A Randomized, Concurrent Controlled Trial to Assess the Safety and Effectiveness of the Separator 3D as a Component of the Penumbra System in the Revascularization of Large Vessel Occlusion in Acute Ischemic Stroke
Phase: NA
Conditions: Acute Ischemic Stroke From Large Vessel Occlusion
Sponsor: Penumbra Inc.

 
 
 
 
 
A randomized, concurrent controlled trial to assess the safety 
and effectiveness of the Separator 3D as a component of the 
Penumbra System in the revascularization of large vessel 
occlusion in acute ischemic stroke   
 
Protocol  
CLP 4853.D   
 
Date of Protocol 
June 27, 2012  
 
Device Name 
Penumbra System® 
 
Principal Investigators 
 
Don Frei, MD 
 Endovascular Surgical Neuroradiology 
Swedish Medical Center 
10700 East Geddes Ave, Suite 200 
Englewood, CO 80112 
 (720) 493-3406 
 
Raul Nogueira, MD 
Department of Neurology 
Grady Health System 
80 Jesse Hill Jr. Drive,  
SE Atlanta, GA 30303 
(404) 616-1111 
 
Adnan Siddiqui, MD, PhD 
Neurosurgery 
Kaleida Health 
3 Gates Circle 
Buffalo, NY 14209 
(716) 887-5200  
 

 
 
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CLP 4853.D 
 
Sponsor 
Penumbra, Inc. 
1351 Harbor Bay Parkway 
Alameda, CA 94502 
USA 
 
Contact Person 
Elan Mualem 
Telephone: 
510-748-3254 
Fax: 
510-814-8305 
E-mail: 
elan.mualem@penumbrainc.com 

 
 
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CLP 4853.D 
 
Investigator Agreement and Certification 
 
 
 
A randomized, concurrent controlled trial to assess the safety and effectiveness of the Separator 3D 
as a component of the Penumbra System in the revascularization of large vessel occlusion in acute 
ischemic stroke  
I hereby agree to participate in the clinical investigation of the use of the Penumbra System 
sponsored by Penumbra, Inc. (“Study Sponsor”).  I agree to conduct this investigation according 
to the requirements of the investigational plan provided by the Study Sponsor and in accordance 
with applicable regulations and conditions imposed by the reviewing Institutional Review Board 
(IRB) or Ethics Committee (EC).  I agree to supervise all use of the investigational devices at my 
institution and to ensure appropriate informed consent is obtained from all patients prior to 
inclusion in this study. 
 
I understand that this investigation will be monitored by the Study Sponsor or its designee.  This 
monitoring will involve periodic inspection of my investigational site and ongoing review of the 
data that is submitted by me to the Study Sponsor. 
 
My current curriculum vitae is attached, along with the curriculum vitae of those physicians at 
this institution who will be using this investigational device or participating in this study as co-
investigators under my supervision.  These include the extent and type of our relevant experience 
with pertinent dates and locations. 
 
Accepted by: 
 
 
 
 
Principal Investigator Signature 
Date     
Printed Name 
 
 
 
 
 

 
 
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CLP 4853.D 
TABLE OF CONTENTS 
Contents 
1. 
INTRODUCTION ............................................................................................................ 9 
2. 
STUDY OVERVIEW .................................................................................................... 13 
2.1 
STUDY DESIGN ................................................................................................... 13 
2.2 
STUDY OBJECTIVES/ENDPOINTS ......................................................................... 13 
2.3 
STUDY POPULATION ........................................................................................... 14 
2.4 
STUDY RATIONALE ............................................................................................. 15 
2.5 
DEVICE DESCRIPTION/PRINCIPLES OF OPERATION ............................................. 15 
3. 
STUDY PROCEDURES ................................................................................................ 16 
3.1  
SCREENING ......................................................................................................... 16 
3.2 
PRE-TREATMENT (ADMISSION) EVALUATIONS .................................................. 16 
3.3 
ENROLLMENT ..................................................................................................... 16 
3.4 
PROCEDURE PREPARATION FOR THE PENUMBRA SYSTEM: ................................. 17 
3.5 
PENUMBRA REPERFUSION CATHETER PREPARATION AND USE .......................... 17 
3.6 
PENUMBRA SEPARATOR 3D PREPARATION AND USE ......................................... 18 
3.7 
PENUMBRA SEPARATOR PREPARATION AND USE ............................................... 20 
3.8 
ANGIOGRAPHIC IMAGING ................................................................................... 22 
3.9 
ADJUNCTIVE THERAPIES AND PROTOCOL DEVIATION ........................................ 22 
3.10 
POST-TREATMENT EVALUATIONS ...................................................................... 22 
4. 
ASSESSMENT OF SAFETY, EFFECTIVENESS ..................................................... 23 
4.1 
SAFETY ............................................................................................................... 24 
4.2 
EFFECTIVENESS .................................................................................................. 24 
4.3 
RISK/BENEFIT ANALYSIS .................................................................................... 25 
5. 
INVESTIGATOR RESPONSIBILITIES .................................................................... 26 
5.1 
INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEE APPROVAL .................... 26 
5.2 
INFORMED CONSENT .......................................................................................... 27 
5.3 
ADVERSE EVENT REPORTING ............................................................................. 27 
5.4 
ADHERENCE TO PROTOCOL/AMENDMENTS ........................................................ 28 
5.5 
CASE REPORT FORM COMPLETION ..................................................................... 28 
5.6 
ADMINISTRATION OF NEUROLOGICAL EXAMS AND STROKE SCALES ................. 28 
5.7 
DEVICE INVENTORY REQUIREMENTS ................................................................. 29 
5.8 
 REPORTS ............................................................................................................ 29 
5.9 
RECORDS RETENTION ......................................................................................... 29 
6. 
SPONSOR RESPONSIBILITIES ................................................................................ 30 
6.1 
TRAINING ........................................................................................................... 30 
6.2 
INVESTIGATOR LIST ............................................................................................ 30 
6.3 
ADVERSE EVENT REPORTING ............................................................................. 30 
6.4 
DATA MONITORING ............................................................................................ 30 
6.5 
DATA MANAGEMENT ......................................................................................... 31 
7. 
CONTACT INFORMATION ....................................................................................... 32 
8. 
ETHICAL REQUIREMENTS ..................................................................................... 32 
8.1 
DECLARATION OF HELSINKI ............................................................................... 32 
8.2 
PATIENT INFORMATION AND CONSENT............................................................... 32 
8.3 
PATIENT DATA PROTECTION .............................................................................. 32 
8.4 
CLINICAL TRIAL TERMINATION .......................................................................... 33 
9. 
STATISTICAL PROCEDURES .................................................................................. 33 

 
 
