Investigation of Clot in Ischemic Stroke and Hematoma Evacuation
Conditions: Ischemic Stroke, Intracranial Hematoma
Sponsor: Penumbra Inc.

 
 
 
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INSIGHT: Investigation of Clot in Ischemic Stroke and 
Hematoma Evacuation 
 
 
Protocol  
CLP-15131.E 
 
Date of Protocol 
28 April 2022 
 
Sponsor 
Penumbra, Inc. 
One Penumbra Place 
Alameda, CA 94502 
USA 
 
 
 

 
 
 
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TABLE OF CONTENTS 
1. 
Introduction ........................................................................................................................... 6 
1.1 Thrombus Composition ................................................................................................................. 6 
1.2 Conclusion and Rationale .............................................................................................................. 7 
2. 
Risk Analysis ......................................................................................................................... 7 
2.1 Risk to Patients ............................................................................................................................... 7 
3. 
Registry Overview ................................................................................................................. 7 
3.1 Study Design ................................................................................................................................... 7 
3.2 Study Objectives ............................................................................................................................ 8 
3.2.1 
Primary Objectives ............................................................................................................... 8 
3.2.2 
Secondary Objectives ............................................................................................................ 8 
4. 
Study Population ................................................................................................................... 8 
4.1 
Inclusion Criteria .................................................................................................................. 8 
4.2 
Exclusion Criteria ................................................................................................................. 9 
5. 
Study Procedures .................................................................................................................. 9 
5.1 Overview of Study Flow ................................................................................................................ 9 
5.2 Study Visits ..................................................................................................................................... 9 
5.3 Screening and Baseline Evaluation ............................................................................................ 10 
5.4 Informed Consent ........................................................................................................................ 10 
5.5 Procedure ...................................................................................................................................... 10 
5.5.1 
Specimen for Acute Ischemic Stroke Cases ...................................................................... 11 
5.5.2 
Specimen for Minimally Invasive Surgery ........................................................................ 11 
5.6 Discharge or 7 Days (whichever occurs first) ............................................................................ 11 
5.7 90 Day Follow-Up ±14 Days (Optional phone visit) .................................................................. 11 
6. 
Specimen Collection and Shipment ................................................................................... 14 
6.1 Specimen Destruction .................................................................................................................. 14 
7. 
Investigator Responsibilities .............................................................................................. 14 
7.1 Institutional Review Board Approval ........................................................................................ 14 
7.2 Informed Consent ........................................................................................................................ 15 
7.3 Adherence to Protocol/Amendments and Applicable Law ...................................................... 15 
7.4 Case Report Form Completion ................................................................................................... 15 
7.5 Reporting ...................................................................................................................................... 15 
7.5.1 
Adverse Events .................................................................................................................... 16 
7.5.2 
Device Deficiencies .............................................................................................................. 16 
7.5.3 
Protocol Deviation ............................................................................................................... 16 
7.6 Records Retention ........................................................................................................................ 16 
8. 
Sponsor Responsibilities ..................................................................................................... 17 
8.1 Training ........................................................................................................................................ 17 
8.2 Investigator List ........................................................................................................................... 17 
8.3 Data Monitoring ........................................................................................................................... 17 
8.3.1 
Site Qualification ................................................................................................................. 17 
8.3.2 
Site Initiation ....................................................................................................................... 17 
8.3.3 
Interim Monitoring ............................................................................................................. 18 
8.3.4 
Site Close Out ...................................................................................................................... 18 
8.4 Data Management ........................................................................................................................ 18 
9. 
Ethical Requirements ......................................................................................................... 19 
9.1 Declaration of Helsinki ................................................................................................................ 19 
9.2 Informed Consent ........................................................................................................................ 19 
9.3 Patient Data Protection ............................................................................................................... 19 

 
 
 
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10. Statistical Procedures ......................................................................................................... 20 
10.1 General Statistical Considerations ............................................................................................. 20 
10.2 Sample Size Estimation ............................................................................................................... 20 
10.3 Control of Systematic Error and Bias ........................................................................................ 20 
10.4 Missing Data and Imputation Methods ..................................................................................... 20 
10.5 Definition of Populations ............................................................................................................. 20 
10.5.1  Enrolled ................................................................................................................................. 20 
10.5.2 Completed ............................................................................................................................ 20 
10.5.3 Early Termination ............................................................................................................... 20 
10.6 Definition of Analysis Population ............................................................................................... 21 
10.7 Interim Analysis ........................................................................................................................... 21 
10.8 Statistical Analysis ....................................................................................................................... 21 
10.9 Pooling Across Centers ................................................................................................................ 21 
10.10 
Final Report ............................................................................................................................. 21 
11. Study Committees: Core Lab(s) ........................................................................................ 21 
11.1 Central Core and Pathophysiology Lab .................................................................................... 21 
12. Study Administration ......................................................................................................... 22 
12.1 Clinical Trial Termination/Withdrawal ..................................................................................... 22 
12.2 Protocol Adherence and Amendments ....................................................................................... 23 
12.3 Trial Registration ......................................................................................................................... 23 
13. Publication of Information ................................................................................................. 23 
14. Contact Information ........................................................................................................... 23 
15. References ............................................................................................................................ 24 
16. Appendix .............................................................................................................................. 27 
16.1 Modified Rankin Scale 27 ............................................................................................................. 27 
16.2 Glasgow Coma Scale 28 ................................................................................................................ 28 
16.3 National Institute of Health Stroke Scale 29 ............................................................................... 29 
16.4 Abbreviations ............................................................................................................................... 38 
 
 
 

 
 
 
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1. Introduction 
Globally, cerebrovascular accidents are a leading cause of death and disability.1 In 2013, 
an estimated 10.3 million new strokes were identified, of which two thirds were ischemic 
(incidence 99-132 per 100,000) and one third were hemorrhagic (incidence 56-65 per 
100,000) or other non-ischemic cases.2  
The recent publication of multiple randomized controlled trials established the efficacy of 
mechanical thrombectomy in treating stroke and have dramatically changed first-line 
treatments and recommendations for acute ischemic stroke.3, 4 Clinical studies have also 
addressed hemorrhagic stroke, for which current surgical options and therapies are more 
limited5; treatments for this stroke subtype focus on the evacuation of hematoma and 
removal of clot volume using minimally invasive techniques.6-9 
Despite these rapid advances in stroke treatment, mortality remains high: ischemic stokes 
accounted for 3.3 million deaths in 2013, and hemorrhagic strokes for an additional 3.2 
million deaths globally.2 Rates of global mortality in 2013 were 57.3 per 100,000 people 
for ischemic stroke and 52.8 per 100,000 people for hemorrhagic stroke.10 
In ischemic stroke, good clinical outcomes are often contingent on timely clot removal to 
attain revascularization.3, 11 Consequently, understanding clot characteristics could inform 
vital pre-treatment decisions and guide secondary prevention strategies by revealing 
stroke etiology.12 Historically, data from stroke-implicated clot has been scarce, but the 
expansion of contemporary endovascular technologies provides an ideal opportunity to 
collect thrombus material for direct study.12 
 
1.1 Thrombus Composition 
Clots removed during endovascular procedures can differ in consistency and 
removability13, leading to an increased focus on thrombus composition as a crucial 
variable for improving outcomes in both AIS and minimally invasive hematoma 
evacuation patients. Clot age14, component ratios15, and etiology16-18 can each affect 
the structural properties of a clot, impacting success rates of thrombolytic 
treatments15, 19 and the choice of clinical intervention18. 
 
