End of Study Definition ................................................................................................................. 20 
5 
STUDY POPULATION ............................................................................................................................ 20 
5.1 
Inclusion Criteria ............................................................................................................................ 20 
5.2 
Exclusion Criteria .......................................................................................................................... 20 
5.3 
Lifestyle Considerations ............................................................................................................... 21 
5.4 
Screen Failures ............................................................................................................................. 21 
5.5 
Strategies for Recruitment and Retention ................................................................................... 21 
6 
STUDY INTERVENTION ........................................................................................................................ 23 
6.1 
Study Intervention(s) Administration ........................................................................................... 23 
6.1.1 
Study Intervention Description .................................................................................. 23 
6.2 
Measures to Minimize Bias: Randomization and Blinding ........................................................ 23 
6.3 
Study Intervention Compliance .................................................................................................... 23 
6.4 
Concomitant Therapy.................................................................................................................... 23 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................................ 24 
7.1 
Discontinuation of Study Intervention .......................................................................................... 24 
7.2 
Participant Discontinuation/Withdrawal from the Study............................................................. 24 
7.3 
Lost to Follow-Up .......................................................................................................................... 25 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................................................. 25 
8.1 
Efficacy Assessments ................................................................................................................... 25 
8.2 
Safety and Other Assessments ................................................................................................... 28 
8.3 
Adverse Events and Serious Adverse Events ............................................................................ 28 
8.3.1 
Definition of Adverse Events (AE) ............................................................................ 28 
8.3.2 
Definition of Serious Adverse Events (SAE)............................................................ 28 
8.3.3 
Classification of an Adverse Event ........................................................................... 29 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up...................... 29 
8.3.5 
Adverse Event Reporting........................................................................................... 29 
8.3.6 
Serious Adverse Event Reporting ............................................................................ 30 
8.3.7 
Reporting Events to Participants .............................................................................. 31 


  
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8.3.8 
Events of Special Interest .......................................................................................... 31 
8.3.9 
Reporting of Pregnancy ............................................................................................. 31 
8.4 
Unanticipated Problems ............................................................................................................... 31 
8.4.1 
Definition of Unanticipated Problems (UP) .............................................................. 31 
8.4.2 
Unanticipated Problem Reporting ............................................................................. 32 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................. 32 
9 
STATISTICAL CONSIDERATIONS ....................................................................................................... 32 
9.1 
Statistical Hypotheses .................................................................................................................. 32 
9.2 
Sample Size Determination .......................................................................................................... 33 
9.3 
Populations for Analyses .............................................................................................................. 33 
9.4 
Statistical Analyses ....................................................................................................................... 33 
9.4.1 
General Approach ...................................................................................................... 33 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ........................................................... 34 
9.4.3 
Analysis of the Secondary Endpoint(s) .................................................................... 34 
9.4.4 
Safety Analyses .......................................................................................................... 34 
9.4.5 
Baseline Descriptive Statistics .................................................................................. 35 
9.4.6 
Planned Interim Analyses .......................................................................................... 35 
9.4.7 
Sub-Group Analyses .................................................................................................. 35 
9.4.8 
Tabulation of Individual participant Data .................................................................. 35 
9.4.9 
Exploratory Analyses ................................................................................................. 35 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................. 35 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................ 35 
10.1.1 
Informed Consent Process ........................................................................................ 35 
10.1.2 
Study Discontinuation and Closure .......................................................................... 36 
10.1.3 
Confidentiality and Privacy ........................................................................................ 36 
10.1.4 
Future Use of Stored Specimens and Data ............................................................. 37 
10.1.5 
Key Roles and Study Governance ........................................................................... 37 
10.1.6 
Safety Oversight ......................................................................................................... 37 
10.1.7 
Clinical Monitoring ...................................................................................................... 37 
10.1.8 
Quality Assurance and Quality Control .................................................................... 38 
10.1.9 
Data Handling and Record Keeping ......................................................................... 38 
10.1.10 
Protocol Deviations .................................................................................................... 38 
10.1.11 
Publication and Data Sharing Policy ........................................................................ 38 
10.1.12 
Conflict of Interest Policy ........................................................................................... 39 
10.2 
Abbreviations ................................................................................................................................. 39 
10.3 
Protocol Amendment History ....................................................................................................... 41 
 


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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP) and the following:  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion 
Recanalized Endovascularly 
 
Study Description: 
This is a phase 2 randomized single-center open label clinical trial with 
randomization of 1:1 to either best medical management vs. best medical 
management and endovascular revascularization of COICA. The study will 
utilize best medical management and will randomize patients to 
endovascular balloon angioplasty and stenting. 
• 
A third study group will be included that meet selected exclusion 
criteria. This group will not be randomized, only eligible for best 
medical management and prospective observation.  
 
Objectives: 
 
Primary Objective: 
To test the hypothesis that endovascular revascularization of COICA 
improves significantly cognitive function assessed by a specifically 
designed battery of 14 cognitive tests including the Montreal Cognitive 
Assessment (MoCA).  
Secondary Objective: 
To test the safety of endovascular revascularization of chronically occluded 
ICA.  
Tertiary/exploratory Objectives: 
To test the hypothesis that subjects with symptomatic COICAs and 
mild/moderate cognitive dysfunction have the following biomarkers: 


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A) Presence of lactate and decreased Naa/Cr in the watershed area 
(specifically centrum semiovale) on 1H-MRI-spectroscopy, and 
B) Decreased size of the hippocampus and amygdala on MRI.  
C) increased MTT and/or PTT on CTP in the ipsilateral side of the occluded 
ICA specifically in the MCA territory when compared to the opposite 
unaffected hemisphere.   
 
 
 
 
Endpoints: 
Primary endpoints: 
1. Cognitive outcome at 12-month follow-up assessed mainly by a 
specifically designed battery of 14 cognitive tests including the MoCA. 
Secondary Endpoints: 
1. Safety: Occurrence of Stroke, Cerebral Hemorrhage, or Death 
Exploratory endpoints: 
Biomarkers:   
1. Resolution/improvement of previously increased of MTT and/ or PTT 
(normalization of MTT/ PTT) on CTP specifically in the ipsilateral MCA 
territory. 
2. The presence/absence of lactate on 1H-MRI spectroscopy in centrum 
semiovale in the ipsilateral side of COICA;   
3. The change in size of amygdala and hippocampus in the ipsilateral side 
of COICA. 
4.Subgroups: Gender difference 
 
 
 
 
Study Population: 
 
 
  
Age ≥ 21  
Patients with complete occlusion of cervical ICA on imaging studies (MRA 
or CTA) and confirmed with DSA, a history of TIA or stroke , increased MTT 
and/or TPP on CTP in the ipsilateral side of the occluded ICA specifically in 
the MCA territory when compared to the opposite unaffected hemisphere, 
all occlusion is due to atherosclerotic disease and MoCA < 26 or abnormal 
result on another test in the battery (abnormal defined as 1.5 SD below 
age/ gender/ education matched norms).   
• 
Subjects without increased MTT or TPP on CTP may still be 
included in the unrandomized prospective observational 3rd arm.  
 
Phase: 
 
Phase 2 
Description of 
Sites/Facilities Enrolling 
Participants: 
University of Iowa Hospitals and Clinics  
Description of Study 
Intervention: 
Endovascular balloon angioplasty and stenting  
Study Duration: 
5 years 
Participant Duration: 
12 months 
 
 


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1.2 
SCHEMA 
 
 
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
 
Visit 1 
Pre-Op 
 
  
 
Visit 2 
6 months  
 
 
 
 
 
 
Visit 3 
12 months 
 
 
 
Total N:  Obtain informed consent. Screen potential participants by inclusion and 
exclusion criteria; obtain history, document. 
Perform baseline assessments. 
Follow-up assessments of study endpoints and safety 
Cognitive Testing 
MRI 
Final Assessments 
Cognitive Testing 
MRI 
DSA if applicable 
Arm 2 
19 
Arm 1  
 19 
Randomize 
Arm 3 
19 
Meets  
particular 
exclusion 
criteria 
Subjects only 
eligible for 
best medical 
management 


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Screening /Baseline assessments 
Baseline visit day -30 to  -10 
days
•Obtain informed consent
•Screen potential participants by inclusion and exclusion criteria
•Obtain history, document
Randomization 1:1 (not applicable for 3rd arm)
day -20  to -10 days
•Intervention Group 1 (n=19)
•Placebo (n=19)
Study Intervention
Day 0
Follow-up assessments of study endpoints and safety
Day 100-140; Day 160-200
End of Study Assessments
Day 330- 390


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Day -30 to Day -10
Screening, Baseline  
Assessment
Day -20 to -10 
Randomization
(not applicable for 3rd arm)
6 Months
Cognitive Assessment
MRI
12 Months
Cognitive Assessment
MRI 
DSA (if applicable)
Study Intervention N=19
Eligibility will be confirmed by 
adjudicator(s)
Medical Mgmt. N=19
Monthly  
telephone 
contacts
Intervention
Day 0


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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
The schedule below is provided as an example and should be modified as appropriate.  
 
 
Procedures 
Screening 
Day -30 to -1 
Enrollment/Baseli
ne 
Visit 1, Day 0f 
Study Visit 4 
6 Months +/- 6 
weeks 
Final Study Visit 
12 monthsh 
+/- 6 weeks 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Randomizationa 
X 
 
 
 
Administer study 
intervention 
 
Xe 
 
 
Concomitant 
medication review 
X 
X 
Physical exam 
(including height and 
weight) 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Height 
X 
 
 
 
Weight 
X 
 
 
 
Performance status 
X 
 
 
 
Hematology  
X 
 
 
 
Serum chemistry a 
X 
 
 
 
Pregnancy test b 
X 
 
 
 
Blood Test c 
 
X 
 
 
EKG (as indicated)  
X 
 
 
 
Adverse event review 
and evaluation 
X 
X 
CTP 
X 
X 
 
 
MRA  or CTA 
X 
 
 
 
Radiologic/Imaging 
assessment (MRI of the 
brain)  
X 
 
X 
X 
Cognitive testing  
X 
 
X 
X 
Complete Case Report 
Forms (CRFs) 
X 
X 
X 
X 
Diagnostic angiogram  
Xd 
 
 
Xc 
Medication check  
 
 
X 
X 
a- 
Not applicable to 3rd study arm 
b- 
Only if necessary, to confirm surgery eligibility 
c- 
Surgical arm only  
d- 
Only applicable if the subject has not had one in the past 6 months 
e- 
Prior to surgical intervention eligibility will be confirmed by adjudicator(s)  
f- 
Enrollment for surgical arm may be delayed due to OR schedule 


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g- 
6-month follow up visit timeframe is based on the date of randomization for non-surgical 
arms, 
date of surgery for surgical arm 
h- 
12-month follow up visit timeframe is based on same dates as 6-month visit 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Complete occlusion of the Internal carotid artery (ICA) by atherosclerotic disease (COICA) causes 
approximately 15%–25% of ischemic strokes in the carotid artery distribution. 
(11,17,48,54,57,70,71,84,92,98) Patients treated with medical therapy have a 7%–10% risk of recurrent 
stroke per year for any stroke and a 5%–8% risk per year for ipsilateral ischemic stroke during the first 2 
years after ICA occlusion. (41,42,46,49,50,68,69) Internal carotid artery occlusion causes an estimated 
61,000 first-ever strokes per year in the US (1,15,34,57,70,92,105)  an incidence more than twice the 
annual occurrence of ruptured intracranial aneurysms (14)  Additionally, 40% of subjects with COICA 
who present with TIA and 70% of COICA who present with stroke have cognitive decline with increased 
risk of vascular dementia and Alzheimer’s’ disease (AD) with time (2,3).   
 
Symptomatic COICA subjects are at increased risk of developing cognitive impairment and progressive 
development of vascular dementia and AD with time. Our proposal leverages several compelling 
retrospective and prospective preliminary data from human to perform this exploratory trial with  
go/no-go criteria to proceed to a phase 3 based on the data generated 
 
2.2 
BACKGROUND  
A. New COICA classification based on anatomy and radiographic findings:  
We analyzed the diagnostic cerebral angiogram (DSA) for 100 consecutive subjects with a diagnosis of 
COICA in the interval of 2009–2017 at the University of Iowa Hospitals and Clinics 43. Initial diagnosis of 
the occluded cervical ICA along with an assessment of collateral filling was reported by a member of our 
neuroradiology team based on MRA and/or CTA. Then, an endovascular neurosurgeon (lead PI) used the 
morphology and location of the occlusion, as well as the presence or absence of reconstitution of the 
distal ICA on DSA, to stratify this cohort into 4 categories. The rationale for this classification was to 
determine whether it could predict upfront which COICA subject would be a viable candidate for the 
revascularization procedure using endovascular techniques.  For the type A category (Figs. 1A and 2A–
C), occlusion of the cervical ICA is tapered with proximal ICA lumen patency. In addition, the cavernous 
and/or petrous segments are reconstituted by collateral vessels from the external carotid artery (ECA) 
and/or retrograde filling from the supraclinoid segment. For the type A category (Figs. 1A and 2A–C), 
occlusion of the cervical ICA is tapered with proximal ICA lumen patency. In addition, the cavernous 
and/or petrous segments are reconstituted by collateral vessels from the external carotid artery (ECA) 
and/or retrograde filling from the supraclinoid segment. For type B (Figs. 1B and 2D–F), occlusion of the 
cervical ICA is not tapered; instead, a stump is present, and the immediate proximal portion of the 
cervical ICA lumen is patent. In addition, the cavernous and/or petrous segments are reconstituted by 
collateral vessels from the ECA and/or retrograde filling from the supraclinoid segment. For type C (Figs. 
1C and 3A–C), occlusion of the cervical ICA is at the common carotid artery bifurcation (the cervical ICA 
appears completely amputated at the bifurcation), and no ICA lumen is observed. The common carotid 
artery continues as the ECA. However, the cavernous and/or petrous segment is reconstituted by either 


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collateral vessels from the ECA and/or retrograde filling from the supraclinoid segment. Type D (Figs. 1D 
and 3D–F) is the same as type C, except that there is no reconstitution of the cavernous and/ or petrous 
segments. In our analysis of the radiographic images for 100 consecutive subjects with a diagnosis of 
COICA, we found type A represented 29/100 (29%) COICAs; type B: 28/100 (28%); type C: 33/100 (33%); 
and type D: 10/100 (10%).  We then assessed whether our proposed classification could predict upfront 
the technical feasibility and safety of endovascular revascularization for symptomatic COICA. 
 