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9.1 
SAMPLE SIZE JUSTIFICATION .............................................................................. 33 
9.2 
STATISTICAL ANALYSIS ..................................................................................... 33 
9.3 
EFFECTIVENESS .................................................................................................. 33 
9.4 
SAFETY ............................................................................................................... 35 
9.5 
ADVERSE EVENT ANALYSIS ............................................................................... 35 
9.6 
INTERIM ANALYSIS............................................................................................. 35 
10. 
PUBLICATION OF INFORMATION ........................................................................ 36 
11. 
REFERENCES ............................................................................................................... 37 
11.1 
SCHEMATIC OF STUDY DESIGN ........................................................................... 37 
11.2 
ACRONYMS......................................................................................................... 38 
11.3 
DEFINITIONS ....................................................................................................... 39 
11.4 
MODIFIED RANKIN SCALE .................................................................................. 42 
11.5 
NATIONAL INSTITUTE OF HEALTH STROKE SCALE ............................................. 43 
12. 
BIBLIOGRAPHY .......................................................................................................... 50 
 
 
 
 
 
 
 
 

 
 
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CLP 4853.D 
 
CLP 4853 Protocol Synopsis  
Study Title: 
A randomized, concurrent controlled trial to assess the safety and effectiveness 
of the Separator 3D as a component of the Penumbra System in the 
revascularization of large vessel occlusion in acute ischemic stroke 
Study Objective: To assess the safety and effectiveness of the Separator 3D as a component of 
the Penumbra System in the revascularization of patients presenting with acute 
ischemic stroke secondary to intracranial large vessel occlusion. 
Study Design: 
Prospective, randomized, single blind, concurrent controlled, multi-center 
study. Patients presenting with symptoms of acute ischemic stroke who have 
evidence of a large vessel (>2.5mm in diameter) occlusion in the cerebral 
circulation will be assigned to either the Penumbra System with the Separator 
3D or the Penumbra System without the Separator 3D. Each treated patient will 
be followed and assessed for 3 months after randomization.   
Patient 
Population: 
Up to 230 evaluable patients at up to 50 centers presenting with acute ischemic 
stroke in vessels accessible to the Penumbra Separator 3D System for 
revascularization within 8 hours of symptom onset. They must be either 
refractory to or not eligible for thrombolytic therapy. Each center will have two 
roll-in patients before actual enrollment. These patients will not be part of the 
trial but will be followed for 90 days post-procedure for safety.   
Hypothesis 
Testing and 
Sample Size 
Justification: 
The sample size calculations assume that 80% of the standard Penumbra 
System patients experience success (TICI of 2 to 3) and 80% of the Penumbra 
System with Separator 3D patients experience success.  Based on a binomial 
non-inferiority analysis with a non-inferiority margin of 15%, a study of 103 
patients per group will have 85% power with a one-sided alpha of 0.05.  The 
sample size was adjusted to 115 patients per group to account for up to10% 
attrition rate. 
Inclusion 
Criteria: 
 From 18 to 85 years of age 
 Present with symptoms consistent with an acute ischemic stroke for 
revascularization within 8 hours from symptom onset 
 Refractory to or not eligible for IV rtPA therapy,  e.g., presenting between 0 
and 3 hours from symptom onset AND contraindicated for IV rtPA, or 
presenting between 3 and 8 hours of symptom onset, or evidence of 
persistent occlusion from vascular imaging after IV rtPA  
 Evidence of a large vessel  (>2.5mm in diameter) occlusion in the cerebral 
circulation  
 NIH Stroke Scale (NIHSS) score >8 
 Signed informed consent 
Exclusion 
Criteria: 
 
 
 
 
 History of stroke in the past 3 months.  
 Females who are pregnant 
 Pre-existing neurological or psychiatric disease that could confound the 
study results such as a pre-stroke mRS score >1  
 Known severe allergy to contrast media 
 Uncontrolled hypertension (defined as systolic blood pressure >185 mmHg 

 
 
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CLP 4853.D 
CLP 4853 Protocol Synopsis  
Study Title: 
A randomized, concurrent controlled trial to assess the safety and effectiveness 
of the Separator 3D as a component of the Penumbra System in the 
revascularization of large vessel occlusion in acute ischemic stroke 
 
 
 
 
 
 
 
or diastolic blood pressure >110 mmHg) 
 CT evidence of the following conditions at randomization: 
 Significant mass effect with midline shift 
 Large infarct region >1/3 of the middle cerebral artery territory  
 Evidence of intracranial hemorrhage 
 Angiographic evidence of an arterial stenosis proximal to the occlusion that 
could prevent thrombus removal 
 Angiographic evidence of preexisting arterial injury 
 Rapidly improving neurological status prior to enrollment 
 Bilateral stroke 
 Intracranial tumors 
 Known history of cerebral aneurysm or arteriovenous malformation 
 Known hemorrhagic diathesis, coagulation deficiency, or on anticoagulant 
therapy with an International Normalized Ratio (INR) of >1.7 
 Baseline platelets <50,000 
 Use of IV heparin in the past 48 hours with PTT >1.5 times the normalized 
ratio 
 Baseline glucose <50mg/dL or >300mg/dL 
 Life expectancy less than 90 days prior to stroke onset 
 Participation in another clinical investigation that could confound the 
evaluation of the study device 
Primary 
Endpoint: 
 Angiographic revascularization of the occluded target vessel at immediate 
post-procedure as defined by a TICI score of 2 or 3  
 Incidence of device-related and procedure-related serious adverse event 
within 24 hours post-procedure  
Secondary 
Endpoints: 
 Good clinical outcome at 30 days post-procedure as defined by a 10 points 
or more improvement in the NIHSS at Discharge, a NIHSS score of 0-1at 
Discharge; or a 30-day mRS score of 0-2 
 
The proportion of patients with a modified Rankin Scale (mRS) score of ≤ 2 
at 90days post procedure 
 Good neurological outcome at 90 days post-procedure as defined by an 
mRS score of < 2, or equal to the pre-stroke mRS score if the pre-stroke 
mRS score was higher than 2, or an 10 or more points improvement on the 
NIHSS score 
 All cause mortality 
 Incidence of symptomatic intracranial hemorrhage 
Core 
Laboratory and  
Clinical Event 
An independent Core Lab blinded to treatment allocation will review and score 
all imaging scans for TIMI/TICI scores and intracranial hemorrhage (ICH). A 
Clinical Event Committee/Data Safety Monitoring Board will adjudicate 

 
 
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CLP 4853.D 
CLP 4853 Protocol Synopsis  
Study Title: 
A randomized, concurrent controlled trial to assess the safety and effectiveness 
of the Separator 3D as a component of the Penumbra System in the 
revascularization of large vessel occlusion in acute ischemic stroke 
Committee/Data 
Safety 
Monitoring 
Board 
serious adverse events for causality and attribution as well as monitoring safety 
during the trial. 
Study Rationale: Use of the Penumbra Separator 3D System offers several potential benefits, 
which may include a higher rate of revascularizaton with an acceptable device-
related serious adverse event rate. 
Duration of the 
Trial 
It is anticipated that the trial will last 2-3 years and each patient will be in the 
trial for 3 months.  
 