For example, thrombus maturation results in decreased mechanical compliance due 
to progressive fibrin cross-linking and collagen deposition.14 These lysis-resistant 
fibrin clots can be more recalcitrant to endovascular treatment and are predictive of 
adverse patient outcomes.20 By contrast, erythrocyte-rich thrombi are associated 
with improved efficacy of endovascular thrombectomy.21-23 A recent study of 
patients undergoing intra-arterial thrombectomy with either a stent or suction device 
showed that clots retrieved from successful recanalization trials had a higher 
proportion of red blood cells (RBC) than those from non-recanalization trials; these 
RBC-rich clots were also associated with the presence of a hyperdense clot sign 
during initial brain imaging.23 
 

 
 
 
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Thrombus composition can also depend on patient predisposing factors, including 
Diabetes mellitus, cardiovascular disease, statin use, and anticoagulant use (e.g. 
vitamin-K antagonists, non-vitamin K oral anticoagulants, antiplatelet agents).24-26 
These conditions affect clot structure and fibrin content, indicating that patient 
history may become an important predictor of targeted and successful treatment 
strategies.  
 
1.2 Conclusion and Rationale  
This prospective study will be conducted on ischemic stroke and intracranial 
hematoma evacuation cases. Clot removed during endovascular therapy and 
minimally invasive hematoma evacuations will be collected for histological, RNA 
sequencing, SNPs, and proteomic analysis. 
 
More specifically, this study will examine whether clot composition, genetic, and 
proteomic variables can provide insight into thrombus etiology and/or have impact 
on clinical outcomes in patients with outwardly similar initial presentations. 
 
This registry is not intended to be utilized or support a labelling/indication change 
in the United States. 
 
2. Risk Analysis 
This study uses FDA 510(k) cleared medical devices per indication in the cleared 
labeling. The overall risk profile for the Penumbra Aspiration Pump is low, as the devices 
do not come into contact with the patient. Risk analysis was performed as part of design 
control requirements of the Quality System Regulation (21 CFR 820). 
There are risks associated with the clot evacuation procedure and should be discussed 
with potential patients according to each institution’s routine practice.  
2.1 Risk to Patients 
The primary risk in this study is a potential breach of confidentiality. To minimize 
the risk, all study records containing protected health information (PHI) will be de-
identified and assigned a unique patient identification number. Protocols will be in 
place for the handling and destruction of collected specimen.   
 
Blood collection has minimal risk and will be performed during the procedure 
through the existing procedural vascular access per institution routine practice.   
 
3. Registry Overview 
3.1 Study Design 
This is a prospective, multicenter, registry for the collection and analysis of 
specimen collected from ischemic stroke thrombectomy procedures and minimally 

 
 
 
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invasive interventions for intracranial hematoma evacuation procedures utilizing the 
Penumbra Aspiration Pump.  
Patients eligible for thrombectomy or minimally invasive surgery, and who meet 
the inclusion and none of the exclusion criteria will be considered for enrollment. 
Treatment will be per site routine practice, using FDA cleared devices. 
Patients will be considered enrolled upon signed informed consent and specimen 
collection. Specimen collected during the procedure will be shipped to a study Core 
Lab(s) for analysis.  
Data for each patient will be collected at the time of enrollment and at each 
subsequent follow-up visit. Please refer to the Schedule of Assessments (Table 1) 
below for details.  
3.2 Study Objectives 
3.2.1 Primary Objectives 
o The aim of the study is to collect and analyze specimen from ischemic stroke 
patients undergoing thrombectomy procedures and from patients undergoing 
minimally invasive surgery for intracranial hematoma evacuation. Clot and 
blood specimen will be analyzed via histology, RNA sequencing, Single 
Nucleotide Polymorphisms (SNPs), and proteomic analysis. 
 
3.2.2 Secondary Objectives 
o To prospectively collect and correlate data relating patient’ s clinical 
presentation, hospital course, and length of hospital stay to specimen 
histology, RNA sequencing, SNPs, and proteomic analysis. 
 
4. Study Population 
Up to 400 patients will be enrolled from up to 30 sites in the United States. 
Specimen will be analyzed via histology, RNA sequencing, SNPs, and proteomics.  
 
4.1 Inclusion Criteria  
1. ≥ 18 Years of Age 
2. Frontline treatment with: 
• 
 Penumbra System for ischemic stroke patients eligible for mechanical 
thrombectomy or 
• 
Artemis Neuro Evacuation device for intracranial hematoma evacuation in 
patients eligible for minimally invasive surgery (MIS) 
3. Extracted thrombus/embolus  

 
 
 
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4. Informed consent is obtained from either patient or legally authorized 
representative (LAR) 
 
4.2 Exclusion Criteria  
1. Pregnancy or positive pregnancy test according to site routine practice (only 
required for women of childbearing potential; serum or urine acceptable)  
2. Currently participating in an investigational drug or device clinical trial that 
may confound the ability to capture clot and/or influence clot composition. 
Patients in observational, natural history, and/or epidemiological studies not 
involving intervention are eligible. 
 
5. Study Procedures 
5.1 Overview of Study Flow 
Screening information will be reported in the Screening and Enrollment Log.  
Figure 1: Study Flow 
 
  
^  May be obtained up to 1 calendar day post-procedure, prior to specimen shipment to Core Lab 
!  Must be shipped as quickly as possible, but no later than 72 hours post procedure 
+ Whichever comes first 
* Optional Visit (conducted by phone) 
  
5.2 Study Visits 
Patients enrolled in this study will follow the visit schedule below. Procedure is 
considered day 0 to determine subsequent follow-up visit dates.  
• Baseline Evaluation 
• Procedure 
• Discharge or 7 Days (whichever occurs first) 
• 90 Day Follow-Up ± 14 Days (Optional phone call) 

 
 
 
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5.3 Screening and Baseline Evaluation 
Patients will be clinically evaluated per site routine practice. The following 
information will be collected at Baseline: 
• Medical History  
• Demographics 
• Clot/Hematoma Location   
• Medications (including antiplatelet and anticoagulant use) 
• The National Institutes of Health Stroke Scale (NIHSS) 
• Glasgow Coma Score (GCS) – (MIS only)  
• Historical (Pre-stroke) Modified Rankin Score (mRS) 
5.4 Informed Consent 
The Investigator or designee will obtain written informed consent from the patient 
or approved delegate using the current IRB approved consent form per IRB policy.  
The patient or legally authorized representative (LAR) may provide informed 
consent up to one calendar days post-procedure.  
All informed consent documents used under this protocol will be consistent with 
applicable elements of I.S. EN ISO 14155, Clinical investigation of medical devices 
for human subjects – Good Clinical Practice and 21 CFR Part 50 and will be 
approved by the site’s reviewing IRB prior to registry initiation.  
• Any modification to the sample informed consent form made by the study site 
must be approved by the Sponsor and the IRB before use. Each study site will 
provide the Sponsor with a copy of the IRB approved consent forms.  
• Informed consent completion will be monitored regularly by the Sponsor.  
 