B. Proof-of-concept and pilot study of the feasibility and safety of revascularizing symptomatic COICA 
based of the proposed new radiographic classification of COICA mentioned above: 
Using the above classification, we conducted a pilot study 43 in which we treated 31 subjects for their 
symptomatic COICAs in the interval of 2016–2017. Institutional Review Board approval was obtained. 
Subjects were included in the study if they had a COICA with ischemic symptoms refractory to medical 
therapy, i.e., subjects who were having recurrent ipsilateral hemispheric stroke (emboli or watershed 
infarcts) while on dual antiplatelet therapy or anticoagulation. Symptoms were evaluated based on the 
North American Symptomatic Carotid Endarterectomy Trial (NASCET) 31criteria. Asymptomatic subjects 
with COICA were not included in this study. All occlusions were due to atherosclerosis; those that were 
not, such as dissection, were excluded from the study. Acute carotid artery occlusions were not included 
in the study. Carotid occlusion was defined as 100% cross-sectional obliteration of the vessel lumen as 
documented on CTA or MRA and confirmed with DSA. In the pilot study, 31 subjects, five (16.12%) of 
whom were female, had 32 symptomatic COICAs and underwent endovascular recanalization and stent 
deployment across the occluded section of the vessel. The mean age was 65.77 years (range 49–84 
years). The mean (± standard deviation) follow-up among the 31 patients since diagnosis of the ICA 
occlusion was 13.70 ± 3.77 months (median 11 months, range 7 days–4.5 years). Among the 
revascularized group, the mean follow-up was 10 months and the median was 12 months. Sixteen 
subjects had only right ICA occlusion, 14 had only left ICA occlusion, and one subject had bilateral ICA 
occlusion. Recanalization was successful in 68.75% (22/32) of symptomatic COICAs. Among type A, 8/8 
(100%) COICAs were successfully revascularized (Fig. 2A–C).  Among type B, 8/8 (100%) had successful 
revascularization (Fig. 2D–F). As for types C and D, the success rate was 50.00% (4/8) and 25.00% (2/8), 
respectively (Fig. 2). The perioperative complication rate was 18.75% (6/32), and 4 of the cases were 
transient. Persistent complications were limited to a minor/silent hemorrhagic transformation in the 
right parietooccipital lobe and the right basal ganglia in 2 subjects who had type C& D occlusions. None 
of the subjects with type A or B COICAs had any perioperative complications. Overall, none of the 
complications resulted in any permanent morbidity or death.  Twenty (64.52%) of 31 subjects had 
improvement in their neurological symptoms at the 6 months’ follow-up. Four of the subjects that did 
not have successful revascularization (12.90%; 3 with type D, 1 with type C) had a recurrent TIA/stroke 
after 30 days postprocedure. Hence, the rate of TIA/stroke more than 30 days after the procedure was 
4/10 (40.00%) in the cohort in which revascularization had failed. None of the successfully 
revascularized subjects suffered any ischemic events at follow-up 
 
In a literature search for any studies published in English language that addressed endovascular 
revascularization of COICA, we identified 16 studies that satisfied our inclusion criteria. Studies that did 
not involve endovascular treatment for COICA or that did not present data amenable to meta-analysis 
were excluded.  A total of 333 patients with COICA underwent endovascular recanalization. The mean 
age of the patient sample was 67.2 years old (SD = 9.3). Male patients represented 85% of the 
population. The mean duration of known occlusion was 7.4 months (SD = 9.4). Seventy percent (70%) of 
patients had a successful recanalization. A total of 13 patients (3.9%) experienced major complications 
following the procedure, whereas only 8 patients (2.4%) experienced minor complications. Among the 
most common complications were hemorrhagic complications [n = 8, (2.4%)], and ischemic strokes [n =7 


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(2.1%)]. The incidence of periprocedural complication was 5.4%.   Periprocedural  hypotension / 
bradycardia was not included in the complication rates unless it was severe enough alter the treatment 
course. Hyperperfusion syndrome occurred in 0.6%. The rate of restenosis of follow-up was 7.8%. Lin et 
al 54, were the first to show improvement in cognitive function after stenting in COICA subjects with 
objective hemispheric ischemia. They found that subjects with successful recanalization had 
improvement in ipsilateral brain perfusion after the procedure, which was associated with a significant 
improvement in the scores on the Alzheimer Disease Assessment Scale–Cognitive Subtest (before: 
7.7±8.9 versus after: 5.7±7.1; p=0.024), Mini-Mental State Examination (before: 25.8±3.8 versus after: 
27.7±2.7; p=0.015), and Color Trail Making A (before: 123.2±68.6 versus after: 99.3±51.5; p=0.017), 
compared to those who failed recanalization. Fan et al 27, also conducted a prospective, controlled, 
single center study on endovascular recanalization of symptomatic COICA, reporting a success rate of 
88.9%. Additionally, they reported a noticeable clinically and statistically significant cognitive 
improvement (greater than 5 points on MoCA score) in the group that underwent successful 
endovascular recanalization compared to the group receiving conservative management (Table 1).
Summary 
1. As of today there is no definitive treatment for symptomatic COICA.
2. A subset of subjects with COICA has mild to moderate cognitive impairment with accelerated 
progression to vascular dementia.  This is supported by several animal studies (mentioned above)
3. Preliminary data from several studies including ours suggest that recanalization of COICA is feasible 
and safe especially if our COICA classification is used to guide intervention.
4. Three studies (1 retrospective and 2 prospective studies) including ours demonstrated significant 
improvement of cognitive impairment when symptomatic COICA revascularized using endovascular 
techniques.     
2.3
RISK/BENEFIT ASSESSMENT  
2.3.1
KNOWN POTENTIAL RISKS 
Risks include:
1. Ischemic stroke
2. hemorrhagic stroke


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3. Seizure 
4. Carotid cavernous fistula 
5. Visual acuity deficits. 
6. Extravasation of contrast secondary to injury to cervical ICA during the procedure; and  
7. Contrast allergy 
8. Radiation exposure from CTP and x-rays associated with diagnostic angiograms and intervention. 
9. renal dysfunction  
 
Additional risks: 
There is a very minimal risk of violation of confidentiality as some patient identifiers will be collected as 
part of the data collection process. Emotional or psychological risk could ensue if this were to occur. No 
financial, legal, social or physical risks are anticipated. 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Revascularization that may improve cognitive status and may prevent future recurrence of stroke and 
TIAs.  
 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The research team have devised a classification system that helps select subjects that are suitable for 
the procedure and minimize the risks associated with intervention. The research team will use that 
classification to enroll subjects. This classification was tested in pilot study among 4 institutions and was 
very effective. 
 
The study is designed to reduce the risks by careful pre-screening, monitoring and follow up visits. 
To reduce the risk of loss of confidentiality, precautions will be taken to ensure privacy. The 
investigators and the study team will maintain appropriate medical and research records for the study, 
in compliance with ICH E6 GCP, section 4.9 and regulatory and institutional requirements for the 
protection of confidentiality of subjects. Research records generated in this study will be stored in a file 
cabinet in a locked room and/or on a secure electronic database. Only the authorized study team will 
have access to the data. Research team members have separate usernames and passwords. Imaging 
collected during the study will be identified by a subject number, IRB protocol number, and date of 
collection. All personal data will be de-identified and kept separately from patients’ identifiers. A subject 
will be assigned a research study ID and all research data will be identified with this research study ID. 
Whenever possible, all personal information will be blacked out on all hard copy records and replaced 
with research study ID; if research team writes an article or report about the study or share the data 
with others, all personal information that can identify a subject will be removed. 
 
Data and Safety Monitoring Board [DSMB]: 
The DSMB will be appointed by the NIA to monitor the performance of the study. The Steering 
Committee will prepare regular reports summarizing patient accrual and the morbidity and mortality 
experienced in the study, The DSMB will also review the cumulative outcome data at regular intervals 
(every 6 months). 
 
During hospitalization and for the intervention arm, Dr. Samaniego will monitor for adverse events.  He 
will check on the subjects post op and every day while in hospital.  


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Definitions:  
Stroke: any new ischemic changes found either on head CT and/or MRI of the brain and associated with 
new neurological deficits that were not present prior to intervention.  
TIA: any new neurological deficits resolved within 24 hours of symptom onset.  
 
For medical arm:  The subjects will be asked to return for clinical visits and follow up at 3 montes, 6 
months and 12 months. The PI and his research nurse will check on medications, compliance, and any 
side effects. 
Also, the subjects will be given a direct number to clinic and research nurse to contact if there are any 
side effects encountered.   At initiation of medication, they will be instructed/educated about side 
effects of aspirin, Plavix, and statin.  
Additionally the research team will partner with local primary care physician who will help will monitor 
for any side effects  and will report that to the research team.  
 
 
Risks associated with procedure and strategies to mitigate them: 
Potential risks to research subjects are: 
• 
1. Ischemic stroke 
• 
2. hemorrhagic stroke 
• 
3. Seizure 
• 
4. Carotid cavernous fistula 
• 
5. Visual acuity deficits. 
• 
6. Extravasation of contrast secondary to injury to cervical ICA during the procedure; and  
• 
7. Contrast allergy 
• 
8. Radiation exposure from CTP and x-rays associated with diagnostic angiograms and 
intervention 
• 
9. Renal dysfunction  
 
Strategies to mitigate risks to subjects in the trial include 1) exclusion of subjects with COICA type D, 2) 
strict perioperative blood pressure management to minimize hypoperfusion pre-procedure (maintain 
MAP ≥ 80mmHg and ≤120mmHg) and hyper-perfusion post procedure 9maintian MAP≤ 80mmHg and 
≥60mmHg, 4) admission to neuro-intensive critical for management post procedure, and 5) use of IV 
maintenance dose Tirofiban immediately post procedure as a monotherapy for the first 24 hours (no 
aspirin or clopidogrel) to reverse the effect of anti-platelet effect within 90 minutes in case of dreaded 
intracranial hemorrhage secondary hyper-perfusion (from our series, no subjects suffered intracranial 
hemorrhage). If the subject is with signs or symptoms of intracranial hemorrhage, then at the end of 24 
hours, the subject will be given a loading dose of clopidogrel (600 mg) and aspirin (325mg) and Tirofiban 
continued for another 2 hours to allow for the loading dose of aspirin and clopidogrel to reach 
therapeutic effect 
 
Stopping rules or safety triggers for the study: 
The occurrence of following potential side effects and risks associated with procedure will trigger a 
prompt reporting and review by the DSMB to discuss the events and decide on the continuation of the 
trial. The following adverse events will be reported to the DSMB: 1) Any intracranial hemorrhage within 
72 hours post procedure, 2) Any stroke within 30 days post procedure; 3) Any seizure within 72 hours 
post procedure; and 4) Any injury to cervical ICA during the procedure.  


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Based on complication rates in the trial to date (June 2021), the occurrence of one additional event in 
these categories will trigger a suspension of enrollment in the trial and meeting of the DSMB to discuss 
the events and decide on the continuation of the trial 
A combined rate of > 20% of the above adverse events at any time during the study will lead evaluation 
by the DSMB. The cumulative rate of these events will also be assessed at different time points: A) after 
completed enrolment of the first 10 subjects, B) completed enrollment of first 20 subjects, and C) 
Completed enrollment of first 30 subjects.  If any of these thresholds are crossed, the study will 
automatically be placed on hold until the investigators and the DSMB can conduct a review of events. All 
adverse events (AEs) will be collected, recorded, and analyzed. Safety oversight for this study will be 
provided by both the DSMB and an independent Medical Safety Monitor (Dr. Edgar Samaniego). 
 
Adverse Event (AE) Reporting: 
Any potential adverse event or a serious adverse event mentioned above will be reported during the 
trial. An AE will be defined as any unfavorable and/or unintended sign, symptom, or injury temporally 
associated with the procedure or other study medication. A serious adverse event (SAE) is defined as 
any untoward/undesirable adverse experience related to a study intervention/medication that results in 
any of the following outcomes: 1) death; 2) a life-threatening adverse experience; 3) need for additional 
surgery; 4) a permanent or significant disability/incapacity; 5) important medical events that may not 
result in death, be life-threatening, or require additional surgery. 
Adverse events or a serious adverse events which occur during surgery will be communicated to the 
study coordinator and the independent Medical Safety Monitor (Dr. Edgar Samaniego) within 3 hours of 
occurrence by the surgical team. Dr. Samaniego and the study coordinator will then report the 
necessary information to the DSMB, NIH, and or IRB within 24 hours or as quickly as feasible.    
 
 
 


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3 
OBJECTIVES AND ENDPOINTS 
 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Endovascular revascularization that 
improves cognitive outcome 
 
 
Cognitive outcome at 12-month 
follow-up assessed mainly by a 
specifically designed battery of 14 
cognitive tests including the MoCA.   
 
The battery of 14 tests 
including MoCA are 
designed to test tight 
hemisphere domain, 
left hemisphere 
domain, and global 
domain to assess for 
cognitive improvement   
Secondary 
 
 
To test the safety of the procedure  
1. Safety: Occurrence of Stroke, 
Cerebral Hemorrhage, or Death 
1. These are the 
expected adverse 
events from this 
procedure and hence 
will be used to monitor 
safety  
 
   
Tertiary/Exploratory  
 
 
To test the hypothesis that subjects 
with symptomatic COICAs and 
mild/moderate cognitive 
dysfunction have associated, 
measurable biomarkers 
1. Biomarkers:  A) The 
presence/absence of lactate on 1H-
MRI spectroscopy in centrum 
semiovale in the ipsilateral side of 
COICA;  B)The change in size of 
amygdala and hippocampus in the 
ipsilateral side of COICA; C) 
Resolution/improvement of 
increased MTT and/or PTT 
(normalization of MTT and/or PTT) on 
CTP. 
2. Gender difference. 
 
These are objective 
biomarkers of 
improved cerebral 
perfusion and 
improved cognitive 
outcome.  
 
 
 
 
 


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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
Primary Hypothesis: 
Revascularizing symptomatic chronically occluded cervical ICA (COICA) using endovascular 
techniques will significantly improve cognitive outcome. 
Primary Objective: 
To test the hypothesis that endovascular revascularization of COICA ( via endovascular techniques) 
improves significantly cognitive function assessed by a specifically designed battery of 14 cognitive 
tests including the MoCA.  
 
Secondary Objectivs:  
To test the safety of endovascular revascularization of chronically occluded ICA.  
 
Tertiary/Exploratory Objectives: 
To test the hypothesis that subjects with symptomatic COICAs and mild/moderate cognitive 
dysfunction have the following biomarkers: 
A) increased MTT or TTP on CTP in the ipsilateral side of the occluded ICA specifically in the MCA 
territory when compared to the opposite unaffected hemisphere 
B) Presence of lactate and decreased Naa/Cr in the watershed area (specifically centrum 
semiovale) on 1H-MRI-spectroscopy, and 
C) Decreased size of the hippocampus and amygdala on MRI.   
 
Primary endpoints: 
Cognitive outcome at 12-month follow-up assessed mainly by a specifically designed battery of 
14 cognitive tests including MoCA. 
 
Secondary endpoints: 
1. Safety: Occurrence of Stroke, Cerebral Hemorrhage, or Death 
 
Exploratory endpoints: 
Biomarkers:   
A) The presence/absence of lactate on 1H-MRI spectroscopy in centrum semiovale in the 
ipsilateral side of COICA;  
B) The change in size of amygdala and hippocampus in the ipsilateral side of COICA.  
C) Improvement/ normalization of MTT and/or PTT on CTP specifically in the ipsilateral MCA 
territory. 
D) subgroup difference (Gender) 
 
Study Design: 
This is a phase 2 randomized single-center open label clinical trial with randomization of 1:1 to 
either best medical management vs. best medical management and endovascular revascularization 
of COICA. Subjects who meet all inclusion criteria but have a normal CTP may be included in the 
unrandomized prospective observational 3rd arm.  
 