 
 
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1. 
Introduction 
 
In the United States approximately 800,000 patients experience a new or recurrent 
stroke each year. Of these, approximately 87% are diagnosed as ischemic, while the 
remaining 13% are attributable to hemorrhagic events, occurring either in the 
subarachnoid (3%) or intraparenchymal (10%) spaces in the brain.1 Stroke accounted for 
1 in every 18 deaths in the United States, resulting in an annual mortality of 133,990 
deaths/year.1 The literature suggests a majority of these deaths are caused by intracranial 
large vessel occlusions. Mortality rates associated with occlusions of the basilar artery, 
internal carotid artery terminus, and the M1 segment of the middle cerebral artery 
(MCA) are particularly high despite the best available medical therapy.2-4 
 
Substantial evidence in the published literature suggests that early and safe 
recanalization of the primary occlusion correlates with improved clinical outcome.5 The 
likely basis for this correlation is that although some brain tissue experiences near 
immediate and non-reversible infarction during acute stroke, there remains a region of 
ischemic penumbra surrounding this area where at-risk tissues can be salvaged.6  
Therefore, if timely recanalization can be effected and reperfusion established, then 
damage to the penumbral region might be reversed, resulting in diminished neurological 
deficit, reduced stroke-related mortality and morbidity and improved clinical outcome.7 
 
Current therapies for acute stroke are limited to the intravenous administration of a 
intravenous (IV) recombinant human tissue plasminogin activator (rtPA) for 
thrombolysis of the affected cerebral arteries within 3-4.5 hours from symptom onset, and 
the use of intra-arterial (IA) endovascular mechanical clot retrieval devices within 8 
hours from ictus, all of which have limitations as mono therapies. For example, IV lytics 
have a propensity to cause intracranial hemorrhage (ICH) and they are thought to be less 
efficacious for large vessel occlusions. On the other hand, data is lacking on the long 
term effectiveness of the IA mechanical thrombectomy devices in improving patient 
functional outcome.8-15 For these reasons, less than 5% of all ischemic stroke patients are 
treated with IV rtPA or IA treatments.16  
 
In a recent study, Bhatia et al. reported that in patients with large vessel occlusion, IV 
rtPA therapy is indeed associated with a low rate of recanalization (~21%).17 For those 
patients who were successfully recanalized, close to 80% had good outcome as vs. only 
24% for those whose vessel remained closed. They concluded that while recanalization is 
a strong predictor of patient functional independence, IV rtPA is not particularly 
efficacious in patients with large vessel occlusions.  
 
Riedel et al. suggested this lack of efficacy may in part be related to the extent of the clot 
burden, in particular, the actual clot length of the target vessel.18 In their study, they 
measured actual clot lengths before IV rtPA therapy in patients with large vessel 
occlusion in the MCA using nonenhanced CT images reconstructed with 2.5-mm slice 
width. Transcranial Doppler, MRA or CTA were used to determine blood flow in the 
target vessel as an indication of recanalization. The results showed there was a significant 
inverse relationship between clot lengths before treatment and recanalization after IV 
rtPA therapy, i.e., the longer the clot length, the less likely the vessel would be 

 
 
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recanalized by the lytic. Based on this analysis, they concluded that IV rtPA has no 
potential to recanalize an occluded target vessel if the clot length exceeded 8mm.   
 
The Penumbra System® is a new generation of neuro-embolectomy devices specifically 
designed to remove thrombus through aspiration.14-15 The System has received 510(k) 
clearance from the US FDA for an acute ischemic stroke recanalization indication. The 
pivotal trial for this clearance was a prospective, single arm, 125 patient study designed 
to assess the safety and effectiveness of the System to reduce clot burden in acute 
ischemic stroke, using the Concentric clot retriever (Mountain View, CA) as the 
predicate device (historical control).14  The results indicated that the Penumbra System 
was able to recanalize the site of primary occlusion in over 80% of the patients, which 
was higher than those reported for the Concentric clot retriever (43% to 54%), or the 
spontaneous reperfusion rate reported in the untreated control group in the PROACT-II 
study (18%).12,13,19  The high recanalization rate was independent of target vessel 
locations.  Recanalization was successful in 82.6% of patients presenting with occluded 
target vessels in the ICA, and in 83% of patients presenting with occluded target vessels 
in the MCA.  Among the patients recanalized with the device, 12.8% had procedural 
complications of which 3.2% were considered serious.  None was associated with 
malfunction or breakage of the device.  This procedural event rate is quite favorable 
when compared to the published rates for other intra-arterial interventions for acute 
stroke.12,13,19,20  These observations are indicative of the ability of the Penumbra System 
to access the cerebral arteries to safely recanalize the site of primary occlusions in most 
locations of the brain, and often, in patients with significant tortuosity that would 
normally hamper intracranial vascular access.     
 
This favorable safety profile of the Penumbra System extends to the overall rate of 24-
hour ICH of 28%, which is in the low range of the historical rates in this stroke cohort 
with similar demographics and time of presentation from symptom onset, such as the 
PROACT-II (35.9%)19, IMS (48.8%)20, MERCI Phase II (35.5%)12 and Multi-MERCI 
(38.7%)13.  However, the symptomatic ICH rate of 11.2% was in the higher range of 
those reported in these studies (ranging from 4.8% to 14%)12,20  but comparable to those 
reported in the PROACT-II (10.9%)19 and Multi-MERCI (9.0%)13 trials. Regardless, both 
rates are within the 95% confidence intervals of these prior studies. These observations 
were later confirmed in a multicenter post-market trial in Europe and the US.15  
 
The Penumbra System is intended for use to restore blood flow in the neurovasculature 
to remove thrombus by aspiration. This system is comprised of several devices: 
 Penumbra Reperfusion Catheter 
 Penumbra Separator 
 Penumbra Aspiration Pump 
 Penumbra Pump/Canister Tubing 
 Penumbra Aspiration Tubing 
 
The treatment paradigm of this System involves the introduction of the Reperfusion 
Catheter through a guide catheter into the intracranial vasculature, and guided over an 
appropriate guidewire to the site of primary occlusion. The Reperfusion Catheter is used 
in parallel with the Separator and an aspiration source (Aspiration Pump) to separate the 
thrombus and aspirate it from the occluded vessel. The Separator is advanced and 

 
 
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CLP 4853.D 
retracted through the Reperfusion Catheter at the proximal margin of the primary 
occlusion. This facilitates aspiration and debulking of the thrombus and reduces or 
eliminates the endovascular clot burden. 
 
At present, there are 4 sizes of Reperfusion Catheters and Separators: 026, 032, 041 and 
054. Initial approval was obtained for the three smaller sizes (026, 032, 041) and in order 
to facilitate more efficient aspiration, a larger 054 Reperfusion Catheter and Separator 
were developed and later approved for marketing. To maximize flow during removal of 
the thrombus, the 054 Reperfusion Catheter has a large tapered lumen with a minimum 
0.054” inner diameter at the distal end and a minimum 0.064” inner diameter at the 
proximal end. To allow for access to the intracranial neurovasculature the outer diameter 
at the distal end is ≤ 0.071” and the maximum outer diameter of the catheter is ≤ 0.083” 
to ensure its ability to fit through a 6F sheath.   
 