5.5 Procedure  
All procedures are to be conducted per routine practice at each study site.  
 
The following information may be captured in the Case Report Form (CRF):  
• Administration of intravenous thrombolytics (IV rtPA), Anti-coagulation 
agents, and medications 
• Imaging times and results  
o Modified Thrombolysis in Cerebral Infarction (mTICI) scores pre and post 
procedure (AIS only) 
o Pre and post procedure hematoma volume (MIS only)  
• Key procedural time points 
• First pass to specimen extraction (AIS only) 
• SAE collection 

 
 
 
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5.5.3 Specimen for Acute Ischemic Stroke Cases 
Specimen will be collected during the procedure in the filter (clot catcher) by 
study personnel. The clot catcher is part of the single use canister for the 
Penumbra Aspiration Pump.  
 
After the specimen is collected into the RNA collection tube, it is recommended 
to fill the RNA Clot collection tube with the fluid in the canister prior to sealing.  
 
Prior to thrombectomy, and during flushing of the diagnostic or guide catheter, 
approximately 10 mL of extracranial blood should be collected from the 
diagnostic or guide catheter. It is recommended to allow approximately 10-15ml 
waste while backflushing prior to obtaining the 10ml sample.  5 mL will be 
placed into each of the EDT purple top collection tubes provided in the specimen 
collection kit. 
5.5.4 Specimen for Minimally Invasive Surgery  
 
Specimen will be collected during the procedure in the canister within the 
Penumbra Aspiration Pump by study personnel.  
 
The specimen may be obtained in whole piece(s) or fragments after evacuation by 
the Artemis device. After the specimen is collected into the RNA collection tube 
it is recommended to fill the RNA Clot collection tube with the fluid in the 
canister prior to sealing.  
 
Approximately 10 mL of blood should be collected from the arterial line and 
5 mL will be placed into each of the EDT purple top collection tubes provided 
in the specimen collection kit The blood should be collected from the arterial 
line around the same time as the clot evacuation. 
 
5.6 Discharge or 7 Days (whichever occurs first) 
The following assessments will be performed per site routine practice at discharge 
or 7 Days post procedure:  
• National Institutes of Health Stroke Scale (NIHSS)  
• Modified Rankin Scale (mRS)  
• Glasgow Coma Score (GCS) – (MIS only) 
• SAE collection 
5.7 90 Day Follow-Up ±14 Days (Optional phone visit) 
The following assessment will be performed per site routine practice at this optional 
phone visit:  
• Modified Rankin Scale (mRS)  

 
 
 
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6. Specimen Collection and Shipment 
All specimen should be placed within the provided collection tube(s) then securely 
packaged in the specimen collection kit provided, and shipped to the Core Lab(s) as 
quickly as possible, but no later than 72 hours post procedure and after informed 
consent is obtained. 
 
The study sponsor will provide specimen kits, comprised of the following 
components: 
 
• Mini Sample collection tube(s) for the clot 
• Sealable plastic biohazard bags 
• Absorbent material 
• Paraffin tape for mini sample collection tubes(s) 
• Purple collection tubes for blood samples (x2) 
• Return packaging for specimen shipment to the Core Lab(s) 
• UN 3373, Biological substances, Category B label 
• Instructions for specimen collection, packing and shipping the 
specimen kit 
 
Prior to return shipment to the Core Lab(s), document the kit number for 
entry into the database. The samples should be packaged per the packaging 
and shipping instructions and must comply with the Department of 
Transportation (DOT), Hazardous Materials Regulations (HMR), 49 CFR 
Parts 171-180) and the International Airline Transport Associate (IATA) for 
shipping of Hazardous Materials. 
Study personnel responsible for packaging and/or shipping must be trained 
in the packaging and shipping of Category B, biological substance, as 
described in the DOT/IATA division 6.2 and HMR 173.134(b)(10). 
Certification of training will be required for all study personnel delegated to 
perform specimen packaging and shipping as described in this protocol. 
6.1 Specimen Destruction 
 
Specimen collected as part of this registry may be destroyed for the 
following reasons: 
• Requested by the sponsor according to the Core Lab Charter 
• Requested in writing by a patient who has withdrawn their consent to 
participate 
• Informed Consent not obtained as specified in section 5.4 Informed 
Consent 
 
7. Investigator Responsibilities 
7.1 Institutional Review Board Approval 

 
 
 
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Prior to enrolling patients into the study, the Investigator will ensure that proper 
Institutional Review Board (IRB) approval is obtained in accordance with applicable 
local state and federal laws and regulations.  The IRB shall approve all study 
documents as appropriate, including but not limited to: the final protocol, amendments 
to the protocol, Instructions for Use (where applicable), and the informed consent. 
The Investigator will report to the Sponsor or designee immediately if the approval to 
conduct the investigation is withdrawn by the IRB. The report will include a complete 
description of the reason(s) for which approval was withdrawn. 
7.2 Informed Consent 
 
The Investigator is responsible for ensuring that a signed and dated informed consent is 
obtained in accordance with Section 5.4 of this protocol and according to country and 
local requirements prior to conducting any study-related assessments and prior to 
enrollment of patients in the study. 
7.3 Adherence to Protocol/Amendments and Applicable Law 
 
The Investigator is responsible for overseeing, ensuring that the study is conducted, and 
completing the study according to this protocol and in accordance with the relevant 
aspects of I.S. EN ISO 14155:2020, Declaration of Helsinki, along with any conditions 
imposed by the reviewing Institutional Review Board (IRB), and all other applicable 
regulations. The Investigator shall approve and adhere to this protocol and any 
amendments that arise during the course of the study. 
It is the Investigator’s responsibility to ensure that the staff assisting with the study 
have the appropriate qualifications, are fully instructed on the study procedures, and 
will respect study confidentiality.  
7.4 Case Report Form Completion 
The Investigator and study staff shall complete the case report forms (CRFs) associated 
with this study. Patient numbers shall be used to identify individual participants in this 
study. The CRFs should be a complete and accurate record of patient data collected 
during the study according to relevant aspects of I.S. EN ISO 14155, 21 CFR 11, 
Electronic Records; Electronic Signatures, and Good Clinical Practices (GCP) 
requirements. It is the Investigator's responsibility to ensure the quality of the data 
collected and recorded is appropriate and collected in accordance with GCP and all 
applicable regulations. Data entry will be performed by the study site(s). Investigators 
are responsible for completion and timely submission of data to Penumbra, Inc. Every 
reasonable effort should be made to complete data entry within 7 days of data 
collection.  
7.5 Reporting 

 
 
 
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The Investigator will be responsible for reporting the following: 
7.5.1 Adverse Events 
Serious Adverse Events (AE) will be collected in this registry on patients treated 
with any of the RED reperfusion catheters from procedure through discharge. 
Serious device related events, serious procedure related adverse events, 
symptomatic ICH at 24 hours, device deficiencies leading to adverse events, and 
symptomatic embolization of new territory (ENT) and will be collected on the 
case report form through 7 days post procedure. No additional risk is associated 
with specimen collection. 
 