Intervention: Surgical intervention - endovascular balloon angioplasty and stenting  


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Protocol: 
Screening, Enrolling, & Randomization: 
All subjects who presents to our tertiary hospital with a diagnosis of COICA will undergo full 
evaluation including 1) documenting previous history of TIA and/or stroke; 2) cervical and brain CTA 
to document complete occlusion; 3) CTP to assess for presence of penumbra evident by increased 
MTT and/or PTT in the ipsilateral side of COICA; and 4) MoCA.    If any subject is found to have 
complete occlusion of COICA, evident of abnormal/prolongation of MTT/ PTT on CTP, previous 
history of TIA and or stroke, and MoCA <26 or one abnormal neuropsychological test, then further 
evaluation is obtained including: 1H-MRI spectroscopy to assess for presence/absence of lactate in 
the ipsilateral watershed area (centrum semiovale), ratio of Naa/Cr, and size of ipsilateral 
hippocampus and amygdala, additional cognitive testing battery, and DSA to document adequately 
the type of COICA the subject have (type A-D). 
 
If any subject has  complete occlusion, and/or MoCA >26 or abnormal neuropsychological test but 
no abnormalities on CTP, then the subject is eligible for arm 3. This arm will only be prospective 
observational with best medical management. No randomization will be completed for these 
subjects.  
 
If the subject does not meet inclusion/ exclusion criteria (except for the circumstance described 
above) the subject’s participation will be discontinued. No further testing will be required.  
 
If the subject meets all inclusion criteria, then a baseline of complete neurological testing, full 
demographics, CTA or MRA, CTP, MoCA, additional neurological testing (see below), 1H-MRI 
sectroscopy and DSA are obtained and subject is randomized 1:1 to either best medical 
management or best medical management + endovascular balloon angioplasty and stenting. If the 
subject is randomized to this treatment, their pre-op visit will include a blood draw (CBC and 
chemistry/BMP) 
 
Follow up clinic visits are arranged at 6 and 12 months. Repeat testing of MoCA and additional 
cognitive testing battery are done at these clinical follow-up visits (6 and 12 months). MRI of the 
brain and  DSA is performed at 6 month and 1 year follow-up to assess brain biomarkers and 
revascularization respectively. All MRI images required by the protocol may be completed under 
sedative, if subject requests and PI deems them eligible.   
 
Definitions  
1. Stroke: ischemic changes noted on CT/MRI of brain and associated with new neurological deficits 
within 120 days prior to enrolment.    
2. TIA: New neurological deficits that resolve within 24 hours of onset and within 120 days prior to 
enrolment.     
3. Abnormal neuropsychological test: any tests included in the screening battery that is scored 
below 1.5 SDs below the gender, age, and education matched norms.  
 
Procedure: 
Procedure will be performed under general anesthesia.  Prior to induction of general anesthesia, A-
line will be paced to monitor for blood pressure.  The mean arterial pressure  (MAP) will be 
maintained above 80mmHG during the procedure till complete revascularization of the occluded 
cervical ICA. At that time MAP will be lowered to < 80mmHG.  The anesthesia team will use their 
standard of care medications to maintain the pressure as describe d above.  


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The groin area will be prepped and draped in the usual sterile fashion.  Femoral access will be 
obtained using 18 gauge needle. Nine French sheet will be placed over the guide wire provided.  
5 French Bernstein catheter and 6 French Cook shuttle catheter will be advanced over 0.038 Terumo 
guide wide to the common carotid artery of the occluded cervical ICA.  At the time, the 5 French 
Bernstein catheter will be withdrawn and contrast will be injected to obtain selective images.  
After that, attempt to cross the occluded segment will be done, first using SL-10 microcatheter and 
0.014 synchro soft microwire, if unsuccessful, then will use the 0.038 exchange Terumo guide wire.  
If not successful, then will use the stiffer end of the 0.038 exchange Terumo guide wire.  If not 
successful, then abort procedure.  If successful, then advance the microwire or the Terumo wire 
across the occlusion till identifying normal lumen.   Following that, angioplasty and stenting using 
approved angioplasty balloons and carotid stents will be sued to recanalize the occluded ICCA.   
During that time, anesthesia will monitor for bradycardia.  If any bradycardia, they treat per 
standard care and use atropine.  Once recanalization is achieved, the MAP will be lowered to < 
80mm Hg using standard care medication per anesthesia.  IV maintenance dose Tirofiban (0.1 
microgram/kg/min) immediately post procedure as a monotherapy for the first 24 hour 
Following that the puncture site will be closed using angioseal device.   The patient will be extubated 
and transferred to surgical ICU for BP monitoring.   If the subject is doing well, he/she is transferred 
to the normal floor. Aspirin and plavix will be continued for 12 months.   
 
Strategies to mitigate risks to subjects during hospitalization include: 
1) exclusion of subjects with COICA type D, 2) performing the procedure only by the PI, 3) strict 
perioperative blood pressure management to minimize hypoperfusion pre-procedure (maintain 
MAP ≥ 80mmHg and ≤120mmHg) and hyper-perfusion post procedure (maintain MAP≤ 80mmHg 
and ≥60mmHg, 4) admission to neuro-intensive critical for management post procedure, and 5) use 
of IV maintenance dose Tirofiban immediately post procedure as a monotherapy for the first 24 
hours (no aspirin or clopidogrel) to reverse the effect of anti-platelet effect within 90 minutes in 
case of dreaded intracranial hemorrhage secondary hyper-perfusion (from our series, no subjects 
suffered intracranial hemorrhage).  If the subject is with no signs or symptoms of intracranial 
hemorrhage, then at the end of 24 hours, the subject will be given a loading dose of clopidogrel (600 
mg) and aspirin (325mg) and Tirofiban continued for another 2 hours in order for the loading dose 
of aspirin and clopidogrel to reach therapeutic effect. 
 
Diagnostic and Follow- up angiograms:  
These procedures will be done under monitored anesthetic are per standard care.    The groin area 
will be prepped and draped in the usual sterile fashion.  Femoral access will be obtained using 18 
gauge needle. Five French sheet will be placed over the guide wire provided.  
5 French Bernstein catheter will be advanced over 0.038 Terumo guide wide to the common carotid 
artery of the same side of previous recanalization.  Dye will be injected and multiple images will be 
obtained to assess patency of stents. Following that, the puncture site will be closed using angioseal 
device.   The subject will then be transferred to second stage and kept flat for 2 hours then 
discharged home.  
 
Cognitive Testing: 
Participants who are enrolled in this study will undergo a standardized neuropsychological test 
battery at 3 time points with the test score calculated at 12-month follow-up is considered the 
primary endpoint for the trial: 
(1) Baseline: prior to procedure.  


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(2) Early Post-op: At 6 months post-discharge from hospital, to investigate short-term cognitive 
outcome; 
(3) Late Post-op: At 12 months post-discharge from hospital, to investigate long-term cognitive 
outcome. 
 
We selected a battery of tests that includes a standard screening measure (the MoCA), to facilitate 
comparisons to other studies that have used this as the primary cognitive outcome measure.  The 
battery includes a number of well-standardized, widely used cognitive tests that measure various 
aspects of cognitive and behavioral functioning, including intelligence, attention, processing speed, 
memory, speech and language, visuoconstruction, and executive functioning.  We selected a set of 
tests that can be administered in a one-hour session, and that are highly efficient (providing the 
highest yield for time required).  Also, for all of these tests we have standardized information about 
the effects of repeat assessment, and/or multiple forms of the tests that allow practice effects to be 
either obviated or measured and factored into the analyses.  A general reference for the 
neuropsychological assessment battery we are proposing is Lezak, Howiesen, Bigler, and Tranel 
(2012)53 , the standard textbook on neuropsychological assessment on which one of the current co-
investigators (Tranel) is a co-author. 
 
The test battery at each time point will include the following measures: 
1. Montreal Cognitive Assessment (MoCA): This is a widely used screening instrument designed for 
the detection of cognitive impairment 62. Total points possible on this test range from 0 – 30. 
2. Wide Range Achievement Test-5 (WRAT-5)104, Word Reading subtest: This is a single-word oral 
reading test, well-validated as an estimate of baseline general intelligence (Wilkinson & Robertson, 
2017). The number of correctly read words is converted to an age-adjusted standard score (mean = 
100, standard deviation = 15). 
3. Wechsler Adult Intelligence Scale – IV (WAIS-IV), Digit Span subtest: This test measures complex 
attention and working memory. The participant is asked to repeat a series of aurally presented digits 
of increasing length (a) verbatim, (b) in reverse order, and then (c) sequentially from lowest to 
highest 102. The total score is converted to an age-corrected scaled score (mean = 10, standard 
deviation = 3). 
4. WAIS-IV, Coding subtest: This test measures sustained attention and processing speed. Using a 
key, the participant writes the symbol corresponding to its number as quickly and accurately as 
possible. The total score is converted to an age-corrected scaled score (mean = 10, standard 
deviation = 3). 
5. WAIS-IV, Matrix Reasoning subtest: This test measures concept formation and abstract 
reasoning. The participant selects one of five options to complete a visual pattern. The total score is 
converted to an age-corrected scaled score (mean = 10, standard deviation = 3). 
6. Hopkins Verbal Learning Test – Revised (HVLT-R): This is a test of learning and memory. The 
participant is read a list of 12 semantically categorized words (four words in each of three 
categories) and asked to recall as many as possible. The test consists of three learning trials, 
followed by delayed recall and yes/no recognition trials 13. The scores from this test are (a) sum of 
the total correct responses for the learning trials, (b) the number recalled at the delay, and (c) the 
recognition discrimination index (number of correctly recognized – number of false positives).  
Scores are converted to T-scores. 
7. Benton Visual Retention Test (BVRT) 7: This test measures attention, working memory, and 
visual  
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designs for 10 seconds, and then is instructed to draw the design(s) immediately after the stimulus 
is removed 88.  Scores are the total number of correct designs (range 0 – 10) and total number of 
errors, converted to z-scores. 
8. Controlled Oral Word Association (COWA) Test: This test measures flexible thinking and verbal 
fluency. The participant is asked to orally generate as many words as possible in 60 seconds, for 
each of three letters 7:. The score (age- and gender-corrected) is the total number of words 
generated across the three trials; this is converted to a percentile score. 
9. Boston Naming Test (BNT): This is a test of confrontation naming in which the participant is 
presented line-drawn pictures and asked to name them 47 . The overall test contains 60 items, from 
which three equivalent short-form versions (20 items each) will be used in the current study 5. The 
score is the number of correctly named items (range 0 – 20), converted to a z-score. 
10. Boston Diagnostic Aphasia Examination, Complex Ideational Material subtest (CIM): This is an 
auditory comprehension test developed to measure sustained attention and receptive language 
skills. It consists of yes/no questions of increasing difficulty in which the participant must recall 
common facts, and infer details contained in short, aurally presented stories 38. The range of scores 
on this test is 0 – 12, and raw scores are converted to T-scores. 
11. Trail-Making Test, part A (TMT-A): This test measures attention, processing speed, and 
visuomotor skills. Participants are asked to connect 25 numbered circles as quickly and accurately as 
possible 78. The score is the time to completion (in seconds), converted to a T-score. 
12. Trail-Making Test, part B (TMT-B): This test measures divided attention, processing speed, 
cognitive flexibility, and executive function. The participant is asked to connect 25 numbered and 
lettered circles, alternating between the two in numerical and alphabetical order (e.g., 1, A, 2, B, 3, 
C, etc.). The score is the time to completion (in seconds), converted to a T-score. 
13. Beck Depression Inventory-Fast Screen (BDI-FS): This is a self-report inventory of depressive 
symptomatology, designed for use in persons with medical illnesses6.  Scores are converted to a 
range of depression severity (none, mild, moderate, severe). 
14. Iowa Scales of Personality Change (ISPC): On this measure, a collateral of the patient (e.g., 
spouse, child) rates behavioral and personality characteristics of the patient before and after a 
particular event (for the current study, this will be the surgical intervention) 4.  The ISPC measures 
changes in personality and behavior, and will be administered only at the post-surgery evaluations 
(to the collateral).  Scores are converted to z-scores. 
The score on the MoCA will serve as an overall proxy for cognitive outcome, and can be used to 
measure change (e.g., pre to post).  Scores from tests 2-12 in the proposed neuropsychological 
battery will be converted to z-scores, to facilitate direct comparisons across the test battery for pre 
to post (including short- and long-term outcomes).  These will also be used to analyze changes in 
specific cognitive domains. The score from the BDI-FS will be used as a covariate to assess the role of 
depressive symptomatology in cognitive performance. 
 
Demographics collected: 
We will collect the following demographics during initial screening visit: age, gender, education 
level, antiplatelets and anticoagulation therapy, statin therapy, NIHSS, pre-procedure modified 
Rankin Scale (mRS), employment, history of depression, use of antidepressant medications, history 
of hypertension, history of stroke/TIA, history of seizures, comorbid diseases, and history of head 
injury. 
 
 
CTP protocol (adopted from Kamath et al; Neuroradiology. 2008 Sep; 50(9): 745–751; Bathla et al, 
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CTP is performed in the radiology department using Siemens CT scanner. Images will be acquired on 
either a 128 slice (SOMATOM definition AS; Siemens AG, Forchheim, Germany) or a 192 slice 
(SOMATOM Force, Siemens AG) scanner. 
18 French IV access is obtained.  Then 40 ml bolus of iodine contrast (Isovue-370, iopamidol, 370 mg 
iodine/mL; Bracco Diagnostics, Princeton, New Jersey, USA) is administered into a vein using a 
power injector (Stellant D; MedRad Inc, Indianola, Pennsylvania, USA), with a 2 s delay between 
contrast injection and scan initiation. The acquisition parameters are 80 kV and 9.6 cm scan range. 
he radiation dose is 2 mSv. Data are acquired using the protocol recommended: with 4 scans 3 s 
apart followed by 15 scans 1.5 s apart, and another 9 scans 3 s apart, totaling 28 scans over 
approximately 60 s. We will utilize the software in the Siemens CT scanner in our radiology 
department [The Syngo software (Syngo.via CT Neuro Perfusion VB30; Siemens Healthineers, 
Erlangen, Germany)].  Initial post-processing using the vendor specified parameters to include initial 
motion correction, bone removal and brain segmentation, 4D noise reduction, and reference vessel 
and arterial input function detection. The software is programmed to use the central volume 
principle will apply the curve fitting by least mean squares to obtain mathematical descriptions of 
the time-density curves for each pixel. A closed-form (non-iterative) deconvolution that accounts for 
delay-related errors is then applied to calculate the mean transit time (MTT) map. The 
deconvolution operation requires a reference arterial input function (AIF). The cerebral blood 
volume (CBV) map is calculated from the area under the time-density curves. Cerebral blood flow 
(CBF) is calculated as the CBV/MTT ratio. In Syngo, infarct core/non-viable tissue (NVT) is defined as 
rCBF <threshold. Voxels not treated as NVT are classified as ‘tissue at risk’ (TAR) if Tmax >6 s. MR 
was calculated as MR=(TAR+NVT)/NVT. 
 