Since the approval and launch of the Reperfusion Catheter and Separator 054, a new 
Penumbra system MAX has been developed to maximize aspiration efficiency for 
smaller Reperfusion Catheters as well. Reperfusion Catheter 4MAX and 3MAX are 
designed to navigate more distally and efficiently to aspirate clot. The specifications of 
the Reperfusion Catheter and Separator 054 remained unchanged but are now being 
marketed as 5MAX (Table 1). The new Reperfusion Catheter 4MAX and 3MAX are 
similar in design to the Reperfusion Catheter 5MAX (054). The difference is the distal 
section of the Reperfusion Catheter 5MAX is reinforced with stainless steel wire and the 
Reperfusion Catheter 4MAX and 3MAX are reinforced with nitinol wire. Shown below 
are the specifications of the 5MAX, 4MAX and 3MAX (Tables 1-3).  
 
Table 1 -- Specifications of 5MAX 
 
 
5 MAX or 054 Reperfusion Catheter 
Distal Inner Diameter  
0.054” 
Proximal Inner Diameter 
0.064” 
Distal Outer Diameter  
≤ 0.071” 
Proximal Outer Diameter 
≤ 0.083” 
Effective Length 
125.0 ± 2.0 cm 
 
Table 2 -- Specifications of 4MAX and 041 Reperfusion Catheters 
 
 
4MAX Reperfusion Catheter 
041 Reperfusion Catheter 
Distal Inner Diameter  
0.041” 
0.041” 
Proximal Inner Diameter 
0.064” 
0.041” 
Distal Outer Diameter  
< 0.058” 
≤ 0.056” 
Proximal Outer Diameter 
< 0.083” 
≤ 0.056” 
Effective Length 
139.0 ± 2.0 cm 
137.0 ± 2.0 cm 
 
 
 
 
 
 

 
 
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Table 3 -- Specifications of 3MAX and 032 Reperfusion Catheters 
 
 
3MAX Reperfusion Catheter 
032 Reperfusion Catheter 
Distal Inner Diameter  
0.035” 
0.032” 
Proximal Inner Diameter 
0.043” 
0.041” 
Distal Outer Diameter  
< 0.052” 
<0.047” 
Proximal Outer Diameter 
< 0.063” 
<0.047” 
Effective Length 
153.0 ± 2.0 cm 
150.0 ± 2.0 cm 
 
The Separator 3D is another component of the current Penumbra System with an 
identical indication. It is a self-expanding 3 dimensional, binary Nitinol device that 
exhibits uniaxial stress-strain characteristics of superelastic Nitinol (Figure 1). The 
specifications of the Separator-3D are shown in Table 4 below. 
 
Figure 1 -- The Penumbra Separator 3D Device 
 
Table 4—Separator 3D Device Specifications 
 
 
Wire 
Distal 
OD 
Tip Diameter 
(Unconstrained) 
Tip 
Length 
Core 
Wire 
Flexible 
Length 
Working 
Length 
Separator 
3D 
0.014” 
Max 
4.6-5.4 mm 
26 mm 
42 cm 
142 cm 
 
The Separator 3D is an additional Separator with a new tip configuration for the 
Penumbra System. The Penumbra System's fundamental mechanism of action is 
aspiration. Aspiration draws clot into the catheter to remove the clot from the body. All 
Separators function to break up the clot inside of the catheter to make it more amenable 
to removal from the body via aspiration.  The current Separators function by shearing 
portions of the clot via a small gap between the outer diameter of the Separator cone and 
the inner diameter of the Reperfusion Catheter while cycling the Separator.  The 
Separator 3D is designed to break up the clot in a 3rd radial dimension as the open body 
of the Separator 3D is compressed and then retrieved into the Penumbra Reperfusion 
Catheter.  The Separator 3D is attached to the same core wire, and is delivered in the 
same manner as the current Separators. The tip has an open-body, three-dimensional 
lattice design. Like the current Separators, aspiration applied during use of the Separator 
3D removes the clot from the body.  The Separator 3D is compatible with Reperfusion 
Catheters that have a distal inner diameter of 0.041” or larger.  A schematic description 

 
 
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CLP 4853.D 
of the functionality of the Separator-3D device with the Reperfusion Catheter is shown in 
Figure 3 (Section 3.6.7). 
 
The purpose of this study is to assess the safety and effectiveness of the Separator 3D as a 
component of the Penumbra System in the revascularization of large vessel occlusion 
(>2.5mm in diameter) in acute ischemic stroke. 
 
2. 
Study Overview 
 
2.1 
Study Design 
 
This is a prospective, randomized, single blind, concurrent controlled, multi-center study 
to assess up to 230 evaluable patients at up to 50 centers presenting with acute ischemic 
stroke from large vessels occlusions (>2.5mm in diameter) accessible to the Penumbra 
Separator 3D System for revascularization within 8 hours of symptom onset. They must 
be refractory to or not eligible for thrombolytic therapy and assigned to either the 
Penumbra System with the Separator 3D or the Penumbra System without the Separator 
3D.  It is anticipated that the trial will last 2-3 years and each treated patient will be 
followed and assessed for 3 months after the procedure. Please refer to the Schedule of 
Assessments (Table 7) in Section 3.10 below for details. Each center will have two roll-
in patients before actual enrollment. These patients will not be part of the trial but will be 
followed for 90 days post-procedure for safety.   
 
2.2 
Study Objectives/Endpoints 
 
The purpose of this study is to assess the safety and effectiveness of the Separator 
3D as a component of the Penumbra System in the revascularization of patients 
presenting with acute ischemic stroke secondary to intracranial large vessel 
(>2.5mm in diameter) occlusion. 
     
2.2.1 The primary endpoints are: 
 Angiographic revascularization of the occluded target vessel at 
immediate post-procedure as defined by a TICI score of 2 or 3  
 Incidence of device-related and procedure-related serious adverse 
event within 24 hours post-procedure  
 
2.2.2 The secondary endpoints are: 
 Good clinical outcome at 30 days post-procedure as defined by a 10 
points or more improvement in the NIHSS at Discharge, a NIHSS 
score of 0-1at Discharge; or a 30-day mRS score of 0-2. 
 The proportion of patients with a modified Rankin Scale (mRS) score 
of ≤ 2 at 90 days post procedure. 
 Good neurological outcome at 90 days post-procedure as defined by an 
mRS score of < 2, or equal to the pre-stroke mRS score if the pre-
stroke mRS score was higher than 2, or an 10 or more points 
improvement on the NIHSS score. 
 All cause mortality 
 Incidence of symptomatic intracranial hemorrhage 

 
 
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2.3 
Study Population 
 
Patients enrolled in this clinical evaluation must meet the following criteria: 
 
2.3.1 Inclusion Criteria 
 
 From 18 to 85 years of age 
 Present with symptoms consistent with an acute ischemic stroke for 
revascularization within 8 hours from symptom onset 
 Refractory to or not eligible for IV rtPA therapy, e.g., presenting 
between 0 and 3 hours from symptom onset AND contraindicated for 
IV rtPA, or presenting between 3 and 8 hours of symptom onset, or 
evidence from vascular imaging of persistent occlusion after IV rtPA  
 Evidence of a large vessel (>2.5mm in diameter) occlusion in the 
cerebral circulation  
 NIH Stroke Scale (NIHSS) score >8 
 Signed informed consent 
 