7.5.2 Device Deficiencies  
Any device deficiency that might lead to serious adverse events if appropriate 
action had not been taken, intervention had not occurred or circumstances had 
been less fortunate will be reported in EDC. All device deficiencies related to the 
identity, quality, durability, reliability, or performance of the devices used shall be 
documented and reported through the post market reporting process.  
 
7.5.3 Protocol Deviation 
Deviations defined in this protocol should be clearly documented, if identified 
during monitoring or through other means. For this study, deviations should be 
reported for the following categories:  
• 
Inclusion/exclusion criteria deviation(s) 
• 
Informed Consent deviation(s) 
 
7.6 Records Retention 
The Investigator shall maintain the records associated with this study for a period of 
at least two years after the date on which the investigation is completed. An eTMF 
will be used as the master repository for all site and Sponsor regulatory documents. 
These records include the following: 
• Correspondence with the Sponsor or designee, and other Investigators 
• Accountability records of receipt, use, and disposition of all study materials 
• Patient source records, including but not limited to: Informed Consent Forms, 
copies of all completed CRFs, and supporting documents (laboratory reports 
and reports of diagnostic tests, medical records, etc.) 
• All versions of study protocol  
• Documentation of protocol deviations  
• A copy of all approvals related to the clinical investigation 
• The approved, blank, informed consent form  

 
 
 
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• All approval/acknowledgment letters from the IRB for all versions of the study 
protocol, ICF and other documents 
• Clinical Trial Agreement(s) 
• Signed and dated curriculum vitae for all study personnel  
• Medical licenses for the Principal Investigator and all participating Sub-
Investigators 
• Financial disclosure for the Principal Investigator and all participating Sub-
Investigators  
• All required regulatory documents such as Delegation of Authority and training 
logs 
• Signed Protocol Signature Page(s) 
8. Sponsor Responsibilities 
8.1 Training 
The Sponsor is responsible for providing training on the protocol, Core Lab(s) 
procedures, and eCRF completion as applicable for all study staff per delegation of 
authority log.  
8.2 Investigator List 
The Sponsor shall keep a list of the names and addresses of the clinical 
Investigators for the study. 
8.3 Data Monitoring 
 
Penumbra is responsible for ensuring that the study is conducted according to the 
appropriate regulations.  
• Guideline for Good Clinical Practice, (ICH E6)  
• Clinical investigation of medical devices for human subjects – Good 
clinical practice (I.S. EN ISO 14155:2020)  
• US Food and Drug Administration 21 CFR Title 21 Parts §11, §50, §54, 
§56, and §812 
 
A Penumbra employee or designee will conduct the following site visits: 
8.3.1 Site Qualification  
Conducted to ensure the study site has the appropriate staff, facilities, and 
expertise to participate in the study. Site Qualification can be waived under 
certain circumstances. 
8.3.2 Site Initiation  

 
 
 
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Conducted to train the investigational staff on CRF completion, Core Lab(s) 
processes, study requirements, and other relevant training. 
8.3.3 Interim Monitoring  
Conducted as needed to ensure the study site is operating in compliance with this 
protocol, continues to have the appropriate staff and facilities, and is correctly 
completing the CRFs.  
The visits ensure that Investigators and their staff understand and accept their 
defined responsibilities, the Sponsor will maintain regular correspondence and 
perform periodic site visits during the course of the study to verify the continued 
acceptability of the facilities, compliance with the investigational plan, and 
maintenance of complete records. Clinical monitoring will include review of 
informed consent forms for enrolled patients. Informed consent, eCRFs and 
medical records for all enrolled patients will be made available to the Sponsor for 
review and collection. 
8.3.4 Site Close Out  
 
Conducted to ensure all study and regulatory-related activities have been 
completed prior to site closure. 
8.4 Data Management 
eCRFs will be used at all study sites. All study data will be entered into 
commercially available web-based electronic data capture system (EDC). Data 
entry will be performed by the study site personnel. Investigators are responsible 
for completion and timely submission of the data to the Sponsor. Every reasonable 
effort should be made to complete data entry within 7 days of data collection. This 
EDC system requires no on-site software installation or specific hardware to 
operate. Investigators, clinical coordinators, data managers, Core Lab personnel, 
and Penumbra clinical personnel access project information and study data centrally 
via a web browser.  
Automated data quality checks will display warnings for invalid data. Additionally, 
manual review of data listings may be used to identify data discrepancies or 
inconsistencies. The study site may be queried for clarification concerning CRF 
discrepancies or inconsistencies identified. If CRF corrections are necessary, they 
will be made by the Investigator or an authorized member of the Investigator's staff 
that is delegated to the CRF/EDC. Questions or problems with submitted data will 
be addressed with the Principal Investigator via an electronic querying system, or 
through direct contact. The Investigator will review the CRFs for completeness and 
accuracy and provide his/her electronic signature and date to CRFs as evidence 
thereof. Any data items that have been changed will require reapplication of the 
electronic signature. 

 
 
 
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Study personnel will have an individual login and password to access the clinical 
study information based upon each individual’s roles and responsibilities. The 
application provides hierarchical user permission data entry, viewing, and reporting 
options. 
All data entry and data update information, including the date and person 
performing the action, will be available via the audit trail, which is part of the EDC 
system. 
All eCRFs and data files will be secured to ensure confidentiality. Investigators are 
required to maintain source documents required by the protocol, including 
laboratory results, reports, supporting medical records, and Informed Consent 
Forms. The source documents will be used during the regular monitoring visits to 
verify information entered on the CRFs. 
9. Ethical Requirements 
9.1 Declaration of Helsinki 
The study will be performed in accordance with the applicable aspects I.S. EN ISO 
14155, recommendations guiding physicians in biomedical research involving 
human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland 
(1964 and later revisions), ICH, and US FDA GCP guidelines. 
It is the responsibility of the Investigator to obtain approval of the study protocol 
from the Institutional Review Board (IRB) and to keep the IRB informed of any 
amendments to the protocol and informed consent forms. All correspondence with 
the IRB should be filed by the Investigator and copies sent to the Sponsor or its 
designee. 
9.2 Informed Consent 
The Investigator is responsible for ensuring that a completed informed consent is 
obtained in accordance with Section 5.4 of this protocol, as delegated by the site-
specific Delegation of Authority, and according to country and local requirements. 
9.3  Patient Data Protection 
Each patient will be assigned a unique patient identification number at the time of 
enrollment. This patient identification number will be retained throughout the study. 
Study sites will keep a log that notes the patient’s name and corresponding patient 
identification number. All case report forms (CRFs) will be tracked, evaluated, and 
stored using only the patient ID number. No personal identifying information will 
be included on the case report forms. 
The informed consent form will notify patients that study monitors, auditors, and 
representatives of government agencies and ethics committees will have access to 

 
 
 
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personal identifying information to ensure that data reported on the CRFs 
corresponds to the person who signed the consent form and the information contained 
in the source documentation.  
10. Statistical Procedures 
10.1 General Statistical Considerations 
All statistical analyses will be descriptive in nature. Descriptive statistics will include 
the number of observations, mean, median, standard deviation, inter-quartile range, 
minimum and maximum for continuous variables and counts and percentages for 
discrete variables.  All confidence intervals presented will be two-sided. Analyses 
will be conducted using SAS (SAS Institute, Cary, NC). The specific details of the 
planned analyses are described completely in the statistical analysis plan. 
10.2 Sample Size Estimation  
Due to the descriptive nature of this registry, no formal sample size calculations were 
performed. Approximately up to 400 patients will be enrolled in the registry. 
 