MRI protocol: 
MR Image Acquisition MR imaging will be performed on a GE 750W 3T scanner using a 32-channel 
head coil. Anatomical images will include volumetric T1 MPRAGE (TI=900ms, TE=3ms, TR=3000ms, 
flip angle=10°, FOV=210x210x210mm, matrix=420x420x420, bandwidth= 244Hz/pixel, 
acceleration=4) and T2 CUBE (TE= 90ms, TR= 3000ms, echo train length=130, 
FOV=210x210x210mm, matrix=420x420x420, bandwidth= 488Hz/pixel, acceleration=4) sagittal 
scans with a 0.5 mm isotropic spatial resolution. The 1H MRS data will be acquired from voxels 
placed in the centrum semiovale in the ipsilateral side of COICA using a single-voxel semi-LASER 
sequence with the following parameters: TE=288, TR=4000ms, Voxel size = 20x20x20mm, Spectral 
Width=5000Hz, Vector size=4096, and NEX=32. Data will be collected with and without water  
suppression. 
 
Volumetric Anatomical Image Analysis: The volumetric anatomical T1- and T2-weighted images will 
be analyzed using BRAINS AutoWorkup 72 that includes a FreeSurfer 22,32,33 module using Nipype 
39. The default FreeSurfer pipeline will be updated to segment the brain and generate the cortical 
surface using a 0.5mm resolution for the reconstruction. The original images and the automated 
pipeline results will be checked for validity by a trained technician who is blind to subject status.  Of 
primary interest for this analysis is the volume of the hippocampus and amygdala as generated by 
this pipeline 
 
MRI-Specteroscpy  (MRS) Analysis. The 1H MRS data will be analyzed using LCModel 77. The water 
suppressed and non-water suppressed data will be analyzed to generate absolute concentrations 
after performing phase and eddy current correction. We will obtain concentrations measurements 
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the 1H data. Only metabolites with a Cramer-Rao lower bound of less than 20% will be included in 
further analyses. Lactate concentrations will be the primary metabolite of interest for this study. 
 
MRI protocol for checking silent infarcts/strokes will contain the same sequences described 
previously in addition to adding T2 and SWI sequences.  Each will add 2-3 minutes with a total of 4-6 
minutes   
 
All MRI images required by the protocol may be completed under sedative, if subject requests and 
PI deems them eligible.   
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Control is observation and best medical management for the carotid occlusion which is the standard of 
care. 
 
4.3 
JUSTIFICATION FOR DOSE 
Not applicable here.  
 
 
4.4 
END OF STUDY DEFINITION 
1) Successful completion is 1-year cognitive assessment 
2) Early termination due to intracranial hemorrhage, stroke, death, seizure or injury to cervical ICA 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
• 
Age ≥ 21  
• 
Complete occlusion of cervical ICA on imaging studies (MRA or CTA) and confirmed with DSA 
• 
History of TIA or stroke  
• 
Increased MTT and/or TTP on CTP as defined as TMax threshold of > 10cc > 4 seconds in the 
territory of the occluded carotid specifically in the MCA territory when compared to the 
opposite unaffected hemisphere 
• 
All occlusion is due to atherosclerotic disease 
• 
MoCA < 26 and/or one abnormal test on the rest of the neuropsychological battery 
administered at screening 
• 
Occlusion is class A or B using COICA classification 
• 
Study team able to gain consent from subject or LAR  
• 
7. Failed best medical treatment (continued TIA symptoms despite medical management)  
 
5.2 
EXCLUSION CRITERIA 
 
• 
History of Moyamoya or Moyamoya like disease 
• 
Tandem occlusion 
• 
No evidence of increased MTT or TTP on CT perfusion   


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• 
Severe co-morbid diseases: renal insufficiency, end-stage renal disease, liver cirrhosis, COPD 
requiring home oxygen, terminal illness such as cancer, Parkinson disease or other 
neurodegenerative  diseases, severe cognitive heart failure, seizures, debilitating stroke, mRS 
≥3.  
• 
Short life expectancy due to cancer or other co-morbid diseases   
• 
Class C or D on COICA classification  
• 
Occlusion of the Common Carotid Artery  
• 
Normal neuropsychological battery results  
• 
Subject unwilling to participate in follow up and/ or unwilling to be randomized to surgery 
 
 If subject meets any combination of these exclusion criteria, they may be applicable for the non-
randomized third arm.  
 
If a subject meets all criteria and is randomized to surgery their eligibility will be confirmed by 1 outside 
adjudicator. If this decision is not in agreement with the PI then a second adjudicator will 
review. Despite ruling, inclusion will be confirmed by two clinicians (PI and adjudicator or both 
adjudicators). 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Smoking cessation.  
 
5.4 
SCREEN FAILURES 
These subjects will be monitored longitudinally per standard of care for any signs of stroke/TIAs or 
other neurological deterioration including cognitive decline.  If during the study period, the subjects 
re-meet the criteria of inclusion, then they will be approached again for enrollment.   
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 Recruitment 
Participants will present to either to the emergency department and/or neurosurgery/neurology clinic for 
evaluation of symptomatic chronic cervical internal carotid artery (ICA) occlusion (COICA).   Imaging 
studies will be obtained to confirm diagnosis of COICA.  
To be recruited and enrolled for the trial, the following inclusion/exclusion criteria must be satisfied:   
E.2 Inclusion and Exclusion Criteria:  
Inclusion Criteria 
Exclusion Criteria 
Age ≥ 21  
History of Moyamoya or Moyamoya like disease 
Complete occlusion of cervical ICA on imaging studies 
(MRA or CTA) and confirmed with DSA 
Tandem occlusion 
History of TIA or stroke  
No evidence of penumbra (increased MTT and/or 
PTT) on CT perfusion  
Increased MTT and/or TTP on CTP as defined as TMax 
threshold of > 10cc > 4 seconds in the territory of the 
occluded carotid specifically in the MCA territory when 
compared to the opposite unaffected hemisphere 
Severe co-morbid diseases: end-stage renal 
disease, liver cirrhosis, COPD requiring home 
oxygen, terminal illness such as cancer, Parkinson 
disease or other neurodegenerative  diseases, 


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severe congetive heart failure, seizures, debilitating 
stroke, mRS ≥3. 
All occlusion is due to atherosclerotic disease 
Short life expectancy due to cancer or other co-
morbid diseases   
MoCA < 26 and/or one or more abnormal test on the rest of 
the neuropsychological battery administered at screening 
MoCA ≥ 26 and normal screening battery 
Study team able to gain consent from subject or LAR  
 
Subject unwilling to participate in follow up and/ or 
unwilling to be randomized to surgery  
Class A or B occlusion based on COICA classification 
Class Cor D occlusion based on  COICA 
classification  
 
Occlusion of the Common Carotid Artery 
 If a subject meets any combination of these exclusion criteria, they may be applicable for the non-
randomized third arm. 
E.3 Definitions:  
• 
Chronically Occluded Cervical ICA (COICA): documented complete occlusion of cervical ICA 
evident on CTA, and/or MRA for at least 4 weeks. 
• 
Symptomatic (COICA): subjects with chronically occluded ICA with a presentation of TIA and/or 
stroke corresponding to anatomical structures supplied by the ipsilateral COICA. 
• 
Abnormal test is considered 1.5 SD below age, gender, and education norms   
• 
Severity of impairment 
o Mild cognitive impairment:  MoCA score < 26 but ≥23  
o Moderate cognitive impairment: MoCA score < 23 but ≥18 
o Severe cognitive impairment: MoCA < 18  
 
I. 
The proposed NIA SCORE trial is committed to aggressively recruit and include women and 
members of minority groups.  
 
II. MINORITY RECRUITMENT 
The investigators have set a goal of enrolling at least 15-30% of minorities in this trial. To ensure adequate 
recruitment and enrolment of minorities to the trial, we will employ the following strategies:   
1. The research team will be educated and made aware of the attention that must be given to 
cultural, historical, social, and political factors that may influence minority participation.  In focus 
groups with African-Americans, many of them needed clarification of a clinical trial, and the term 
“research study” had more meaning.  Most indicated that certain criteria had to be in place before 
they would consider participating: benefit to family/community, pastor’s encouragement, type of 
research, understanding of study, and who is conducting the research. 
2. Social workers will be involved to help arrange for transportation for these study subjects who 
lack them, which is important for follow-up in clinic. 
3. Clinic office hours may need to be extended to allow for the schedules of working individuals or 
those with caregiving responsibilities.  
4. The accessibility and location of the clinic/hospital would also be considered to encourage 
compliance with follow-up appointments. 
III. RECRUITMENT OF WOMEN:   


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The investigators have set a goal of enrolling at least 30-50% women in this trial. The staff and 
investigators will make it a priority to make extra time and commitment to understand other issues in the 
subject’s personal life that may affect her enrollment and compliance. 
IV. Specific strategies that we will use to enhance recruitment and retention of underrepresented 
minorities and women into your trial: 
The research team will employ the following additional strategies to ensure adequate enrolment of 
women and minorities in the trial by suing these specific strategies:  
1. The research team will be urged to appropriately present the trial to women and all minority 
patients with emphasis on presenting the facts in regard to the potential impact of  the study on 
their health and standard care. 
2. The nurse research coordinator will periodically communicate with women and minority subjects 
to address their concerns and attempt to facilitate compliance and retention and minimize drop 
out.  
3. Financial voucher ($75) per annual clinic visit will be provided to cover gas mileage, parking, and 
a small meal. 
 
 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Endovascular balloon angioplasty and stenting  
Medical management: Aspirin 325 mg po daily; Plavix 75 mg po daily; Statin.  
 
         
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
1) Randomized 1:1 ratio 
2) Blinded assessment of cognition, MRI and exploratory endpoints 
 
6.3 
STUDY INTERVENTION COMPLIANCE 
Percent revascularized 
 
 
6.4 
CONCOMITANT THERAPY 
 
Best Medical Management: daily dual antiplatelet therapy (aspirin: 325 mg p.o. qd and Clopidogrel: 75 
mg p.o. qd), optimization of systolic blood pressure (120 -140 mmHg), smoking cessation, and statin 
therapy. These primary risk factors (systolic blood pressure, smoking, and cholesterol level) will be 
managed mainly by the local primary care physician with inputs from the research team. The goal is 
targeting a systolic blood pressure (SBP) 120-140 mmHg and smoking cessation. Subjects will be 
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of risk factors during the first year, then annually thereafter.  Also during follow up visits, the research 
team will ensure compliance with medications.  
Also keeping the SBP > 120mmHg will ensure prevention of potential hypoperfusion of the brain 
resulting into cerebral hemodynamic compromise and potential TIA and/or stroke. 
Statin: the subject will be started on Lipitor 20 mg po qd.  Lipid profile will be monitored by the primary 
care physician.  
 
Smoking Cessation: We chose a target level of complete cessation of smoking in our trial for the 
following reasons: 1. Several studies have shown that smoking is associated with worsening 
atherosclerotic disease and stroke. 2. Smoking cessation is recommended for all patients by the US 
Department of Health and Human Services and by the AHA/ASA guidelines for the Primary Prevention of 
stroke. and management of UIA. 3. Light and intermittent smoking have been associated with increased 
cardiopulmonary and cerebrovascular risks and death. If the patient doesn’t quit smoking, he/she will 
continue to be encouraged to quit smoking and he/she will be kept enrolled in the study.   
 
To insure compliance with recommendation and best medical management plan, we will implement the 
following: A) The study will provide each subject with a blood pressure cuff to measure blood pressure 
in siting position biweekly and document pressure measurements in a diary notebook.  These 
measurements will be taken at home and in clinic.  The measurements will be reviewed by the PCP of 
the study, the research nurse, and local PCP.  Family member will be educated on how to take the blood 
pressure. The nurse research will observe the family member perform BP measurements on the subject 
during the initial training and in random visits to ensure adequate technique.  B) Counting bills by the 
research team during clinic visits will be used to monitor for compliance. C) Lipid profile panel will be 
used to monitor compliance for using statin.   D) A survey of over the counter medications will be obtain 
during each clinic visit.    
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
None   
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention such as 
development of cancer, severe COPD, end stage renal disease, …  
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation.  


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The reason for participant discontinuation or withdrawal from the study will be recorded on the REDCap 
Case Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not 
receive the study intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will not be replaced. 
7.3 
LOST TO FOLLOW-UP 
Enrolled subjects in the study are expected to be followed for 12 months post intervention.   The 
followup included assessment of cognitive function using the designed battery of tests (including Moca), 
DSA, CTP and MRI of the brain. 
Participants are considered lost to follow-up when they stop reporting to scheduled study visits and 
cannot be reached to complete all protocol-required study procedures.  
To minimize that:  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The research nurse will attempt to contact the participant and reschedule the missed visit within 
30 days from scheduled visit and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain if the participant wishes to and/or should continue in the 
study. 
• 
Before a participant is deemed lost to follow-up, the PI will make every effort to regain contact 
with the participant (where possible, 3 telephone calls and, if necessary, a certified letter to the 
participant’s last known mailing address or local equivalent methods). These contact attempts 
will be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
Cognitive Testing: 
Participants who are enrolled in this study will undergo a standardized neuropsychological test battery 
at 3 time points with the test score calculated at 12-month follow-up is considered the primary endpoint 
for the trial: 
(1) Baseline: prior to procedure.  
(2) Early Post-op: At 6 months post-discharge from hospital, to investigate short-term cognitive 
outcome; 
(3) Late Post-op: At 12 months post-discharge from hospital, to investigate long-term cognitive 
outcome. 
 