2.3.2 Exclusion Criteria 
 History of stroke in the past 3 months  
 Females who are pregnant 
 Pre-existing neurological or psychiatric disease that could confound 
the study results such as a pre-stroke mRS score >1  
 Known severe allergy to contrast media 
 Uncontrolled hypertension (defined as systolic blood pressure >185 
mmHg or diastolic blood pressure >110 mmHg) 
 CT evidence of the following conditions at randomization: 
 Significant mass effect with midline shift 
 Large infarct region >1/3 of the middle cerebral artery territory  
 Evidence of intracranial hemorrhage 
 Angiographic evidence of an arterial stenosis proximal to the 
occlusion that could prevent thrombus removal 
 Angiographic evidence of preexisting arterial injury 
 Rapidly improving neurological status prior to enrollment 
 Bilateral stroke 
 Intracranial tumors 
 Known history of cerebral aneurysm or arteriovenous malformation 
 Known hemorrhagic diathesis, coagulation deficiency, or on 
anticoagulant therapy with an International Normalized Ratio (INR) of 
>1.7 
 Baseline platelets <50,000 
 Use of IV heparin in the past 48 hours with PTT >1.5 times the 
normalized ratio 
 Baseline glucose <50mg/dL or >300mg/dL 
 Life expectancy less than 90 days prior to stroke onset 

 
 
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 Participation in another clinical investigation that could confound the 
evaluation of the study device 
 
 
2.4 
Study Rationale 
 
Use of the Separator 3D as a component of the Penumbra System offers several 
potential benefits, which may include a higher rate of recanalization with an 
acceptable device-related serious adverse event rate. 
 
2.5 
Device Description/Principles of Operation 
 
Detailed description of the Penumbra System is contained in the Instructions for 
Use for the device. Described herein are brief descriptions of the System and the 
principles of operation. 
 
The Penumbra System is intended for use in the revascularization of patients with 
acute ischemic stroke secondary to intracranial large vessel occlusive disease 
(within the internal carotid, middle cerebral – M1 and M2 segments, basilar, and 
vertebral arteries) within 8 hours of symptom onset.  
 
The Penumbra System
 is comprised of several devices:  
• Penumbra Reperfusion Catheter  
• Penumbra Separator  
• Penumbra Separator 3D 
• Penumbra Aspiration Pump  
• Penumbra Pump/Canister Tubing  
• Penumbra Aspiration Tubing  
 
The Reperfusion Catheter and Separator are available in four sizes: 026, 032, 041 
and 054. The recommended selection of these devices for clot burden reduction is 
based on the size of the target vessel as shown in Table 5 (Section 3.6.3).    
 
The Reperfusion Catheter is introduced through a guide catheter or long femoral 
sheath into the intracranial vasculature and guided over a standard guidewire to 
the site of primary occlusion.  The Reperfusion Catheter is used in parallel with 
the Penumbra Separator or Penumbra Separator 3D and an aspiration source to 
separate the thrombus and aspirate it from the occluded vessel.  The Penumbra 
Separator is cycled through the Reperfusion Catheter at the proximal margin of 
the primary occlusion.  The Penumbra Separator 3D is deployed within the 
thrombus and then retrieved into the Penumbra Reperfusion Catheter. This 
facilitates aspiration and debulking of the thrombus and reduces or eliminates the 
endovascular clot burden. For the aspiration source, the Penumbra Reperfusion 
Catheter is used in conjunction with the Aspiration Pump, which is connected 
using the Penumbra Aspiration Tubing and the Penumbra Pump/Canister Tubing. 
The Penumbra Separator or Penumbra Separator 3D is provided with an 
introducer. In addition, the Penumbra Separator is provided with a torque device. 
The Penumbra Reperfusion Catheter is provided with a steam shaping mandrel 

 
 
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and rotating hemostasis valve, and a peelable sheath (for Reperfusion Catheter 
054 size only). The devices are visible under fluoroscopy. 
 
3. 
Study Procedures  
 
3.1  
Screening 
 
Prior to entry into the study, patients presenting with acute stroke symptoms will 
be screened to determine if they meet the inclusion and exclusion criteria for entry 
into the study.  Patients who are found to be ineligible for entry into the study will 
be excused from further participation.  Patients who are eligible for the study will 
review and sign (or have a legally authorized representative review and sign) the 
Patient Information and Consent form prior to enrollment into the study.  All 
patients enrolled will be blinded to treatment allocation and monitored throughout 
the required follow-up period.  
 
3.2 
Pre-Procedure (Admission) Evaluations 
 
3.2.1 Obtain patient medical and therapeutic history. 
 
3.2.2 Females of childbearing potential must have a pregnancy test. 
 
3.2.3 Exclude all patients who are not eligible and record the reason in the 
screening log. 
 
3.2.4 Perform admission NCCT scans, physical examination, neurological and 
functional examinations, and serum chemistries. Physical examination will 
include recording of supine blood pressure and heart rate.  Serum 
chemistry will include blood urea nitrogen (BUN), creatinine, complete 
blood count (CBC) plus platelets, and international normalized ratio 
(INR), prothrombin time (PT) / partial thromboplastin time (PTT). 
 
3.3 
Enrollment 
 
 
Each center will have two roll-in cases prior to actual enrollment. These patients 
will not be part of the trial but will be followed for 90 days for safety. Prior to 
enrollment into the study, each patient will undergo an angiographic 
determination of the suspected vascular occlusion.  Perform an arterial access 
procedure using standard percutaneous technique. 
 
Perform a digital subtraction angiography (DSA) to define the angio-architecture 
of the occluded vascular segment.  While a DSA to define the angio-architecture 
of the occluded vascular segment is preferred, CTA or MRA is an acceptable 
substitute.  When possible, an assessment of collateral blood flow by DSA should 
be done per institutional standard of care, particularly in cases of terminal internal 
carotid artery occlusion.    
 

 
 
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If the occlusion is in a treatable vessel, position an appropriate guide catheter and 
advance the Penumbra Reperfusion Catheter into the occluded target vessel and 
the patient will be randomized to one of the following arms:  
 
1) 
The Penumbra Separator 3D with the Penumbra System, or 
  
2) 
The Penumbra System without the Separator 3D.  
 
The randomization code will be obtained from a system provided by a vendor. A 
patient is considered enrolled once a treatment arm is assigned from the 
randomization system.   
 
All patients will be assessed for a period of 90 days from randomization.  
 
Randomized patients who were excluded for angiographic reasons will be 
followed for 90 days.  The reasons for not including these patients will be 
captured in the Case Report Forms.  
 
3.4 
Procedure Preparation for the Penumbra System   
 
Procedure should be consistent with those listed in the Instructions For Use for 
each device.  Refer to Warnings, Precautions, and Potential Adverse Events in the 
Instructions For Use for each device prior to use. However, for the purpose of this study, 
the Penumbra Separator 3D System should be used first for the revascularization of the 
target vessel if the patient was randomized to the Penumbra Separator 3D arm, to be 
followed by other components of the Penumbra System if necessary at the discretion of 
the investigators. The exception is the use of the 054 or 041 separators in the Separator 
3D arm. Use of these devices in this arm will be considered a protocol deviation. 
Similarly, use of the Separator 3D in the control arm will be considered a protocol 
deviation.  
 
3.4.1 As each device of the Penumbra System is used, remove the device from 
the packaging, and inspect for damage or for kinks. 
 