10.3 Control of Systematic Error and Bias 
The registry will be conducted under a common protocol for each study site with the 
intention of pooling the data for analysis. Every effort will be made to promote 
consistency in study execution at each study site.  
10.4 Missing Data and Imputation Methods 
Every effort is to be made to keep all missing data to a minimum. Despite the clinical 
site’s best efforts, some missing data may be inevitable mainly due to lost-to-follow-
up. (LTFU) 
10.5 Definition of Populations 
10.5.1  Enrolled 
Patients will be considered enrolled upon signed informed consent and specimen 
collection.  
10.5.2 Completed 
All patients who were enrolled and completed the registry follow-up or were known 
to have died prior to the follow-up timepoint.   
10.5.3 Early Termination  
Patients who were enrolled but did not complete follow-up and were not known to 
have died.  

 
 
 
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10.6 Definition of Analysis Population 
All enrolled patients will be analyzed under the intent-to-treat (ITT) principle.  
10.7 Interim Analysis 
No interim analyses are planned for the purpose of stopping the study early. 
Interim analysis may be performed for publication of registry results. No 
adjustments will be made to the confidence bounds for the final analysis.  
 
10.8 Statistical Analysis  
Clot characteristics, such as clot location, clot organization, composition, source of 
thrombus, and clot dimensions will be summarized using descriptive statistics.  
 
Baseline data including, but not limited to demographics, clinical, procedural, and 
imaging characteristics from ischemic stroke patients and patients eligible for 
minimally invasive hematoma evacuation will be summarized using descriptive 
statistics. 
Sub-group analyses will be performed to examine patient outcomes based on initial 
presentations and radiologic characteristics. Exploratory multivariate analyses will 
be conducted. 
 
Results collected at multiple visits will be summarized at each visit for which they 
are collected as described Schedule of Assessments Table.  Summaries for all 
measures will include all observed data for each visit. 
 
10.9 Pooling Across Centers 
Analyses will be present using data pooled across centers. Descriptive statistics 
for key variables will be presented to assess any potential site effects. 
 
10.10 Final Report 
A final report will be completed, even if the study is prematurely terminated. At the 
conclusion of the registry, a multi-center abstract reporting the results will be 
prepared and may be presented at a major meeting(s). A multi-center publication 
may also be prepared for publication in a reputable scientific journal. The 
publication of results from any single center experience within the registry is not 
allowed until the aggregate study results have been published, unless there is 
written consent from the Sponsor. 
 
11. Study Committees: Core Lab(s)  
11.1 Central Core and Pathophysiology Lab 

 
 
 
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Up to three independent laboratories will follow the Study Core Lab Charter to analyze 
collected samples via histology, proteomics, and RNA sequencing. The Core Lab(s) 
will also be responsible for appropriate sample storage and destruction.  
 
12. Study Administration 
12.1 Clinical Trial Termination/Withdrawal 
Patients may be terminated or withdrawn from the study for the following reasons: 
• Voluntary withdrawal of consent–– meaning that a patient voluntarily chooses 
not to participate further in the study.  All data collected up to the withdrawal of 
consent will be maintained in the study database. Withdrawn patients will not 
have any additional follow-up and will not be replaced. 
• Patients may also be withdrawn at the Investigator’s discretion if within their 
best interest. A patient’s participation in the clinical study will be terminated if 
the Investigator believes that this is in the patient’s best medical interest or if the 
patient no longer complies with the clinical study requirements. 
• Upon withdrawal of consent, all specimens collected prior to receipt of notice of 
withdrawal will not be destroyed and will remain part of this registry and stored 
for future research by Sponsor unless written notification from the patient is 
received requesting that all samples are to be destroyed, as specified in Section 
6.1 Specimen Destruction. 
The sponsor may temporarily suspend or prematurely terminate the study at any 
time for the following reasons: 
• Suspicion of risk to patients 
• If no positive IRB decision is obtained or if the judgement of the IRB is revoked 
• If the applicable regulatory body has made an irrevocable objection 
• If it transpires that continuation of study cannot serve any scientific purpose, 
and this is confirmed by the IRB 
• Business reasons  
The Sponsor will document reasons for study suspension or premature termination 
and notify the PIs. The Sponsor will ensure that the IRB and regulatory authorities 
are notified in a timely manner.  
The Sponsor will continue to provide resources to fulfil the obligations from the 
study protocol and existing agreements for following up the patients enrolled in the 
study. 
The Principal Investigators will promptly inform the enrolled patients at his/her site, 
if appropriate. 
If the Sponsor temporarily suspends the study and wishes to resume it, the Sponsor 
will inform the PIs, IRB, and (if appropriate) regulatory authorities.  The Sponsor 

 
 
 
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will provide a rationale for resuming the study.  IRB must provide written approval 
before the study is resumed. 
 
12.2 Protocol Adherence and Amendments 
Prior to beginning the study, the Principal Investigator must sign the Protocol 
Signature Page documenting his/her agreement to conduct the study in accordance 
with this protocol. Deviations outlined in section 6.5.1 must be documented and 
reported to Penumbra as soon as possible, and to the IRB per local guidelines and 
government regulations. 
12.3 Trial Registration 
The study will be registered in a publicly accessible trial database (e.g., clinical 
trials.gov) prior to study initiation. 
13.  Publication of Information 
All information and data generated in association with this study will be held in strict 
confidence and remain the sole property of the Sponsor. The Investigator agrees to use 
this information for the sole purpose of completing this study and for no other purpose 
without written consent from the Sponsor. 
The results of this study may be offered for publication. The Investigators and the 
Sponsor shall collaborate in the writing of the study to ensure accuracy.  All information 
not previously published concerning the research, including patent applications, 
manufacturing processes, basic scientific data, etc., is considered confidential and should 
remain the sole property of Penumbra.  The Investigator agrees to use this information 
only in connection with this study and will not use it for other purposes without written 
permission from the Sponsor. 
14.  Contact Information 
The address of Penumbra Incorporated is: 
Penumbra, Inc. 
One Penumbra Place 
Alameda, CA 94502 
Tel. (510) 748-3200 
Fax (510) 814-8305 
Key contacts for the Study include: 
 
 
 
  
 
 
 
 

 
 