We selected a battery of tests that includes a standard screening measure (the MoCA), to facilitate 
comparisons to other studies that have used this as the primary cognitive outcome measure.  The 
battery includes a number of well-standardized, widely used cognitive tests that measure various 
aspects of cognitive and behavioral functioning, including intelligence, attention, processing speed, 
memory, speech and language, visuoconstruction, and executive functioning.  We selected a set of tests 
that can be administered in a one-hour session, and that are highly efficient (providing the highest yield 
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repeat assessment, and/or multiple forms of the tests that allow practice effects to be either obviated 
or measured and factored into the analyses.  A general reference for the neuropsychological assessment 
battery we are proposing is Lezak, Howiesen, Bigler, and Tranel (2012)53 , the standard textbook on 
neuropsychological assessment on which one of the current co-investigators (Tranel) is a co-author. 
The test battery at each time point will include the following measures: 
1. 
Montreal Cognitive Assessment (MoCA): This is a widely used screening instrument designed for 
the detection of cognitive impairment 62. Total points possible on this test range from 0 – 30. 
2. 
Wide Range Achievement Test-5 (WRAT-5)104, Word Reading subtest: This is a single-word oral 
reading test, well-validated as an estimate of baseline general intelligence (Wilkinson & Robertson, 
2017). The number of correctly read words is converted to an age-adjusted standard score (mean = 100, 
standard deviation = 15). 
3. 
Wechsler Adult Intelligence Scale – IV (WAIS-IV), Digit Span subtest: This test measures complex 
attention and working memory. The participant is asked to repeat a series of aurally presented digits of 
increasing length (a) verbatim, (b) in reverse order, and then (c) sequentially from lowest to highest 102. 
The total score is converted to an age-corrected scaled score (mean = 10, standard deviation = 3). 
4. 
WAIS-IV, Coding subtest: This test measures sustained attention and processing speed. Using a 
key, the participant writes the symbol corresponding to its number as quickly and accurately as possible. 
The total score is converted to an age-corrected scaled score (mean = 10, standard deviation = 3). 
5. 
WAIS-IV, Matrix Reasoning subtest: This test measures concept formation and abstract 
reasoning. The participant selects one of five options to complete a visual pattern. The total score is 
converted to an age-corrected scaled score (mean = 10, standard deviation = 3). 
6. 
Hopkins Verbal Learning Test – Revised (HVLT-R): This is a test of learning and memory. The 
participant is read a list of 12 semantically categorized words (four words in each of three categories) 
and asked to recall as many as possible. The test consists of three learning trials, followed by delayed 
recall and yes/no recognition trials 13. The scores from this test are (a) sum of the total correct 
responses for the learning trials, (b) the number recalled at the delay, and (c) the recognition 
discrimination index (number of correctly recognized – number of false positives).  Scores are converted 
to T-scores. 
7. 
Benton Visual Retention Test (BVRT) 7: This test measures attention, working memory, and 
visual  
perceptual-constructional skills. The participant is shown a page containing one to three geometric  
designs for 10 seconds, and then is instructed to draw the design(s) immediately after the stimulus is 
removed 88.  Scores are the total number of correct designs (range 0 – 10) and total number of errors, 
converted to z-scores. 
8. 
Controlled Oral Word Association (COWA) Test: This test measures flexible thinking and verbal 
fluency. The participant is asked to orally generate as many words as possible in 60 seconds, for each of 
three letters 7:. The score (age- and gender-corrected) is the total number of words generated across 
the three trials; this is converted to a percentile score. 
9. 
Boston Naming Test (BNT): This is a test of confrontation naming in which the participant is 
presented line-drawn pictures and asked to name them 47. The overall test contains 60 items, from 
which three equivalent short-form versions (20 items each) will be used in the current study 5. The score 
is the number of correctly named items (range 0 – 20), converted to a z-score. 
10. 
Boston Diagnostic Aphasia Examination, Complex Ideational Material subtest (CIM): This is an 
auditory comprehension test developed to measure sustained attention and receptive language skills. It 
consists of yes/no questions of increasing difficulty in which the participant must recall common facts, 
and infer details contained in short, aurally presented stories 38. The range of scores on this test is 0 – 
12, and raw scores are converted to T-scores. 


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11. 
Trail-Making Test, part A (TMT-A): This test measures attention, processing speed, and 
visuomotor skills. Participants are asked to connect 25 numbered circles as quickly and accurately as 
possible 78. The score is the time to completion (in seconds), converted to a T-score. 
12. 
Trail-Making Test, part B (TMT-B): This test measures divided attention, processing speed, 
cognitive flexibility, and executive function. The participant is asked to connect 25 numbered and 
lettered circles, alternating between the two in numerical and alphabetical order (e.g., 1, A, 2, B, 3, C, 
etc.). The score is the time to completion (in seconds), converted to a T-score. 
13. 
Beck Depression Inventory-Fast Screen (BDI-FS): This is a self-report inventory of depressive 
symptomatology, designed for use in persons with medical illnesses6.  Scores are converted to a range 
of depression severity (none, mild, moderate, severe). 
14. 
Iowa Scales of Personality Change (ISPC): On this measure, a collateral of the patient (e.g., 
spouse, child) rates behavioral and personality characteristics of the patient before and after a particular 
event (for the current study, this will be the surgical intervention) 4.  The ISPC measures changes in 
personality and behavior, and will be administered only at the post-surgery evaluations (to the 
collateral).  Scores are converted to z-scores. 
The score on the MoCA will serve as an overall proxy for cognitive outcome, and can be used to measure 
change (e.g., pre to post).  Scores from tests 2-12 in the proposed neuropsychological battery will be 
converted to z-scores, to facilitate direct comparisons across the test battery for pre to post (including 
short- and long-term outcomes).  These will also be used to analyze changes in specific cognitive 
domains. The score from the BDI-FS will be used as a covariate to assess the role of depressive 
symptomatology in cognitive performance. 
 
MR Image Acquisition MR imaging will be performed on a GE 750W 3T scanner using a 32-channel head 
coil. Anatomical images will include volumetric T1 MPRAGE (TI=900ms, TE=3ms, TR=3000ms, flip 
angle=10°, FOV=210x210x210mm, matrix=420x420x420, bandwidth= 244Hz/pixel, acceleration=4) and 
T2 CUBE (TE= 90ms, TR= 3000ms, echo train length=130, FOV=210x210x210mm, matrix=420x420x420, 
bandwidth= 488Hz/pixel, acceleration=4) sagittal scans with a 0.5 mm isotropic spatial resolution. The 
1H MRS data will be acquired from voxels placed in the centrum semiovale in the ipsilateral side of 
COICA using a single-voxel semi-LASER sequence with the following parameters: TE=288, TR=4000ms, 
Voxel size = 20x20x20mm, Spectral Width=5000Hz, Vector size=4096, and NEX=32. Data will be collected 
with and without water suppression.  
 
Volumetric Anatomical Image Analysis: The volumetric anatomical T1- and T2-weighted images will be 
analyzed using BRAINS AutoWorkup 72 that includes a FreeSurfer 22,32,33 module using Nipype 39. The 
default FreeSurfer pipeline will be updated to segment the brain and generate the cortical surface using 
a 0.5mm resolution for the reconstruction. The original images and the automated pipeline results will 
be checked for validity by a trained technician who is blind to subject status.  Of primary interest for this 
analysis is the volume of the hippocampus and amygdala as generated by this pipeline 
MRI-Specteroscpy  (MRS) Analysis. The 1H MRS data will be analyzed using LCModel 77. The water 
suppressed and non-water suppressed data will be analyzed to generate absolute concentrations after 
performing phase and eddy current correction. We will obtain concentrations measurements for NAA, 
glutamate+glutamine (Glx), total creatine (Cr+PCr), total choline (tCho), and lactate from the 1H data. 
Only metabolites with a Cramer-Rao lower bound of less than 20% will be included in further analyses. 
Lactate concentrations will be the primary metabolite of interest for this study 
 
All MRI images required by the protocol may be completed under sedative, if subject requests and PI 
deems them eligible.   
 


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8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Stopping rules or safety triggers for the study: 
The occurrence of the following potential side effects and risks associated with procedure will trigger 
prompt reporting and review by the DSMB to discuss the events and decide on the continuation of the 
trial. The following adverse events, will be reported to the DSMB: 1) Any intracranial hemorrhage within 
72 hours post procedure, 2) Any stroke within 30 days post procedure; 3)Any seizure within 72 hours 
post procedure; and 4) any injury to cervical ICA during the procedure.  
Based on complication rates in the trial to date (June 2021), the occurrence of one additional event in 
these categories will trigger a suspension of enrollment in the trial and meeting of the DSMB to discuss 
the events and decide on the continuation of the trial 
The cumulative rates will also be assessed at different time points: A) after completed enrollment of the 
first 10 subjects, B) completed enrollment of first 20 subjects, & C) Completed enrollment of first 30 
subjects. A rate of > 20% will lead to automatic stop and evaluation by the DSMB.    
Safety oversight for this study will be provided by both the DSMB and an independent Medical Safety 
Monitor (Dr. Edgar Samaniego). 
 
 
 
 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Potential risks to research subjects are: 1. Intracranial hemorrhage secondary to re-perfusion injury; 2. 
Stroke; 3. Seizures; 4. Extravasation of contrast secondary to injury to cervical ICA during the procedure; 
and 5. Contrast allergy.  Strategies to mitigate risks to subjects in the trial include 1) exclusion of subjects 
with COICA type D, 2) performing the procedure only by the PI, 3) strict perioperative blood pressure 
management to minimize hypoperfusion pre-procedure (maintain MAP ≥ 80mmHg and ≤120mmHg) and 
hyper-perfusion post procedure maintain MAP≤ 80mmHg and ≥60mmHg, 4) admission to neuro-
intensive critical for management post procedure, and 5) use of IV maintenance dose Tirofiban 
immediately post procedure as a monotherapy for the first 24 hours (no aspirin or clopidogrel) to 
reverse the effect of anti-platelet effect within 90 minutes in case of dreaded intracranial hemorrhage 
secondary hyper-perfusion (from our series, no subjects suffered intracranial hemorrhage).  If the 
subject is with no signs or symptoms of intracranial hemorrhage, then at the end of 24 hours, the 
subject will be given a loading dose of clopidogrel (600 mg) and aspirin (325mg) and Tirofiban continued 
for another 2 hours in order for the loading dose of aspirin and clopidogrel to reach therapeutic effect 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
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Any potential adverse event or a serious adverse event mentioned above will be reported during the 
trial. An AE will be defined as any unfavorable and/or unintended sign, symptom, or injury temporally 
associated with the procedure or other study medication. A serious adverse event (SAE) is defined as 
any untoward/undesirable adverse experience related to a study intervention/medication that results in 
any of the following outcomes: 1) death; 2) a life-threatening adverse experience; 3) need for additional 
surgery; 4) a permanent or significant disability/incapacity; 5) important medical events that may not 
result in death, be life-threatening, or require additional surgery. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 
All adverse events (AEs) will be collected, recorded, and analyzed. Safety oversight for this study will be 
provided by both the DSMB and an independent Medical Safety Monitor (Dr. Edgar Samaniego). 
All AEs will be classified as related to the intervention based on severity, relatedness and outcome. 
 
8.3.3.2 EXPECTEDNESS  
 
Potential risks to research subjects are: 1. Intracranial hemorrhage secondary to re-perfusion injury; 2. 
Stroke; 3. Seizures; 4. Extravasation of contrast secondary to injury to cervical ICA during the procedure; 
and 5. Contrast allergy, 6. carotid fistula, 7. Radiation exposure  
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
Strategies to mitigate risks to subjects in the trial include 1) exclusion of subjects with COICA type D, 2) 
performing the procedure only by the PI, 3) strict perioperative blood pressure management to 
minimize hypoperfusion pre-procedure (maintain MAP ≥ 80mmHg and ≤120mmHg) and hyper-perfusion 
post procedure (maintain MAP≤ 80mmHg and ≥60mmHg, 4) admission to neuro-intensive critical for 
management post procedure, and 5) use of IV maintenance dose Tirofiban immediately post procedure 
as a monotherapy for the first 24 hours (no aspirin or clopidogrel) to reverse the effect of anti-platelet 
effect within 90 minutes in case of dreaded intracranial hemorrhage secondary hyper-perfusion (from 
our series, no subjects suffered intracranial hemorrhage).  If the subject is with no signs or symptoms of 
intracranial hemorrhage, then at the end of 24 hours, the subject will be given a loading dose of 
clopidogrel (600 mg) and aspirin (325mg) and Tirofiban continued for another 2 hours in order for the 
loading dose of aspirin and clopidogrel to reach therapeutic effect.  
All AEs will be followed until resolution with treatment by best medical or surgical management. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
Safety oversight for this study will be provided by both the DSMB and an independent Medical Safety 
Monitor (Dr. Edgar Samaniego). Reports will be done of comparison of the intervention groups every 10 
patients to the DSMB. 
 


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Data and Safety Monitoring Board [DSMB]: 
The DSMB will be appointed by the NIA to monitor the performance of the study. The Steering 
Committee will prepare regular reports summarizing patient accrual and the morbidity and mortality 
experienced in the study, The DSMB will also review the cumulative outcome data at regular intervals 
(every 6 months). 
 
Stopping rules or safety triggers for the study: 
The occurrence of the following potential side effects and risks associated with procedure will trigger 
prompt reporting and review by the DSMB to discuss the events and decide on the continuation of the 
trial.  
The following adverse events will be reported to the DSMB: 1) Any intracranial hemorrhage within 72 
hours post procedure, 2) Any stroke within 30 days post procedure; 3) Any seizure within 72 hours post 
procedure; and 4) Any injury to the cervical ICA during the procedure.  
Based on complication rates in the trial to date (June 2021), the occurrence of one additional event in 
these categories will trigger a suspension of enrollment in the trial and meeting of the DSMB to discuss 
the events and decide on the continuation of the trial. 
Safety oversight for this study will be provided by both the DSMB and the Independent Medical Safety 
Monitors.   
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
AEs will be reported as they occur to the medical monitor. Safety oversight for this study will be 
provided by both the DSMB and an independent Medical Safety Monitor (Dr. Edgar Samaniego). Serious 
AEs will be reported to the DSMB and IRB as required. 
Any potential adverse event or a serious adverse event mentioned above will be reported during the 
trial. An AE will be defined as any unfavorable and/or unintended sign, symptom, or injury temporally 
associated with the procedure or other study medication. A serious adverse event (SAE) is defined as 
any untoward/undesirable adverse experience related to a study intervention/medication that results in 
any of the following outcomes: 1) death; 2) a life-threatening adverse experience; 3) need for additional 
surgery; 4) a permanent or significant disability/incapacity; 5) important medical events that may not 
result in death, be life-threatening, or require additional surgery. 
Study Monitoring 
Local IRB monitors will conduct yearly monitoring visit. Review of the protocol and all data collection 
forms will be conducted, confirming the investigators’ compliance and thereby ensuring appropriate and 
accurate data collection, regulatory committee approval, and informed consent procedures. Any minor 
concerns in data collection issues will be dealt with by the IRB. All significant concerns regarding either 
data collection or the nature of an investigator’s participation which are not immediately solved will be 
reported by the IRB designated monitor and further evaluated by the IRB. Should an investigators 
deviate from the study protocol, the IRB will raise the issue with the Steering Committee, which will 
determine an appropriate course of action. 
Participant Confidentiality 


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All imaging studies (MRA, CTA, and/or DSA), case report/evaluation forms, laboratory specimens, and 
other records will be de-identified and assigned Study Identification Number (SID) to maintain subject 
confidentiality.  All records will be kept in a secure and locked file cabinet with keys to this cabinet only 
kept by the PI and/or nurse research coordinator.  No clinical information will be shared or released 
without the written permission/consent of the patient, except as necessary for minoring by the IRB. 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Adverse Event (AE) Reporting: 
Any potential adverse event or a serious adverse event mentioned above will be reported during the 
trial. An AE will be defined as any unfavorable and/or unintended sign, symptom, or injury temporally 
associated with the procedure or other study medication. A serious adverse event (SAE) is defined as 
any untoward/undesirable adverse experience related to a study intervention/medication that results in 
any of the following outcomes: 1) death; 2) a life-threatening adverse experience; 3) need for additional 
surgery; 4) a permanent or significant disability/incapacity; 5) important medical events that may not 
result in death, be life-threatening, or require additional surgery. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
Not applicable.  
 