3.4.2 Prepare Penumbra System devices for use by flushing the packaging hoop 
and device with heparinized saline (includes Penumbra Reperfusion 
Catheter and Penumbra Separator only). 
 
3.4.3 Prepare a guide catheter or long femoral sheath according to the 
manufacturer’s Instructions for Use. 
 
3.4.4 Place the guide catheter or long femoral sheath into the appropriate 
cerebral artery that is proximal to the thrombus occlusion site.  
 
3.5 
Penumbra Reperfusion Catheter Preparation and Use 
 

 
 
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3.5.1 Confirm vessel diameter, and select an appropriate size Penumbra 
Reperfusion Catheter per the Instructions for Use. 
 
3.5.2 The Penumbra Reperfusion Catheter tip may be shaped using the steam 
shaping mandrel provided. 
 
3.5.3 Attach the rotating hemostasis valve provided to the Penumbra 
Reperfusion Catheter. 
 
3.5.4 Insert the Penumbra Reperfusion Catheter into a rotating hemostasis valve 
connected to the proximal hub of a guide catheter. If a guide catheter is 
not used, insert the Penumbra Reperfusion Catheter through the valve of 
the long femoral sheath using the peelable sheath.  After inserting the 
Penumbra Reperfusion Catheter, remove the peelable sheath from the 
vascular sheath, and peel from the Penumbra Reperfusion Catheter Shaft. 
 
3.5.5 Using conventional catheterization techniques under fluoroscope guidance 
advance the Penumbra Reperfusion Catheter into the target vessel over an 
appropriate neurovascular guidewire. Position the Penumbra Reperfusion 
Catheter proximal to the thrombus.  Remove the guidewire from the 
Penumbra Reperfusion Catheter.   
 
3.6 
Penumbra Separator 3D Preparation and Use 
 
3.6.1 For the purpose of this study, the Penumbra Separator 3D System should 
be used first for the revascularization of the target vessel, to be followed 
by other components of the Penumbra System at the discretion of the 
investigators.  
 
3.6.2 Attach the Penumbra Aspiration Tubing to the Aspiration Pump and turn 
on the Aspiration Pump (Refer to the Aspiration Pump Operation 
Manual). Allow the Aspiration Pump to run for at least one minute prior to 
use, and confirm that the Aspiration gauge reads 20inHg. Ensure the 
valve on the Penumbra Aspiration Tubing is switched to the OFF position. 
 
3.6.3 Penumbra Separator 3D is offered in one size and is designed to fit into 
the listed Penumbra Reperfusion Catheters (see Table 5). 
 
Table 5 -- Separator-3D / Reperfusion Catheter Device Sizes 
 
Vessel Size (mm) 
Reperfusion Catheters for the Separator-3D 
2.5 to 3.0 
032 / 3MAX 
3.0 – 4.0 
041 / 4MAX 
>4.0 
054 / 5MAX 
 

 
 
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3.6.4 Advance the Penumbra Reperfusion Catheter to gently penetrate the 
thrombus. 
 
NOTE: Access to the site of occlusion may be aided by the triaxial use of a 
compatible inner microcatheter of 0.025” ID or greater. 
 
3.6.5 Using the introducer sheath provided, insert the Penumbra Separator 3D 
through the rotating hemostasis valve and into the proximal hub of the 
Penumbra Reperfusion Catheter or triaxial microcatheter. 
 
3.6.6 Connect the Aspiration Tubing to the side port of the rotating hemostasis 
valve as shown in Figure 2. 
 
Figure 2 – Assembled Aspiration System with Penumbra Separator 3D 
Separator-3D
To Aspiration
Aspiration Tubing, Distal
Sheath
Reperfusion
Catheter
Aspiration Tubing, Proximal
ON/OFF Switch
 
 
 
3.6.7 Advance the 3D delivery catheter to the distal edge of the thrombus, then 
unsheath the Penumbra Separator 3D.  To begin aspiration, open the valve 
on the Penumbra Aspiration Tubing to the ON position. Retract the 
Penumbra Separator 3D to assist with aspiration and retrieval of the 
thrombus as shown in Figure 3. If necessary, the entire thrombus can be 
engaged and retrieved with the aid of aspiration by withdrawing the entire 
system. Note:  The maximum number of times to engage and retrieve 
the thrombus by the Penumbra Separator 3D should not exceed 5 
attempts. 
 
Figure 3 -- Schematic of the Penumbra Separator-3D device with Reperfusion 
Catheter 
Reperfusion Catheter
Thrombus
Separator-3D
 
 
3.6.8 To stop aspiration, switch the valve on the Penumbra Aspiration Tubing to 
the OFF position, and turn off the Aspiration Pump. 
 

 
 
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3.6.9 Remove the Penumbra Separator 3D. 
 
3.6.10 If necessary, additional Penumbra Separators, Penumbra Separator 3Ds, 
and Reperfusion Catheters may be used to further remove thrombus at the 
discretion of the physician. 
 
3.6.11 Using a 5cc or 10cc syringe, aspirate approximately 5cc of blood from the 
Penumbra Reperfusion Catheter to remove any thrombus that may remain 
in the catheter. 
 
3.6.12 Obtain a post-treatment angiogram by injecting contrast media through the 
guide catheter. 
 
3.7 
Penumbra Separator Preparation and Use 
 
3.7.1 Attach the Penumbra Aspiration Tubing to the Aspiration Pump and turn 
on the Aspiration Pump (refer to the Aspiration Pump Operation, Service, 
and Maintenance Manual).  Allow the Aspiration Pump to run for at least 
one minute prior to use, and confirm that the Aspiration gauge reads 
20inHg.  Ensure the valve on the Penumbra Aspiration Tubing is 
switched to the OFF position. 
 
3.7.2 Select the appropriate size Penumbra Separator corresponding to the 
Penumbra Reperfusion Catheter (see Table 6 below). 
 
Table 6 – Separator/Reperfusion Catheter Device Size Selection 
 
Vessel Size (mm) 
Penumbra Reperfusion 
Catheter 
Penumbra 
Separator 
< 2.0  
026  
026  
2.0 to 3.0  
032/3MAX  
032/3MAX  
3.0 to 4.0  
041/4MAX  
041/4MAX  
> 4.0  
054/5MAX  
054/5MAX  
 
 
3.7.3 Advance the Penumbra Reperfusion Catheter to gently embed the distal tip 
into the thrombus. Note: Access to the site of occlusion may be aided by 
the triaxial use of a compatible inner microcatheter. 
 
3.7.4 Using the introducer sheath provided, insert the Penumbra Separator 
through the rotating hemostasis valve and into the proximal hub of the 
Penumbra Reperfusion Catheter.  
 
3.7.5 Connect the Penumbra Aspiration Tubing to the side port of the rotating 
hemostasis valve as shown in Figure 4 below. 
 
Figure 4 – Assembled Aspiration System with Penumbra Separator 
 

 
 
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Separator
To Aspiration
Aspiration Tubing, Distal
Introducer
Reperfusion
Catheter
Aspiration Tubing, Proximal
ON/OFF Switch
 
 
3.7.6 To begin aspiration, open the valve on the Penumbra Aspiration Tubing to 
the ON position, and advance/retract the Penumbra Separator to assist 
with aspiration and removal of the thrombus as shown in Figure 5. 
 