 
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15.  References 
 
1. 
Johnson, W., Onuma, O., Owolabi, M., and Sachdev, S. (2016). Stroke: A global 
response is needed. Bull World Health Organ. 94(9): p. 634-634A. 
2. 
Benjamin, E.J., Blaha, M.J., Chiuve, S.E., Cushman, M., Das, S.R., Deo, R., . . . Stroke 
Statistics, S. (2017). Heart disease and stroke statistics-2017 update: A report from the 
american heart association. Circulation. 135(10): p. e146-e603. 
3. 
Powers, W.J., Rabinstein, A.A., Ackerson, T., Adeoye, O.M., Bambakidis, N.C., Becker, 
K., . . . American Heart Association Stroke, C. (2018). 2018 guidelines for the early 
management of patients with acute ischemic stroke: A guideline for healthcare 
professionals from the american heart association/american stroke association. Stroke. 
49(3): p. e46-e110. 
4. 
Turk, A.S., 3rd, Siddiqui, A., Fifi, J.T., De Leacy, R.A., Fiorella, D.J., Gu, E., . . . Mocco, 
J. (2019). Aspiration thrombectomy versus stent retriever thrombectomy as first-line 
approach for large vessel occlusion (compass): A multicentre, randomised, open label, 
blinded outcome, non-inferiority trial. Lancet. 393(10175): p. 998-1008. 
5. 
Hemphill, J.C., 3rd, Bonovich, D.C., Besmertis, L., Manley, G.T., and Johnston, S.C. 
(2001). The ich score: A simple, reliable grading scale for intracerebral hemorrhage. 
Stroke. 32(4): p. 891-7. 
6. 
Goyal, N., Tsivgoulis, G., Malhotra, K., Katsanos, A.H., Pandhi, A., Alsherbini, K.A., . . 
. Arthur, A.S. (2019). Minimally invasive endoscopic hematoma evacuation vs best 
medical management for spontaneous basal-ganglia intracerebral hemorrhage. J 
Neurointerv Surg. 
7. 
Hanley, D.F., Lane, K., McBee, N., Ziai, W., Tuhrim, S., Lees, K.R., . . . Investigators, 
C.I. (2017). Thrombolytic removal of intraventricular haemorrhage in treatment of severe 
stroke: Results of the randomised, multicentre, multiregion, placebo-controlled clear iii 
trial. Lancet. 389(10069): p. 603-611. 
8. 
Hanley, D.F., Thompson, R.E., Rosenblum, M., Yenokyan, G., Lane, K., McBee, N., . . . 
Investigators, M.I. (2019). Efficacy and safety of minimally invasive surgery with 
thrombolysis in intracerebral haemorrhage evacuation (mistie iii): A randomised, 
controlled, open-label, blinded endpoint phase 3 trial. Lancet. 393(10175): p. 1021-1032. 
9. 
Spiotta, A.M., Fiorella, D., Vargas, J., Khalessi, A., Hoit, D., Arthur, A., . . . Turner, R.D. 
(2015). Initial multicenter technical experience with the apollo device for minimally 
invasive intracerebral hematoma evacuation. Neurosurgery. 11 Suppl 2: p. 243-51; 
discussion 251. 
10. 
Feigin, V.L., Krishnamurthi, R.V., Parmar, P., Norrving, B., Mensah, G.A., Bennett, 
D.A., . . . Group, G.B.D.S.P.E. (2015). Update on the global burden of ischemic and 
hemorrhagic stroke in 1990-2013: The gbd 2013 study. Neuroepidemiology. 45(3): p. 
161-76. 
11. 
Alawieh, A., Vargas, J., Fargen, K.M., Langley, E.F., Starke, R.M., De Leacy, R., . . . 
Spiotta, A.M. (2019). Impact of procedure time on outcomes of thrombectomy for stroke. 
J Am Coll Cardiol. 73(8): p. 879-890. 

 
 
 
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12. 
De Meyer, S.F., Andersson, T., Baxter, B., Bendszus, M., Brouwer, P., Brinjikji, W., . . . 
Clot Summit, G. (2017). Analyses of thrombi in acute ischemic stroke: A consensus 
statement on current knowledge and future directions. Int J Stroke. 12(6): p. 606-614. 
13. 
Brouwer, P.A., Brinjikji, W., and De Meyer, S.F. (2018). Clot pathophysiology: Why is it 
clinically important? Neuroimaging Clin N Am. 28(4): p. 611-623. 
14. 
Czaplicki, C., Albadawi, H., Partovi, S., Gandhi, R.T., Quencer, K., Deipolyi, A.R., and 
Oklu, R. (2017). Can thrombus age guide thrombolytic therapy? Cardiovasc Diagn Ther. 
7(Suppl 3): p. S186-S196. 
15. 
Sporns, P.B., Hanning, U., Schwindt, W., Velasco, A., Buerke, B., Cnyrim, C., . . . 
Niederstadt, T. (2017). Ischemic stroke: Histological thrombus composition and pre-
interventional ct attenuation are associated with intervention time and rate of secondary 
embolism. Cerebrovasc Dis. 44(5-6): p. 344-350. 
16. 
Kim, S.K., Yoon, W., Kim, T.S., Kim, H.S., Heo, T.W., and Park, M.S. (2015). 
Histologic analysis of retrieved clots in acute ischemic stroke: Correlation with stroke 
etiology and gradient-echo mri. AJNR Am J Neuroradiol. 36(9): p. 1756-62. 
17. 
Marder, V.J., Chute, D.J., Starkman, S., Abolian, A.M., Kidwell, C., Liebeskind, D., . . . 
Saver, J.L. (2006). Analysis of thrombi retrieved from cerebral arteries of patients with 
acute ischemic stroke. Stroke. 37(8): p. 2086-93. 
18. 
Boeckh-Behrens, T., Schubert, M., Forschler, A., Prothmann, S., Kreiser, K., Zimmer, C., 
. . . Poppert, H. (2016). The impact of histological clot composition in embolic stroke. 
Clin Neuroradiol. 26(2): p. 189-97. 
19. 
Mehta, B.P. and Nogueira, R.G. (2012). Should clot composition affect choice of 
endovascular therapy? Neurology. 79(13 Suppl 1): p. S63-7. 
20. 
Sumaya, W., Wallentin, L., James, S.K., Siegbahn, A., Gabrysch, K., Bertilsson, M., . . . 
Storey, R.F. (2018). Fibrin clot properties independently predict adverse clinical outcome 
following acute coronary syndrome: A plato substudy. Eur Heart J. 39(13): p. 1078-
1085. 
21. 
Hashimoto, T., Hayakawa, M., Funatsu, N., Yamagami, H., Satow, T., Takahashi, J.C., . . 
. Toyoda, K. (2016). Histopathologic analysis of retrieved thrombi associated with 
successful reperfusion after acute stroke thrombectomy. Stroke. 47(12): p. 3035-3037. 
22. 
Maekawa, K., Shibata, M., Nakajima, H., Mizutani, A., Kitano, Y., Seguchi, M., . . . 
Miya, F. (2018). Erythrocyte-rich thrombus is associated with reduced number of 
maneuvers and procedure time in patients with acute ischemic stroke undergoing 
mechanical thrombectomy. Cerebrovasc Dis Extra. 8(1): p. 39-49. 
23. 
Shin, J.W., Jeong, H.S., Kwon, H.J., Song, K.S., and Kim, J. (2018). High red blood cell 
composition in clots is associated with successful recanalization during intra-arterial 
thrombectomy. PLoS One. 13(5): p. e0197492. 
24. 
Drabik, L., Wolkow, P., and Undas, A. (2017). Fibrin clot permeability as a predictor of 
stroke and bleeding in anticoagulated patients with atrial fibrillation. Stroke. 48(10): p. 
2716-2722. 
25. 
Maatman, B.T., Schmeisser, G., and Kreutz, R.P. (2018). Fibrin clot strength in patients 
with diabetes mellitus measured by thrombelastography. J Diabetes Res. 2018: p. 
4543065. 
26. 
Undas, A. and Zabczyk, M. (2018). Antithrombotic medications and their impact on 
fibrin clot structure and function. J Physiol Pharmacol. 69(4). 