8.3.9 REPORTING OF PREGNANCY  
Not applicable  
 
 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
Definition of unanticipated problems:  unanticipated adverse device effect, 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 (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
 
This includes: 
1. Development of carotid cavernous fistula 
2. loss of vision 
3. renal dysfunction due to contrast toxicity   
4. seizures  
 


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An incident, experience, or outcome that meets the definition of an UP generally will warrant 
consideration of changes to the protocol or consent in order to protect the safety, welfare, or rights of 
participants or others. Other UPs may warrant corrective actions.  Examples of corrective actions or 
changes that might need to be considered in response to an UP include: 
 
• 
Modification of inclusion or exclusion criteria to mitigate the newly identified risks 
• 
Implementation of additional safety monitoring procedures 
• 
Suspension of enrollment of new participants or halting of study procedures for enrolled 
participants  
• 
Modification of informed consent documents to include a description of newly recognized risks 
• 
Provision of additional information about newly recognized risks to previously enrolled 
participants. 
 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The PI will report unanticipated problems (UPs) to the reviewing DSMB and the Institutional Review 
Board (IRB).  The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Not applicable   
 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
Primary endpoints: 
Cognitive outcome at 12-month follow-up assessed mainly by a specifically designed battery of 14 
cognitive tests including MoCA. 
 
Secondary endpoints: 
1. Safety: Occurrence of Stroke/TIA, Cerebral Hemorrhage, or Death 
 
Exploratory endpoints: 
1. Biomarkers:  A) The presence/absence of lactate on 1H-MRI spectroscopy in centrum semiovale in the 
ipsilateral side of COICA;  B) The change in size of amygdala and hippocampus in the ipsilateral side of 


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COICA; C) improved and/or normalization of MTT and/or PTT on CTP specifically in the ipsilateral MCA 
territory. 
 
Subgroups: Gender difference. 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
To maximize success of the intervention, we will only enroll subjects with classification of A, B, or C. 
The current success rate for revascularizing types A & B using EVT is 100% and type C using the Hybrid 
technique is 80% making the success rate for the whole sub-cohort is 93%. Based on our preliminary 
data and others, the mean difference in the pre- and post-procedure MoCA score was between 5-8 
points. Using two comparisons: A) comparison between intervention vs. best medical management and 
B) pre- and post-intervention for successful vs unsuccessful intervention.  We pooled the data for these 
studies, and then used the lower and upper ends of the confidence interval calculated between the 
suggested groups for the trial (best medical management vs. intervention). Doing so, we will assume 
the difference between pre- and post-procedure MoCA score to be 2 points and standard deviation to 
be 2 points. Assuming α=0.05; β=0.8; and power of 80%, then our total sample size needed is 34 (Table 
2).  Based on our previous clinical trial experiences, we anticipate maximum of 10% drop out.  Given 
that, then total sample size needed is 38 subjects with 19 subjects in each group. 
 
 
 
 
9.3 
POPULATIONS FOR ANALYSES 
 
Data analysis will be performed based on Intention-to-Treat (ITT). 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
The analysis will be intention to treat. 


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1) Comparison of treatment groups of baseline variables 
2) Comparison of primary endpoint 
a. MOCA change 
b. Cognitive battery summary score 
3) Comparison of secondary endpoints 
4) Exploratory analysis of associations of exploratory endpoints with cognitive change 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Primary Endpoint: Montreal Cognitive Assessment (MoCA) and cognitive battery of tests. They will be 
administered by a neuropsychologist masked to treatment at the pre-treatment, at 3 month and 12 
month assessments. The battery is designed to assess left hemisphere function, right hemisphere 
function, and global function. All tests had published age-adjusted norms 
10,12,38,59,60,76,80,95,101,108.  All subjects will undergo all 14 cognitive tests. The order of test 
administration will remain constant, accommodating the delays required for recall intervals and 
minimizing stimulus interference in memory tasks.  The raw score for each test for each subject will be 
converted into test-specific z score for each test in the battery.  Then a composite z score based on 
average z score for the tests for each subject (sum of the z scores divided by the number of tests 
included) will be calculated. A two-sided type I error rate of 0.05 will be used. 
 
A linear mixed effect model (PROC MIXED in SAS, Version 9.4) will be used to compare the two groups 
(medical management vs. surgical intervention) with the change in MoCA as the dependent variable 
across the repeated measures of 6 months and 12 months. The main independent variable is the 
intervention. The multivariable model will be adjusted for the following covariates: age, gender, 
education level (≤8th grade, 9th–12th grade [high school], or ≥13 years [some college]), ICA side, and 
pre-treatment depression (as measured by the Center for Epidemiologic Studies–Depression scale). The 
correlation coefficient between MoCA change and the composite cognitive score will be calculated. A 
second comparative model of the interventions will be performed to support the primary analysis. It will 
use the change in composite cognitive z score as the dependent variable. Similar analysis using mixed 
linear models and covariates will be done.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
The safety measures of occurrence of Stroke/TIA, cerebral hemorrhage, or death will be analyzed as 
frequency within the 30-day post-procedure period. Analysis will be done in aggregate of the events 
combined and individually using a Kaplan-Meier survival estimation with a Logrank test. Adjustment for 
age, etiology of ischemia, and side of occlusion will be done using a Cox Model Regression. A two-sided 
type I error rate of 0.05 will be used. 
 
Analysis of the Tertiary/exploratory Endpoint 
Tertiary/exploratory endpoints will be analyzed individually. The presence/absence of lactate will be 
estimated by a proportion and evaluated using a Fisher’s Exact Test. The change in sizes of amygdala 
and hippocampus in the ipsilateral side of COICA will be using a T-Test of the difference.  Improved 
and/or normalization of MTT and/or PTT on CTP specifically in the ipsilateral MCA territory will be 
analyzed using a T-Test. 
 
9.4.4 SAFETY ANALYSES 


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Event rates by treatment group will be reported with 95% confidence intervals. The distribution by 
severity will be compared. Kaplan-Meier time to event curves will be done for AEs and deaths. Logrank 
tests will be performed.  
 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Intervention groups will be compared on baseline characteristics, including demographics and 
laboratory measurements, using descriptive statistics. Baseline descriptive statistics will be done for 
each treatment group and compared using Chi-Square Tests and t-tests as determined by variable type. 
 
 
9.4.6 PLANNED INTERIM ANALYSES  
Interim analysis for safety every 10 patients 
 
 
9.4.7 SUB-GROUP ANALYSES 
By gender 
 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Cognitive measures at baseline, 6 months and 12 months 
 
 
9.4.9 EXPLORATORY ANALYSES 
 
The presence/absence of lactate will be estimated by a proportion and evaluated using a Fisher’s Exact 
Test. The change in sizes of amygdala and hippocampus in the ipsilateral side of COICA will be using a T-
Test of the difference.   Improved and/or normalization of MTT and/or PTT on CTP specifically in the 
ipsilateral MCA territory will be analyzed using a T-Test. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
Informed consent will be obtained after study details are explained in full to the patient, and the patient 
was provided with written informed consent to read it. The patient will be informed that the study is a 
research effort, that participation is fully voluntary and that refusal to participate will in no way 
compromise the patient’s clinical care, with full disclosure of potential risks and benefits for 
participation. 
 


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At presentation to neurosurgery/neurology clinic, the patient will undergo neurologic, neuro-imaging 
evaluation, DSA, and cognitive testing as part of standard clinical care at the participating center. If the 
patient appears eligible on the basis of clinical and imaging (see above), the patient will be be 
approached to obtain written consent. The consent form will contain the background of the proposed 
study and the benefits and risks of the procedures and will be explained in detail to the patient. 
Informed consent must be signed by the patient prior to enrollment. Failure to obtain a signed informed 
consent renders the patient ineligible for the study. Copies of the signed informed consent will be kept 
in the patients’ file and in the medical record. 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
An IRB approved consent form will be utilized.  
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
The consent form will contain the background of the proposed study and the benefits and risks of the 
procedures and will be explained in detail to the patient. Informed consent must be signed by the 
patient prior to enrollment. Failure to obtain a signed informed consent renders the patient ineligible for 
the study. Copies of the signed informed consent will be kept in the patients’ file and in the medical 
record. 
Unless otherwise stated, all consents are done following the strictest Good Clinical Practice (GCP) 
protocol. This includes proper assessment of ability to consent, time to consider enrollment with loved 
ones, opportunity to discuss consent with study staff, time to ask questions and receive all appropriate 
answers, and all other applicable components.  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
Participants will be informed if the study is closed prematurely or at the end of the study.  
 
Recruitment and Enrolment will be assessed every 6 months.  We anticipate enrolling 1 subject every 5 
weeks and allowing for 12 months follow up visit.  If the recruitment/enrolment is averaged at 1 subject 
per 10 weeks for 24 months, then the study will be futile and will be stopped for failure of accrual.   
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
All research activities will be conducted in as private a setting as possible. 
 
All imaging studies (MRA, CTA, and/or DSA), case report/evaluation forms, laboratory specimens, and 
other records will be de-identified and assigned Study Identification Number (SID) to maintain subject 
confidentiality.  All records will be kept in a secure and locked file cabinet with keys to this cabinet only 
kept by the PI and/or nurse research coordinator.  No clinical information will be shared or released 
without the written permission/consent of the patient, except as necessary for minoring by the IRB. 
 


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The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting will 
be stored on secure servers. Password access for data collection and analysis will be used. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Specimens will be retained for assessment of biomarkers only with permission of the participants 
through the informed consent.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Provide the name and contact information of the Principal Investigator and the Medical Monitor. 
Principal Investigator 
Medical Monitor 
David Hasan, MD 
TBN 
University of Iowa 
 
University of Iowa Hospitals and 
Clinics 
 
Phone Number 
 
david-hasan@uiowa.edu 
 
 
 
 
10.1.6 SAFETY OVERSIGHT 
 
Data and Safety Monitoring Board [DSMB]: 
The DSMB will be appointed by the NIA to monitor the performance of the study. The Steering 
Committee will prepare regular reports summarizing patient accrual and the morbidity and mortality 
experienced in the study, The DSMB will also review the cumulative outcome data at regular intervals 
(every 6 months) or every 10 patients. 
 
All adverse events (AEs) will be collected, recorded, and analyzed. Safety oversight for this study will be 
provided by both the DSMB and an independent Medical Safety Monitor (Dr. Edgar Samaniego). 
 
 
10.1.7 CLINICAL MONITORING 


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The DSMB and Medical Safety Monitor (Dr. Edgar Samaniego) will assess the performance of the study 
including accrual, intervention execution, adverse events and clinical outcome assessment. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
Data collection will be in compliance with ICH GCP and regulatory and UI institutional requirements for 
the protection of confidentiality of participants.  As part of participating in a NIH-sponsored or NIH-
affiliated study, the records and data will be available for authorized representatives of the NIH, 
sponsor, and regulatory agencies to examine (and when permitted by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits, and evaluation of the study safety, 
progress, and data validity. Records will be available to study staff and to IRB staff for review. 
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection will be done through case report forms created and utilized via REDCap software.  
Quality control will examine range checks, missing data and incomplete data. 
Data analysis for reporting and statistical analysis will be done with SAS Version 9.4.  
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study records will be maintained for access and review for at least 3 years after the last patient follow-
up. 
 
 
 
 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their policies. The 
site investigator is responsible for knowing and adhering to the reviewing IRB requirements. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 


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This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers x years after the 
completion of the primary endpoint by contacting <specify person or awardee institution, or name of 
data repository>.  
 
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of these 
data for subsequent research. Large-scale data include genome-wide association studies (GWAS), single 
nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene 
expression data.] 
 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
10.2 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized 
for each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
COICA 
Chronically occluded cervical ICA 
MRI 
Magnetic resonance imaging  
CTP 
CT perfusion  
CTA 
CT angiogram 
MTT 
Mean transient time 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  


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IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 


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10.3 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
V3.0 
8/13/20 
Revision to study design to reflect I/E 
adjustment 
Including changes to make study 
endpoints consistent with I/E 
criteria 
V3.0 
8/13/20 
Change 3 month visit to 6 month follow 
up 
Makes study protocol more 
consistent with surgical/ clinical 
procedures 
V3.0 
8/13/20 
Inclusion/ exclusion criteria adjusted 
Includes more subjects and reflects 
issues we have faced so far with 
recruitment 
V3.0 
8/13/20 
Added blood draw, if subject is 
randomized to intervention  
 
V4.0 
1/25/21 
Updated study to include study arm 
3 
Allows study to follow subjects 
who are relevant to study aims 
but not eligible for treatment 
V4.0 
1/25/21 
Inclusion/ exclusion criteria adjusted 
Includes subject who are 
impaired but do not show 
impairment on MoCA 
V4.0 
1/25/21 
Updated MRI protocol 
Allows study team to measure 
white matter integrity.  
V4.0 
2/4/2021 
Added 6 month MRI 
Allows the study team to 
compare 6 months post op 
V5.0 
5/15/2021 
Inclusion of DSA to confirm COICA 
classification 
Definitive COICA classification  
V5.0 
5/15/2021 
Inclusion/ exclusion criteria adjusted 
Based on DSMB 
recommendations 
V5.0 
5/15/21 
Further definition of 3rd non-
randomized arm 
Necessitated by adjustments to 
I/E criteria 
V.50 
5/15/2021 
Inclusion of adjudicators to confirm 
eligibility of surgical arm 
Included to minimize surgical 
risk 
V5.0 
6/21/21 
Adjusted stopping rules 
Protocol adherence with DSMB 
ruling  
V6.0 
9/3/21 
Added Co-PI Dr. Derdeyn 
New study requirements  
V6.0 
9/3/21 
Inclusion criteria adjustment 
Provided specifications on 
MTT/TTP measurements 
V6.0 
9/3/21 
Removed inaccurate wording of primary 
objective 
Clerical mistake corrected 
V6.0 
9/3/21 
Clarified AE reporting workflow 
Included for more thorough team 
roles 
V6.1 
10/12/21 
Wording changes for medical 
management 
Promoting clarity and consistency  
V6.1 
10/12/2021 
Defined Visit windows 
Promoting clarity and consistency  
 
 
 
 


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ICF_000.pdf: 



NeurocognitiveImpairmentAssessmentinSymptomaticCarotid
OcclusionRecanalizedEndovascularly