Figure 5 – Thrombus Aspiration Using the Penumbra Separator 
 
Separator Tip
Thrombus
Separator Cone
Reperfusion Catheter
I0
 
 
3.7.7 To stop aspiration, switch the valve on the Penumbra Aspiration Tubing to the 
OFF position, and turn off the Aspiration Pump. 
 
3.7.8 Remove the Penumbra Separator. 
 
3.7.9 If necessary, additional Penumbra Separators and Reperfusion Catheters 
may be used to further remove thrombus at the discretion of the 
investigator. 
 
3.7.10 Using a 5cc or 10cc syringe, aspirate approximately 5cc of blood from the 
Penumbra Reperfusion Catheter to remove any thrombus that may remain 
in the catheter. 
 
3.7.11 Obtain a post-treatment angiogram by injecting contrast media  through 
the guide catheter. 

 
 
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3.8 
Angiographic Imaging 
 
At screening, perform a DSA to define the angio-architecture of the occluded 
vascular segment.  While a DSA to define the angio-architecture of the occluded 
vascular segment is preferred, CTA or MRA is an acceptable substitute.    
 
When possible, an assessment of collateral blood flow by DSA should be done 
per institutional standard of care, particularly in cases of terminal internal carotid 
artery occlusion.     
 
Prior to mechanical thrombectomy by the Penumbra Device, obtain a baseline 
TIMI/TICI scores by DSA.  CTA or MRA is not an acceptable substitute for this 
assessment.  The investigator shall make an initial assessment of TIMI/TICI flow 
in the target vessel territory.   
 
TIMI/TICI scores are to be assessed after completion of the procedure by the 
Separator 3D. If necessary, other components of the Penumbra System can be 
used at the discretion of the investigator with the TIMI/TICI scores recorded 
before and after each use. In the event that adjunctive treatments were used, 
TIMI/TICI scores should be assessed and recorded before and after each 
treatment.  The TIMI/TICI scores after the use of the Penumbra System as well as 
after adjunctive treatments will be used for analysis.   
 
Pre-procedure and post-procedure angiograms shall be sent to an unbiased Core 
Laboratory blinded to treatment allocation to make a final determination on 
TIMI/TICI flow. 
 
3.9 
Adjunctive Therapies and Protocol Deviation 
 
If the Penumbra System with Separator 3D or the Penumbra System alone is 
unable to revascularize the target vessel to TIMI/TICI 2 or 3, use of other rescue 
therapies are considered a protocol deviation and must be reported in the Case 
Report Forms. Any use of IA tPA or other non-FDA-approved treatments for the 
purpose of reducing the clot burden will be considered a treatment failure. 
TIMI/TICI scores must be recorded before and after the use of rescue therapy. 
 
3.10 
Post-Procedure Evaluations 
 
All patients will be assessed for 90 days from time of procedure. 
 
A follow-up noncontrast CT scan will be performed at 24+12 hours after 
procedure, and will be reviewed to assess hemorrhagic transformation based on 
ECASS definitions21,22:   
 
 HI 1 (small petechiae along the margins of the infarcted area without space-
occupying effect),  

 
 
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 HI 2 (more confluent petechiae within the infarcted area but without space-
occupying effect),  
 PH 1 (hematoma in <30% of the infarcted area with some slight space-occupying 
effect),  
 PH 2 (hematoma in >30% of infarcted area with substantial space-occupying 
effect).   
 
In addition, any neurological deterioration should be evaluated by urgent CT scan 
and other evaluations as indicated according to investigator/hospital best practice.   
 
A symptomatic intracranial hemorrhage will be defined as 24+12 hour CT 
evidence of an ECASS defined ICH and a 4-point or more worsening of the 
NIHSS score.   
 
Patients will be evaluated for neurological and/or functional status immediately  
post- procedure, 7 days after procedure  (or day of discharge from the hospital, 
whichever is earlier), 30 days (+ 10 days), and 90 days (+ 10 days) after 
procedure.  The assessments shown in Table 7 must be performed: 
 
 
Table 7 – Schedule of Assessments 
 
Assessment 
Pre-
Admission 
Evaluation 
 
Baseline 
Evaluation  
Immediate 
Post-
Procedure  
24+12 Hr 
Follow-Up  
7 days 
Follow-Up 
or 
Discharge D 
30 Days 
Follow-Up  
(+ 10 days) 
90 Days 
Follow-Up  
(+ 10 Days) 
History 
 
√ 
 
 
 
 
 
Physical Exam A 
 
√ 
 
 
√ 
√ 
√ 
NCCT B   
 
√ 
 
√ 
 
 
 
TIMI/TICI Scores 
from Angiography C 
 
√ 
√  
 
 
 
 
NIHSS 
 
√ 
 
√ 
√ 
√ 
√ 
mRS 
√ 
√ 
 
 
 
√ 
√ 
Lipids Profile 
 
 
 
 
√ 
 
 
Liver Enzymes 
 
√ 
 
 
√ 
 
 
BUN, Creatinine 
 
√ 
 
 
√ 
√ 
 
CBC/Platelets/ 
INR/PT/PTT 
 
√ 
√ 
 
√ 
√ 
 
 
Pregnancy Test 
 
√ 
 
 
 
 
 
Adverse Events 
 
 
√ 
√ 
√ 
√ 
√ 
A: Includes recording of supine blood pressure and heart rate 
B: In addition to the evaluation at Admission, standard CT scans must be obtained within 24+12 hours post-procedure and 
 immediately after any neurologic decline that occurs within 90-day follow-up 
C: From digital subtracted angiography 
D: Assessments can be done either at 7 days from procedure or at Discharge, whichever occurs sooner. 
 
4. 
Assessment of Safety and Effectiveness  
 
 

 
 
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4.1 
Safety 
 
Safety will be assessed by collecting adverse event data during the endovascular 
procedure, at 24 hours, 7 days or discharge (whichever occurs sooner), as well as 
at the 30-day and 90-day follow up.   
 
4.2 
Effectiveness 
 
The effectiveness of the Penumbra Separator 3D will be assessed by the ability 
of the system to achieve TICI 2 or 3 flow in the target vessel at the site of the 
target occlusion. TIMI/TICI flow are classified in Tables 8 A&B.  
 