 
 
 
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27. 
Banks, J.L. and Marotta, C.A. (2007). Outcomes validity and reliability of the modified 
rankin scale: Implications for stroke clinical trials: A literature review and synthesis. 
Stroke. 38(3): p. 1091-6. 
28. 
Moore, L., Lavoie, A., Camden, S., Le Sage, N., Sampalis, J.S., Bergeron, E., and 
Abdous, B. (2006). Statistical validation of the glasgow coma score. J Trauma. 60(6): p. 
1238-43; discussion 1243-4. 
29. 
Meyer, B.C., Hemmen, T.M., Jackson, C.M., and Lyden, P.D. (2002). Modified national 
institutes of health stroke scale for use in stroke clinical trials: Prospective reliability and 
validity. Stroke. 33(5): p. 1261-6. 
 
 
 
 
 
 
 

 
 
 
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16.2 Glasgow Coma Scale 28 
 
 
 

 
 
 
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You know how.  
Down to earth.  
I got home from work.  
Near the table in the dining room.  
They heard him speak on the radio 
last night. 
 

 
 
 
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MAMA 
TIP – TOP 
FIFTY – FIFTY 
THANKS 
HUCKLEBERRY 
BASEBALL PLAYER 
 

 
 
 
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16.4 Abbreviations 
AE 
Adverse Event 
AIS 
Acute Ischemic Stroke 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DNA 
Deoxyribonucleic Acid 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EN 
European Norm 
ENT 
Embolization to Uninvolved or New Territories 
FDA 
Food and Drug Administration 
FU 
Follow-Up 
GCP 
Good Clinical Practices 
GCS 
Glasgow Coma Score 
I/E 
Inclusion/Exclusion 
IA 
Intra-Arterial 
ICF 
Informed Consent Form 
IFU 
Instructions For Use 
IRB 
Institutional Review Board 
I.S.  
Irish Standard 
ISO 
International Organization for Standardization  
ITT 
Intent To Treat 
IV 
Intravenous 
LAR 
Legally Authorized Representative 
LTFU 
Lost to Follow-Up 
MIS 
Minimally Invasive Surgery 
mRS 
Modified Rankin Scale 
MT 
Mechanical Thrombectomy 
mTICI 
Modified Treatment in Cerebral Ischemia 
NIHSS 
National Institute of Health Stroke Scale 
PP 
Per Protocol 
RNA 
Ribonucleic Acid  
SAE 
Serious Adverse Event 
sICH 
Symptomatic Intracerebral Hemorrhage; defined 
as 24 hour CT evidence of an ECASS defined 
ICH and a 4-point or more worsening of the 
NIHSS score 
SNPs 
Single Nucleotide Polymorphism  
tPA 
Tissue Plasminogen Activator 
US 
United States 
   

 
 
 
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16.5 Definitions  
16.5.3 Adverse Event (AE): any untoward medical occurrence, unintended 
disease or injury, or untoward clinical signs (including abnormal 
laboratory findings) in participants, users or other persons, whether or not 
related to the study device and whether anticipated or unanticipated. 
• Serious Adverse Event (SAE) An adverse event is serious if the event led to the 
following: 
o Death  
o Serious deterioration in the health of the participant that resulted in any of 
the following: 
 Life-threatening illness or injury  
 Permanent impairment of a body structure or a body function  
 Hospitalization or prolongation of patient hospitalization  
 Medical or surgical intervention to prevent life-threatening illness 
or injury or permanent impairment to a body structure or a body 
function  
o Fetal distress, fetal death or a congenital physical or mental impairment 
or birth defect 
• Unanticipated Adverse Device Event (UADE): An unanticipated adverse device 
effect is 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 protocol, IFU, or risk analysis. Unanticipated adverse device effect also 
includes any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of participants.  
• Relationship to the Device  
o Definite: The temporal sequence is relevant and the event abates upon 
study device application completion/removal, or reappearance of the 
event on repeat study device application.  
o Probable: The temporal sequence is relevant or the AE abates upon study 
device application completion/removal or the AE cannot be reasonably 
explained by the participant’s condition or comorbidities. The AE is 
related or most likely associated with the study device.  
o Possible: The temporal sequence between the study device and the AE is 
such that the relationship is not unlikely or there is no contradicting 
evidence that can reasonably explain the participant’s condition. There is 
a possibility of a relationship between the AE and the study device.  
o Unrelated: The AE is not associated with the device. There is no relation 
between the AE and the study device. 
 
Similar grading will be used for assessing the relationship to index procedure. 
 

 
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INSIGHT: Investigation of Clot in Ischemic Stroke and 
Hematoma Evacuation 
 
 
STATISTICAL ANALYSIS PLAN  
CLP-15131 
 
Version 3.0 
 
Sponsor 
Penumbra, Inc. 
One Penumbra Place 
Alameda, CA 94502 
USA 
 
 
 

 
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Contents 
1. 
Overview ................................................................................................................................ 3 
2. 
Study objectives ................................................................................................................... 3 
2.1  Primary Objectives ........................................................................................................ 3 
2.2  Secondary Objectives ................................................................................................... 4 
3. 
Sample size ........................................................................................................................... 4 
4. 
Interim analysis ..................................................................................................................... 4 
5. 
General Statistical methods ................................................................................................ 4 
6. 
Patient Disposition ............................................................................................................... 4 
6.1  Enrolled ........................................................................................................................... 4 
6.2  Completed....................................................................................................................... 5 
6.3  Early Termination........................................................................................................... 5 
7. 
Definition of Analysis Population ....................................................................................... 5 
8. 
Statistical Analysis ............................................................................................................... 5 
9. 
Analysis of adverse events ................................................................................................. 6 
10. Subgroup analysis ................................................................................................................ 6 
11. Pooling across centers ........................................................................................................ 7 
12. Lost to follow-up and missing data .................................................................................... 7 
13. Central Core and Pathophysiology Lab ............................................................................ 8 
14. Changes to planned analysis ............................................................................................. 8 
15. References ............................................................................................................................ 8 
16. Revision History .................................................................................................................... 8 
 
 
 
 
 

 
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1.   Overview 
This is a prospective, multicenter, registry for the collection and analysis of 
specimen collected from ischemic stroke thrombectomy procedures and 
minimally invasive interventions for intracranial hematoma evacuation utilizing 
the Penumbra Aspiration Pump. The aim of the study is to collect and analyze 
specimen via histology, RNA sequencing, Single Nucleotide Polymorphisms 
(SNPs), and proteomic analysis. This will then be correlated to comprehensive 
data relating to patient’s clinical presentation, hospital course, and length of 
hospital stay. Patients eligible for thrombectomy or minimally invasive surgery, 
who meet the inclusion and none of the exclusion criteria will be considered for 
enrollment. Treatment will be per site routine practice, using FDA cleared 
devices. Patients will be considered enrolled upon signed informed consent and 
specimen collection. Up to 400 patients from up to 30 sites in the United States 
will be enrolled into this registry. Each site will be limited to a maximum 
enrollment of 60 subjects (approximately 15% of the total enrolled). It is 
anticipated that enrollment will take approximately 2 years. Each patient will be 
in the registry for up to 90 days from enrollment to last follow-up. Data for each 
subject will be collected at the time of enrollment, discharge or 7days (whichever 
comes first) and 90 Days (optional) follow-up.  
 