NCT04219774

DocumentDate: 04/20/2023


Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 1 of 16
Subject*Initials_________
Form
M0345
You are being asked to take part in this research study because you have been diagnosed with complete 
occlusion of your cervical internal carotid artery and you have symptoms from this condition.  Research 
studies are voluntary and include only people who choose to take part.  Please read this consent form 
carefully and take your time making your decision. As your study doctor or study staff discusses this 
consent form with you, please ask him/her to explain any words or information that you do not clearly 
understand.  We encourage you to talk with your family and friends before you decide to take part in this 
CONCISE SUMMARY
This is a research study to examine the relationship of chronically occluded internal carotid artery 
(ICA) and your cognition (process of thinking), memory, and mental control and self-regulation 
(executive function). This will be assessed by using a well-designed set of cognitive tests. In 
addition, we compare imaging findings with cognition, memory, mental control and self-regulation.  
Lastly, we are also seeking to understand whether opening the chronically occluded ICA using 
endovascular techniques (balloon angioplasty and stenting) will reverse the impairment of cognition, 
memory, mental control and self-regulation, and minimize recurrent strokes and/or transient 
ischemic attacks (TIAs).
You will have tests, exams and procedures that are for study purposes, such as imaging studies, 
physical and neurologic exams, and blood work. You will be randomized (like flipping a coin) to 
either surgery and opening the occluded carotid in addition to medical management or medical 
management alone by placing you on blood thinners and cholesterol medications. 
Participation in this trial will last for 12 months.  You will be asked to return to clinic for 
examination at 6 and 12 months and each visit will last about 2 ½ hours.
There are risks from the study drugs and procedures that are described in this document. Some risks 
may include: indigestion, allergic reaction, bruising, pain, redness, swelling, headache, dizziness, 
fatigue, muscle pain, sleep problems, low platelet counts, blood clots, infection, nerve damage, 
stroke, seizure, bleeding, injury to leg or kidneys, radiation exposure, and bleeding in the brain. We 
hope that, in the future, the information learned from this study will benefit others with your 
condition. 
You do not have to participate in this research to be treated for your condition. Your personal 
healthcare provider can discuss all available options.
If you are interested in learning more about this study, please continue reading below.
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 2 of 16
Subject*Initials_________
Form
M0345
research study.  The nature of the study, risks, inconveniences, discomforts, and other important 
information about the study are listed below.
Please tell the study doctor or study staff if you are taking part in another research study.
Dr. David Hasan will conduct the study and it is funded a grant from the National Institutes of Health 
(NIH) will sponsor this study.  Portions of Dr. David Hasan and his research team’s salaries will be paid 
by this grant.
WHO WILL BE MY DOCTOR ON THIS STUDY?
If you decide to participate, Dr. David Hasan will be your doctor for the study and will be in contact 
with your regular health care provider throughout the time that you are in the study and afterwards, if 
needed.
WHY IS THIS STUDY BEING DONE?
The purpose of this study is:
1.  To examine the possible connection between long-standing blocked (or chronically blocked) internal 
carotid artery and your cognition (process of thinking), memory, mental control and self-regulation. This 
will be assessed by using a well-designed set of cognitive tests.
 2. To compare findings on magnetic resonance imaging (MRI) and computerized tomography perfusion 
scan (CTP) on cognition, memory, mental control and self-regulation.
 3. To examine whether opening the chronically blocked internal carotid artery using balloon 
angioplasty and stenting will reverse the impairment of cognition, memory, mental control and self-
regulation. 
 4. To examine whether opening the chronically blocked internal carotid artery using balloon 
angioplasty and stenting will minimize recurrent strokes and/or transient ischemic attacks (TIAs).
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Approximately 57 people will take part in this study at two different hospitals and medical facilities, and 
approximately 16 people will take part at Duke.
WHAT IS INVOLVED IN THE STUDY?
If you agree to be in this study, you will be asked to sign and date this consent form.  You will have the 
following tests and procedures to make sure that you are eligible: 
•
Physical exam and medical history
•
Vital signs
•
Blood tests
If you are eligible, you will undergo the following tests and procedures:
•
Neuro-cognitive Testing
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 3 of 16
Subject*Initials_________
Form
M0345
•
Computerized Tomography Perfusion (CTP) to assess the blood flow in your brain
•
Magnetic Resonance Imaging (MRI) spectroscopy to assess for products and size of your brain
•
Brain Diagnostic Angiogram if you have not had one within the past 6 months
If you meet each criterion, you will be randomized (like flipping a coin) to: 
•
receive medications (aspirin, Plavix (blood thinners) and statin (cholesterol medication) only; or 
•
receive medications (aspirin, Plavix and statin) and undergo surgery/procedure to attempt to 
open the occluded carotid artery with balloon and stent
The study is open label, which means you will know which treatment you will be assigned to after 
randomization.
If you do not meet all the criteria for participation or you are not willing or if you are unable to be 
randomized to the surgery arm, you may be eligible to participate in a third group where you would 
receive medications (aspirin, Plavix, and statin) only.
If you are randomized to the “surgical arm” (undergo endovascular balloon angioplasty [surgical repair 
or unblocking of a blood vessel] and stenting), then you will have another CT perfusion done and a 
blood draw.  If you are assigned to medications only, you will not have a second CT perfusion or blood 
draw.
All subjects will be asked to participate in a once monthly phone call follow up where the study team 
will ask how you are doing and check on your medication refills. 
 
All subjects will be asked to return to clinic at 6 months for neurocognitive testing, another special MRI, 
and to check on medications. 
Last visit for the study will be at 12 months. At that time, you will have repeat of the special MRI of the 
brain, check on medications, undergo neurocognitive testing, and have a repeat angiogram (for those 
randomized to surgical arm).  If you did not undergo the angioplasty and you are only assigned to 
medication, then you will not undergo a repeat angiogram.  
All of these procedures, tests, and medications are standard of care for your condition, however, the NIH 
grant will cover the costs of these procedures and medications.
Following this visit, you will be followed as a regular patient (according to standard of care).
Additional Information:
All MRIs preformed as part of this study can be done with oral sedative. This is done per your request 
on a case-by-case basis due to claustrophobia or other severe indication. If you and the PI agree that this 
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 4 of 16
Subject*Initials_________
Form
M0345
would be beneficial to you, a physician that is part of the study team will order the medication for you to 
take before the MRI. A member of the study team will then escort you in a wheelchair to and from the 
MRI. You will not be permitted to drive yourself home if you are given a sedative. 
COVID-19 Related Information:
If your follow up appointments occur during a COVID-19 research restriction period, your appointments 
may be scheduled during your clinical appointments. If this is not possible, the visits will be done via 
telehealth. 
Detailed Description of The Procedure: 
Best Medical management:
Subjects will be placed on aspirin 325 mg by mouth daily + clopidogrel (Plavix) 75 mg by mouth daily 
+ a statin.  This is the standard of care in the management of subjects with symptomatic carotid 
occlusion regardless of your participation in this study. 
Endovascular Technique (Carotid Angiogram with Stenting): 
The procedure, which is similar to an X-ray of your blood vessels, will be performed under general 
anesthesia.  Prior to induction of general anesthesia, an arterial catheter will be paced to monitor your 
blood pressure.  The anesthesia team will use their standard of care medications to maintain your blood 
pressure within standard limits. 
The groin area will be prepped and draped in a sterile fashion.  Femoral access (access to the femoral 
artery on the inner thigh) will be obtained using a needle. A plastic tube will be threaded through this 
needle and up into your occluded internal carotid artery.  The surgical team will then attempt to open the 
occluded artery using balloon catheters and stents.  During the procedure and for a short time afterwards, 
you will receive a medication that is a blood thinner, called tirofiban, to prevent clotting.
Following that, you will be transferred to surgical intensive care unit.
HOW LONG WILL I BE IN THIS STUDY?
If you agree to take part in this study, your involvement will last for 12 months.  You will be asked to 
return to clinic for examination at 6- and 12-months post enrollment or procedure. Each visit will last 
about 2 ½ hours. A one-month follow-up phone call will be implemented to monitor your experiences, 
medications, and any adverse events between these 2 visits. You may also be contacted via email or 
through MyChart to remind you of upcoming visits.
You can choose to stop participating at any time without penalty or loss of any benefits to which you are 
entitled. However, if you decide to stop participating in the study, we encourage you to talk to your 
doctor first.
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 5 of 16
Subject*Initials_________
Form
M0345
We may learn things about you from the study activities, which could be important to your health or to 
your treatment.  If that happens, Dr. Hasan will let you know.  
WHAT ARE THE RISKS OF THE STUDY?
As a result of your participation in this study, you are at risk for the following side effects. You should 
discuss these with the study doctor and your regular health care provider if you choose. 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study. These risks may be associated with the surgery, the non-surgical management of your condition, 
or both. 
Standard of Care Medications:  
Aspirin: 
More Common
•
indigestion and stomach aches – taking your medicine with food may help reduce this risk
•
bleeding or bruising more easily than normal
Uncommon and rare
•
hives – a raised, itchy rash
•
tinnitus – ringing in the ears
•
breathing difficulties or an asthma attack
•
an allergic reaction – this can cause breathing problems, swelling of the mouth, lips or throat, 
and a sudden rash
•
bleeding in the stomach – this can cause dark, tar-like stools or vomiting blood
•
bleeding in the brain – this can cause a sudden, severe headache, vision problems and stroke 
symptoms, such as slurred speech and weakness on one side of the body
Clopidogrel (Plavix):
More common
•
collection of blood under the skin 
•
deep, dark purple bruise 
•
itching, pain, redness, or swelling 
Less common
•
bloody nose 
•
bloody, black, or tarry stools 
•
vomiting of blood or material that looks like coffee grounds 
Rare
•
bleeding in the eye 
•
confusion 
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 6 of 16
Subject*Initials_________
Form
M0345
•
headache, sudden, severe, and continuing 
•
nausea and vomiting 
Statin Drug (such as Lipitor or Crestor):
More Common
•
headache
•
dizziness
•
feeling sick
•
feeling unusually tired or physically weak
•
digestive system problems, such as constipation, diarrhea, indigestion or gas
•
muscle pain
•
sleep problems
•
low blood platelet count
Less Common
•
memory problems
•
hair loss
•
pins and needles
•
inflammation of the liver (hepatitis), which can cause flu-like symptoms
•
inflammation of the pancreas (pancreatitis), which can cause stomach pain
•
skin problems, such as acne or an itchy red rash
•
sexual problems, such as loss of libido (reduced sex drive) or erectile dysfunction
Rare
•
muscle weakness (myopathy)
•
loss of sensation or tingling in the nerve endings of the hands and feet (peripheral neuropathy)
•
tendon problems (tendons are tough cords of tissue that connect muscles to bones)
Tirofiban (Aggrastat):
More common
•
bleeding
•
abdominal (belly) pain or swelling
•
tarry (black) stools 
•
blood in urine
•
blood in eyes
•
back, jaw, or arm pain
•
bruising (purple areas) on the skin
•
chest pain/tightness/discomfort/heaviness
•
coughing up blood
•
decreased alertness
•
fast or irregular heart beat
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 7 of 16
Subject*Initials_________
Form
M0345
•
headache
•
joint pain or swelling
•
nausea
•
nose bleeds
Less common
•
bleeding gums
•
lightheadedness or fainting
•
pinpoint red spots on the skin
•
severe, unusual tiredness or weakness
•
slow heartbeat
•
swelling of the hands, feet, ankles, or lower legs
Rare
•
chills or fever
•
cough 
•
difficulty swallowing
•
puffiness or swelling of the eyelids, or around the eyes, face, lips, or tongue
•
skin rash, hives, or itching
•
trouble breathing
Carotid Angioplasty and Stenting Risks: With any medical procedure, complications might happen. 
Here are some of the possible complications of carotid angioplasty and stenting:
•
Stroke or mini-stroke (TIA): during angioplasty, blood clots that may form can break loose and 
travel to your brain. You will receive blood thinners during the procedure to reduce this risk. A 
stroke can also occur if plaque in your artery is dislodged when the catheters are being threaded 
through the blood vessels.
•
New narrowing of the carotid artery (restenosis): a major drawback of carotid angioplasty is the 
chance that your artery will narrow again within months of the procedure. Special drug-coated 
stents have been developed to reduce the risk of restenosis.
•
Blood clots: blood clots can form within stents even weeks or months after angioplasty. These 
clots may cause a stroke or death. It is important to take aspirin, clopidogrel (Plavix) and other 
medications exactly as prescribed to decrease the chance of clots forming in your stent.
•
Bleeding: you may have bleeding at the site in your groin where catheters were inserted. Usually 
this may cause a bruise, but sometimes serious bleeding occurs and may require a blood 
transfusion or surgical procedures.
Reproductive Risks: Pregnancy increases the risk of blood clots, and women with vascular occlusion 
are strongly advised not to get pregnant because of the increased risk of complications, including 
maternal death.  The effects of angiogram, carotid endarterectomy CT perfusion, and the standard 
medications on fertility and embryo development have not all been well defined. The primary obstetric 
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 8 of 16
Subject*Initials_________
Form
M0345
risk with the use of clopidogrel (Plavix) is potential increased risk for intrapartum and postpartum 
hemorrhage. Reproductive and developmental studies in animals have not been conducted. Aspirin and 
tirofiban are generally not recommended during pregnancy due to increased risk of bleeding. The FDA 
recommends stopping statins once pregnant.  
In addition, the changes your body undergoes during pregnancy may affect your recovery from surgical 
procedures. Angiograms and CT scanning are not often recommended in early pregnancy unless 
medically necessary because of potential risk to the baby. Women who are pregnant, breast-feeding, or 
intend to become pregnant are therefore not allowed to participate in this study.
If you are a woman who could possibly become pregnant (you have not completed menopause, or you 
have not had a hysterectomy and/or both tubes and/or both ovaries removed) and you have a partner 
who is able to father children, a blood pregnancy test will be done and it must be negative in order to 
continue. In women 40 years old and older, blood pregnancy tests can sometimes give a false positive or 
indeterminate result and additional testing may be needed to confirm your eligibility.
You and your partner must agree to either abstain completely from vaginal intercourse for the duration 
of the study or use an effective method of contraception for the same length of time once your study 
doctor informs you that it is safe to resume sexual activity. Because some birth control methods are not 
safe to use because of the risk of blood clots, or need to be stopped around the time of your surgery, 
your study doctor will discuss options with you, depending on your current method, your personal 
preferences, and the level of effectiveness required by this study. 
Because no birth control method is 100% effective, you should notify your study doctor immediately if 
you think there is any chance you could be pregnant. If pregnancy is confirmed, your study doctor will 
help you identify a specialist in high-risk pregnancy and continue to follow you to collect information on 
your health during pregnancy and, if appropriate, on the health of the baby.
Risks of Radiation: Computed Tomography (CT) is a way to make x-ray images of the inside of the 
body. The CT scanner is a doughnut-shaped machine that uses x-rays to create computer pictures that 
show structures inside your body more clearly than regular x-ray pictures. During the procedure, a 
technologist will take you into the CT scan room where you will lie down on the patient table (usually 
on your back) inside of the CT machine. You should get comfortable because it is very important that 
you not move during certain parts of the test.
CT examinations differ depending on the part of your body being studied. For example, if your abdomen 
is being studied, a series of pictures will be taken from your lower chest to your lower pelvis. During the 
study, you will be asked to hold your breath so that the pictures will not be blurred. The machine will 
make some noise, and the table will move during the scan. Also, you may receive signals from the 
technologist or from the machine about your breathing. Before or during the study, you may be given an 
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 9 of 16
Subject*Initials_________
Form
M0345
injection of a contrast liquid in your vein to allow the radiologist to obtain clearer images of your 
organs. If you have any discomfort during the test or after the injection, be sure to tell the technologist.
Magnetic resonance imaging (MRI) uses a magnet and radio waves to make diagnostic medical images 
of the body. There have been no ill effects reported from exposure to the magnetism or radio waves used 
in this test. However, it is possible that harmful effects could be recognized in the future. A known risk 
is that the magnet could attract certain kinds of metal. Therefore, we will carefully ask you about metal 
within your body, including medical implants, devices such as pacemakers and internal defibrillators, or 
certain dyes found in tattoos.  We will also keep the examining room locked so that no one carrying 
metal objects can enter while you are in the scanner.
If there is any question about potentially hazardous metal within your body, you will not undergo the 
MRI.  This may exclude you from participation in this research study. The MRI involves entering a 
large room in which a magnet is present. You will be placed on a narrow bed and then slid into a small 
tunnel approximately 6 feet in length and 25 inches in diameter. You will be asked to lie still for about 
one hour on this bed. You will hear a loud machine-like noise. You may be asked to have a harmless 
monitoring device applied during the MRI. During the MRI, you can have voice contact and physical 
contact with someone in attendance if you desire. Let the study doctor know if you have a fear of 
enclosed spaces.
Risks From Imaging Tests That Use Radiation
If you take part in this research, you may have one or more CT brain perfusion scans, which use 
radiation. To give you an idea about how much radiation you will get each time a CT brain perfusion 
scan is done, we will make a comparison with an every-day situation. Everyone receives a small amount 
of unavoidable radiation each year called the 'natural background'. Some of this radiation comes from 
space and some from naturally-occurring radioactive forms of water and minerals. The chart below the 
amount of time in the natural background that gives an amount of radiation that is about equal to the 
amount of radiation each time you have the test.
A possible health problem seen with radiation exposure is the development of cancer later in life. This 
extra cancer risk is higher at younger ages and for girls and women. The extra lifetime risk of dying of a 
fatal cancer due to the radiation exposure from this research is also shown in the chart. At such low 
radiation exposures, scientists disagree about the amount of risk. These estimates are very uncertain, and 
there may be no extra risk at all. 
Test
'Natural Background Time' 
Equivalent for Each Time 
This Test is Done
Extra Cancer Risk Each 
Time This Test is Done
CT Brain Perfusion Scan
1 Years
Very Low
If you take part in this research, you may have one or more carotid or cerebral arteriograms, which use 
radiation. To give you an idea about how much radiation you will get each time a carotid or cerebral 
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 10 of 16
Subject*Initials_________
Form
M0345
arteriogram is done, we will make a comparison with an every-day situation. Everyone receives a small 
amount of unavoidable radiation each year called the 'natural background'. Some of this radiation comes 
from space and some from naturally-occurring radioactive forms of water and minerals. The chart below 
the amount of time in the natural background that gives an amount of radiation that is about equal to the 
amount of radiation each time you have the test.
A possible health problem seen with radiation exposure is the development of cancer later in life. This 
extra cancer risk is higher at younger ages and for girls and women. The extra lifetime risk of dying of a 
fatal cancer due to the radiation exposure from this research is also shown in the chart. At such low 
radiation exposures, scientists disagree about the amount of risk. These estimates are very uncertain, and 
there may be no extra risk at all.
 Test
'Natural Background Time' 
Equivalent for Each Time 
This Test is Done
Extra Cancer Risk Each 
Time This Test is Done
Carotid Or Cerebral 
Arteriogram
2 Years
Very Low
You may have a number of medical imaging exams that are part of the regular care for your condition, 
and you would have them whether or not you participate in this research. These studies will not add to 
the risk of the research. However, if you have concerns about the overall radiation exposure, you should 
discuss them with your physician.
Risks From Imaging Tests That Do Not Use Radiation
You may have an MRI study as part of this research. MRI uses a magnet and radio waves to make 
diagnostic medical images of the body. There have been no ill effects reported from exposure to the 
magnetism or radio waves used in this test. However, it is possible that harmful effects could be 
recognized in the future. A known risk is that the magnet could attract certain kinds of metal. Therefore, 
we will carefully ask you about metal within your body, including medical implants, devices such as 
pacemakers and internal defibrillators, or certain dyes found in in tattoos. We will also keep the MR 
room locked so that no one carrying metal objects enters the room while you are in the scanner.
If there is any question about potentially hazardous metal within the body, you will not undergo the 
MRI. This may exclude you from participation in this research study. The MRI involves entering a large 
room in which a magnet is present. You will be placed on a narrow bed and then slid into a small tunnel 
approximately 6 feet in length and 25 inches in diameter. You will be asked to lie still for about one 
hour on this bed. You will hear a loud machine-like noise. You may be asked to have a harmless 
monitoring device applied during the MRI. During the MRI, you can have voice contact and physical 
contact with someone in attendance if you desire. Let the study doctor know if you have a fear of 
enclosed spaces.
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 11 of 16
Subject*Initials_________
Form
M0345
You may have a number of medical imaging exams that are part of the regular care for your condition, 
and you would have them whether or not you participate in this research. These studies will not add to 
the risk of the research. However, if you have concerns about the overall radiation exposure, you should 
discuss them with your physician.
If an oral sedative is required for your MRI(s), the following risks may be applicable to you: 
-
Drowsiness
-
Fatigue
-
Muscle weakness
-
Ataxia (poor muscle control)
-
Falls/Injury
Risks of Drawing Blood: Risks associated with drawing blood from your arm include momentary 
discomfort and/or bruising.  Infection, excess bleeding, clotting, or fainting are also possible, although 
unlikely.
Drug and Food Interactions: For your safety, you must tell the study doctor or nurse about all the 
prescribed medical foods and drugs, herbal products, over-the-counter (OTC) drugs, vitamins, natural 
remedies, and alcohol that you are taking before you start the study and before starting to take any of 
these products while you are on the study.
There may be risks, discomforts, drug interactions or side effects that are not yet known.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
There may be no direct benefit to you through participation in this study.  Medical management alone 
may or may not work for you.  If you are randomized to the treatment arm, we don’t know if you will 
benefit from the planned procedure to reopen your carotid artery in addition to routine medical 
management. This procedure may not reduce your risk of future stroke or improve your cognitive 
functions.
WHAT ALTERNATIVES ARE THERE TO PARTICIPATION IN THIS STUDY?
Before you decide whether or not to be in this study, your doctor will discuss the other options that are 
available to you.  Instead of being in this study, you could only receive medications (aspirin, Plavix, and 
statin).
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total confidentiality. Your personal 
information may be viewed by individuals involved in this research and may be seen by people 
including those collaborating, funding, and regulating the study. We will share only the minimum 
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
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M0345
necessary information in order to conduct the research. Your personal information may also be given out 
if required by law. 
As part of the study, results of your study-related laboratory tests, x-rays, and procedures may be 
reported to the NIH and its affiliates. In addition, your records may be reviewed in order to meet federal 
or state regulations. Reviewers may include representatives from the Food and Drug Administration, 
representatives and affiliates of the National Institutes of Health, the Duke University Health System 
Institutional Review Board, and others as appropriate. If any of these groups review your research 
record, they may also need to review your entire medical record.
As part of this study, you will be asked to have certain tests, x-rays, and/or procedures performed. Some 
of these tests, x-rays and/or procedures would have been done as part of your regular care. The study 
doctor will use these test results both to treat you and to complete this research.  These test results will 
be recorded in your medical record and will be reported to the representatives and affiliates of the NIH. 
Results of tests and studies done solely for this research study and not as part of your regular care will 
also be included in your medical record.
The Department of Health and Human Services (HHS) has issued a Certificate of Confidentiality to 
further protect your privacy.  With this Certificate, the investigators may not disclose research 
information that may identify you in any Federal, State, or local civil, criminal, administrative, 
legislative, or other proceedings, unless you have consented for this use. Research information protected 
by this Certificate cannot be disclosed to anyone else who is not connected with the research unless:  
1) there is a law that requires disclosure (such as to report child abuse or communicable 
diseases but not for legal proceedings); 
2) you have consented to the disclosure, including for your medical treatment; or 
3) the research information is used for other scientific research, as allowed by federal 
regulations protecting research subjects. 
Disclosure is required, however, for audit or program evaluation requested by the agency that is funding 
this project or for information that is required by the Food and Drug Administration (FDA).
 
You should understand that a Confidentiality Certificate does not prevent you or a member of your 
family from voluntarily releasing information about yourself or your involvement in this research. If you 
want your research information released to an insurer, medical care provider, or any other person not 
connected with the research, you must provide consent to allow the researchers to release it. This means 
that you and your family must also actively protect your own privacy.
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 13 of 16
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Finally, you should understand that the investigator is not prevented from taking steps, including 
reporting to authorities, to prevent serious harm to yourself or others.
The study results will be retained in your research record for at least six years after the study is 
completed. At that time either the research information not already in your medical record may be 
destroyed or information identifying you will be removed from such study results at Duke University 
Health System (DUHS).  Any research information in your medical record will be kept indefinitely.
This information may be further disclosed by the sponsor of this study.  If disclosed by the sponsor, the 
information is no longer covered by federal privacy regulations.
If this information is disclosed to outside reviewers for audit purposes, it may be further disclosed by 
them and may not be covered by federal privacy regulations.
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your name or other personal information will not be revealed.
Some people or groups who receive your health information might not have to follow the same privacy 
rules. Once your information is shared outside of DUHS, we cannot guarantee that it will remain private. 
If you decide to share private information with anyone not involved in the study, the federal law 
designed to protect your health information privacy may no longer apply to the information you have 
shared.  Other laws may or may not protect sharing of private health information.
WHAT ARE THE COSTS TO YOU?
You will not have any additional costs for being in this research study.  The study will pay for the 
following:
•
The clinic visits while you are enrolled in the study
•
The CT perfusion at the Screening visit and the second CT perfusion while you are in the 
hospital if you are randomized to receive the procedure
•
The magnetic resonance angiography (MRA) or computed tomography angiography (CTA) at 
the Screening visit
•
All of the neurocognitive testing completed as part of the study
•
The brain MRI at the Screening visit, 6 months, and at the 12-month visit 
o
The sedative used during the MRI if you require it
•
The brain diagnostic angiogram at the Screening visit if you have not had one in the previous 6 
months, and again at the 12-month visit if you are randomized to receive the surgery
•
All of the costs associated with the surgical procedure to open the occluded carotid artery, if you 
are randomized to that group
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 14 of 16
Subject*Initials_________
Form
M0345
•
The laboratory tests at the Screening visit and the pre-surgical visit if you are randomized to 
receive the surgery
•
The pregnancy test (females) at the Screening visit
•
The electrocardiogram at the Screening visit
•
The medications (aspirin, plavix, and statin) 
You and/or your medical/hospital insurance carrier will remain responsible for your regular medical care 
expenses. 
WHAT ABOUT COMPENSATION?
If a hotel stay is required because of study visits or your surgery, you may request up to $150 for one 
night to subsidize cost. Additionally, you will receive $200 per completed study visit and $50 for gas for 
your vehicle per completed study visit. 
Payment received as compensation for participation in research is considered taxable income to the 
research subject. If payment to an individual totals $600 or more in one calendar year, Duke University 
is required to report this information to the Internal Revenue Service (IRS). Research subject payments 
to a non-employee of Duke University adding up to $600 or more during any calendar year will result in 
a 1099 (Miscellaneous Income) form being issued to the individual and a copy sent to the IRS.
No further compensation will be provided. 
WHAT ABOUT RESEARCH RELATED INJURIES?
Immediate necessary medical care is available at Duke University Medical Center in the event that you 
are injured as a result of your participation in this research study. However, there is no commitment by 
Duke University, Duke University Health System, Inc., or your Duke physicians to provide monetary 
compensation or free medical care to you in the event of a study-related injury.
For questions about the study or research-related injury, contact Dr. David Hasan at 919-681-2512 
during regular business hours and at 319-400-9455 after hours and on weekends and holidays.
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY?
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw from the 
study at any time. If you withdraw from the study, no new data about you will be collected for study 
purposes unless the data concern an adverse event (a bad effect) related to the study.  If such an adverse 
event occurs, we may need to review your entire medical record.  All data that have already been 
collected for study purposes, and any new information about an adverse event related to the study, will 
be sent to the study sponsor.
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 15 of 16
Subject*Initials_________
Form
M0345
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of 
benefits to which you are entitled, and will not affect your access to health care at Duke. If you do 
decide to withdraw, we ask that you contact Dr. Hasan in writing and let him know that you are 
withdrawing from the study.  His mailing address is: 
Dr. David Hasan
          DUMC Box #3807 
     40 Duke Medicine Circle
         Durham, NC 27710 
We will tell you about new information that may affect your health, welfare, or willingness to stay in 
this study.
Your doctor may decide to take you off this study if your condition gets worse, if you have serious side 
effects, or if your study doctor determines that it is no longer in your best interest to continue.  The 
sponsor or regulatory agencies may stop this study at any time without your consent. Reasons why this 
might occur include the finding that there are no benefits from the study or there are more complications 
than anticipated. If this occurs, you will be notified and your study doctor will discuss other options with 
you.
A description of this clinical trial will be available on https://clinicaltrials.gov/  as required by U.S. Law.  
This Web site will not include information that can identify you.  At most, the Web site will include a 
summary of the results.  You can search this Web site at any time.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury, or if you have problems, concerns, questions 
or suggestions about the research, contact Dr. David Hasan at 919-681-2512 during regular business 
hours and at 319-400-9455 after hours and on weekends and holidays.
For questions about your rights as a research participant, or to discuss problems, concerns or suggestions 
related to the research, or to obtain information or offer input about the research, contact the Duke 
University Health System Institutional Review Board (IRB) Office at (919) 668-5111.
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Consent to Participate in a Research Study
ADULT
Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized 
Endovascularly (NIA-SCORE)
Page 16 of 16
*
Form
M0345
STATEMENT OF CONSENT
"The purpose of this study, procedures to be followed, risks and benefits have been explained to me. I 
have been allowed to ask questions, and my questions have been answered to my satisfaction. I have 
been told whom to contact if I have questions, to discuss problems, concerns, or suggestions related to 
the research, or to obtain information or offer input about the research. I have read this consent form and 
agree to be in this study, with the understanding that I may withdraw at any time.  I have been told that I 
will be given a signed and dated copy of this consent form."
__________________________________________
___________     ____________
Signature of Subject
Date
   Time
__________________________________________
___________     ____________
Signature of Person Obtaining Consent
Date
   Time
(If applicable:)
__________________________________________
___________     ____________
Signature of Legal Representative
Date
   Time
__________________________________________
Relationship to Subject
FOR SUBJECTS WHO REGAIN THE ABILITY TO CONSENT 
I have been told that my legal representative agreed for me to participate in this research. I have read and 
understand the information in this informed consent document. I have had an opportunity to ask 
questions and all of my questions have been answered to my satisfaction. I voluntarily agree to continue 
to participate in this study until I decide otherwise. I do not give up any of my legal rights by signing 
and dating this consent document. I will receive a copy of this signed and dated consent document.
__________________________________________
___________     ____________
Name and signature of Patient
Date
   Time
__________________________________________
___________     ____________
Name and signature of Person Obtaining Consent
Date
     Time
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