2.   Study objectives 
This study will examine whether clot composition, genetic, and proteomic 
variables can provide insight into thrombus etiology and/or have impact on 
clinical outcomes in patients with outwardly similar initial presentations. 
 
   
  
2.1  
Primary Objectives 
The aim of the study is to collect and analyze specimen from, ischemic 
stroke patients undergoing thrombectomy procedures, and from patients 
undergoing minimally invasive surgery for intracranial hematoma 
evacuation. Clot and blood specimen will be analyzed via histology, RNA 

 
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sequencing, Single Nucleotide Polymorphisms (SNPs), and proteomic 
analysis. 
 
   
  
2.2  
Secondary Objectives 
To prospectively collect and correlate data relating patient’s clinical 
presentation, hospital course, and length of hospital stay to specimen 
histology, RNA sequencing, SNPs, and proteomic analysis.  
 
 
3.   Sample size 
Due to the descriptive nature of this registry with no formal statistical hypothesis 
test, sample size calculations were not performed. Up to 400 subjects will be 
enrolled in the registry. 
 
4.   Interim analysis 
No interim analyses are planned for the purpose of stopping the study early. 
Interim analysis may be performed for publication of registry results. No 
adjustments will be made to the confidence bounds for the final analysis.  
 
5.   General Statistical methods  
No formal statistical testing is planned for this study. All statistical analyses will 
be descriptive in nature. Descriptive statistics will include the number of 
observations, mean, median, standard deviation, inter-quartile range, minimum 
and maximum for continuous variables and counts and percentages for discrete 
variables.  All confidence intervals presented will be two-sided. Analyses will be 
conducted using SAS (SAS Institute, Cary, NC).  
 
6.   Patient Disposition 
    
  
6.1  
Enrolled 

 
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   Patients will be considered enrolled upon signed informed consent and 
specimen collection. 
 
    
  
6.2  
Completed 
All patients who were enrolled and completed either the Discharge/7 Day 
or 90 Day Follow-Up visit or were known to have died prior to 90 days are 
considered completed.   
 
    
  
6.3  
Early Termination  
Subjects who were enrolled but did not complete any follow-up visits and 
were not known to have died.  
 
 
7.   Definition of Analysis Population 
7.1 Intent to treat  
All enrolled subjects will be analyzed under the intent-to-treat (ITT) 
principle.  
 
 
8.   Statistical Analysis 
This plan is limited to the analysis of clinical data and specimen histology. The 
number of patients enrolled, patients completing the study, patients not 
completing the study, and patients completing the optional 90 Day Follow-Up 
visit will be summarized. Clot characteristics, such as clot location, clot 
organization, composition, clot etiology, clot dimensions, and specimen 
histology, will be summarized using descriptive statistics1. Baseline data 
including, but not limited to demographics, clinical, procedural, and imaging 
characteristics from ischemic stroke patients and patients eligible for minimally 
invasive hematoma evacuation will be summarized using descriptive statistics. 
Exploratory multivariate analyses will be conducted. Results collected at multiple 

 
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visits will be summarized at each visit for which they are collected as described 
in Schedule of Assessments Table. Summaries for all measures will include all 
observed data for each visit. 
 
9.  Analysis of adverse events 
Serious adverse events will be collected in this registry on patients treated with 
any of the RED reperfusion catheters from procedure through discharge or 7 
days post-procedure. Serious device related adverse events, serious procedure 
related adverse events will be summarized by showing the number and percent 
of subjects which report the event. 
Other safety events collected on the case report form through 7 days post 
procedure will include symptomatic ICH at 24 hours, and symptomatic 
embolization of uninvolved or new territory (ENT)  
All information pertaining to adverse events noted during the study will be listed 
by subject, detailing category, date of onset, date of resolution, relation to 
device or procedure and seriousness. The onset of serious adverse events will 
be shown relative (in number of days) to the day of procedure. 
 
10. Subgroup analysis 
To evaluate the impact of baseline conditions on procedural and clinical 
outcomes as well as clot characteristics, subgroup analyses will be performed 
for procedural outcomes of mTICI score, clinical outcomes of mortality at 90 
days, NIHSS score at discharge and the proportion of patients that achieve 
mRS of 0 to 2 at 90 days (if available) and clot characteristics of gross 
appearance, clot sign, size, weight, volume and histology.  
The subgroups below will be used for these analyses: 
• Stroke type (Ischemic or Hemorrhagic) 
• Location of Intracerebral Hemorrhage (Deep or Lobar) 
• Age (Less than 65 or 65 and older) 
• Gender (Male or Female) 

 
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• Race (White, Black, Asian or Any other) 
• Ethnicity (Hispanic or Non-Hispanic) 
• Smoking status (Current, Former or Never smoked) 
• Covid status (Active, Previous or No History of COVID) 
• Time of stroke onset to procedure. (6 or less hours or More than 6hrs in 
Ischemic subgroup only) 
Descriptive statistics and 95% confidence intervals will be presented for each 
subgroup and the difference between subgroups. Notable differences between 
subgroups will be further evaluated using additional covariates and multivariate 
modeling to describe relationships between subgroups and clinical outcomes. 
These analyses will be performed in the Intent-to-Treat population given adequate 
numbers for robust analysis. 
 
11. Pooling across centers 
Analyses will be presented using data pooled across centers. Descriptive 
statistics for key variables such as age, baseline NIHSS, IV rtPA administration, 
stroke type, target vessel location, mTICI, and mRS will be presented to assess 
any potential site effects. If there is evidence of site heterogeneity, additional 
analyses will be performed to determine confounding factors influencing site 
and clinical outcomes. Appropriate stratified and modeling techniques, including 
contingency tables, logistic regression, and random effects will be used to 
assess differences between study centers to justify pooling data across 
centers. To avoid the influence of small enrolling sites on contingency tables, 
low enrolling sites will be removed as a sensitivity test for contingency table 
analyses. 
 
12. Lost to follow-up and missing data 
Every effort will be made to keep all missing data to a minimum. Patient 
discontinuation rates will be tabulated by the reason for early termination.  Any 

 
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loss of viable or insufficient sample will be noted. The primary analysis will be 
data as observed.  
 
13. Central Core and Pathophysiology Lab 
In addition to the analysis detailed above, up to three independent laboratories 
will follow the Study Core Lab Charter to analyze collected samples via 
histology, proteomics, transcriptomics, and genomics.  
 
14. Changes to planned analysis 
All changes to the statistical analysis plan (SAP) will be documented in a 
revised SAP or in the clinical trial report.  
 
15. References 
1. Agresti (2014) Categorical Data Analysis. John Wiley & Sons: New Jersey 
 
 
16. Revision History 
Version 
Description of Changes 
Prepared by  
1 
Initial Release 
 
2 
Revised to reflect increased enrollment 
of updated protocol. 
Clarified subgroup analysis categories. 
Added section 16 Revision History 
 
3 
Revised Section 9: Analysis of adverse 
event (AE) section as we are collecting 
AE for the RED subgroup in Protocol E