Table 8A – Thrombolysis in Myocardial Infarction (TIMI) Flow Classification* 
 
TIMI 
Score 
Classification of Blood Flow 
TIMI 0 
No Perfusion 
TIMI 1 
Penetration without perfusion.  Penetration past the initial 
occlusion, but no distal branch filling 
TIMI 2 
Partial perfusion of the arterywith incomplete or slow distal branch 
filling 
TIMI 3 
Complete perfusion of the artery 
* From Chesebro et al. Circulation 1987;76:142-154 and Khatri et al. Stroke 2005;36:2400-2403  
Table 8B- Modified Thrombolysis in Cerebral Infarction (TICI) Perfusion Categories** 
** From Higashida et al. Stroke2003;34:e109-37and Tomsick et al. AJNR 2008;29:582-587  
 
The investigator shall make an initial assessment of TIMI/TICI flow in the target 
Grade 0: 
No Perfusion. No antegrade flow beyond the point of occlusion. 
Grade 1: 
Penetration With Minimal Perfusion. The contrast material passes beyond the area of 
obstruction but fails to opacify the entire cerebral bed distal to the obstruction for the 
duration of the angiographic run. 
Grade 2: 
Partial Perfusion. The contrast material passes beyond the obstruction and opacifies the 
arterial bed distal to the obstruction. However, the rate of entry of contrast into the vessel 
distal to the obstruction and/or its rate of clearance from the distal bed are perceptibly 
slower than its entry into and/or clearance from comparable areas not perfused by the 
previously occluded vessel, e.g., the opposite cerebral artery or the arterial bed proximal to 
the obstruction. 
Grade 2a: 
Partial filling with <50% of the entire vascular territory is visualized. 
Grade 2b: 
Partial filling with ≥50% of the entire vascular territory is visualized. If complete filling 
of all of the expected vascular territory is visualized, the filling is slower than normal. 
Grade 3: 
Complete Perfusion. Antegrade flow into the bed distal to the obstruction occurs as 
promptly as into the obstruction and clearance of contrast material from the involved bed 
is as rapid as from an uninvolved other bed of the same vessel or the opposite cerebral 
artery. 

 
 
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vessel. Pre-procedure and post-procedure angiograms shall be sent to an unbiased 
core laboratory blinded to treatment allocation to make a final determination on 
TIMI/TICI flow. A core laboratory with experience in performing intracranial 
angiographic analysis will be used. 
 
4.3 
Risk/Benefit Analysis 
 
The risks associated with the Penumbra System and the Penumbra Separator 3D 
are similar to those associated with cerebral angiography and with other intra-
arterial methods of revascularization. 
 
4.3.1 Angiography 
 
An angiographic procedure requires that a catheter be placed into the 
body, and in this case, threaded through the body to the neurovasculature.  
Once the catheter is in the proper position, contrast media is infused 
through the catheter to examine the vessels. Patients may encounter 
bleeding from vessel perforation, vessel spasm, swelling, or bruising at the 
access site where the catheters are placed in the body (usually the groin 
area). Additionally, once the catheter reaches the neurovasculature, there 
is a chance that the catheter could cause bleeding, hematoma, vessel 
thrombosis, dissection, distal embolization, psuedoaneurysm, and 
arteriovenous fistula formation.  Patients who are allergic to contrast 
media are at further risk and may experience a reaction that may include 
hives, itching, nausea, or breathing difficulty. Contrast media may also 
cause kidney damage in some patients.  The above risks of angiography 
are well known and generally unlikely to occur. However, if any of the 
above risks occur and are severe enough, patient death is possible. 
 
4.3.2 Computed Tomography Scan (CT Scan) 
 
The risks encountered during a CT scan are low. The risks mentioned 
above for contrast media allergy are possible with a CT scan. There is also 
a slight risk of injury from being exposed to the radiation associated with a 
CT scan; however, the levels of radiation, and the risks associated with 
radiation exposure are low. 
 
4.3.3 Thrombectomy/Embolectomy 
 
The risks of intra-arterial thrombectomy/embolectomy are similar to those 
associated with existing intra-arterial methods of recanalization. These 
risks include: 
 allergic reaction and anaphylaxis 
from contrast media 
 hematoma or hemorrhage at access site 
 inability to completely remove thrombus 
 acute occlusion 
 infection 
 air embolism 
 intracranial hemorrhage 
 arteriovenous fistula 
 ischemia 
 death 
 kidney damage from contrast media 

 
 
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 device malfunction 
 neurological deficits including stroke 
 distal embolization 
 vessel spasm, thrombosis, dissection, or 
perforation 
 emboli 
 false aneurysm formation 
 
 
Risks directly associated with the Penumbra System and Penumbra Separator 3D 
are similar to the above. Considerable testing has been completed to ensure that 
the System does not pose a significant risk. Testing includes both in vitro and in 
vivo testing. In addition, the following will be performed to minimize the risks: 
 
 Patients will be carefully evaluated before entering the study to ensure that the 
location of the occlusion and the time of stroke onset are appropriate for 
treatment with the Penumbra System. 
 During the clinical study, the procedure will be performed in an Operating 
Room or in an angiographic suite with an Operating Room standby. 
Therefore, should complications arise requiring surgery or other interventions, 
the surgery or intervention can be initiated without delay. All sites will be 
carefully selected to ensure that either a stroke unit operating according to 
national stroke guidelines or a physician experienced in treating patients 
presenting with acute ischemic stroke is available. 
 Patients will be carefully monitored during the study and the follow-up period. 
The Investigator will examine and perform various diagnostic tests before, 
during, and after the procedure, at 7 days or at hospital discharge, and at 30 
days (+10 days) and 90 days (+10 days) after the procedure. 
 In addition to monitoring data directly related to the Penumbra System, blood 
data will be obtained pre-operatively. This data will be used to determine the 
patients' coagulation status, to assess for infection as indicated by white blood 
cell count, and to detect significant internal bleeding with hemoglobin and 
hematocrit levels. 
 Penumbra or its representatives will conduct site initiation visits at each 
investigational site before the study begins and periodically after patients have 
been enrolled. The first monitoring visit will be conducted at each site after 
inclusion of the first patients at each site in order to ensure that all aspects of 
the protocol are followed as well as to accurately record results, report adverse 
events, and keep records. 
 
Use of the Penumbra System offers several potential benefits, which may include 
a higher success rate of recanalization with an acceptable device-related serious 
adverse rate.     
 
Based on the above information, the benefits of the Penumbra System outweigh 
the potential risks associated with its clinical use. 
 
5. 
Investigator Responsibilities 
 
5.1 
Institutional Review Board / Ethics Committee Approval 
 

 
 
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Prior to enrolling patients into the study, the investigator will ensure that proper 
Institutional Review Board (IRB)/Ethics Committee (EC) approval is obtained.  
The IRB/EC shall approve all study documents as appropriate, including the final 
protocol, amendments to the protocol, investigator brochure (where required), and 
the informed consent.   
 
5.2 
Informed Consent 
 
The investigator is responsible for ensuring that the investigation is conducted 
according to this protocol and that a signed informed consent is obtained 
according to national and state requirements prior to inclusion of patients in the 
study. 
 
5.3 
Adverse Event Reporting 
 
All adverse events or adverse device effects must be recorded by the investigator 
on the CRFs and must be carefully monitored during the entire study. 
 
An Adverse Event is any undesirable clinical event occurring in a patient during a 
clinical trial, whether or not it is considered related to the investigational product.  
This includes a change in a patient's condition or laboratory results that has or 
could have a deleterious effect on the patient's health or well-being. 
 
An Adverse Device Effect is any adverse event related to the investigational 
device. 
 
A Serious Adverse Event, a Serious Adverse Device Effect is an event that: 
  
a) Led to death 
b) Led to a serious deterioration in the health of the patient that: 
 Resulted in life-threatening illness or injury 
 Resulted in permanent impairment of a body structure or a body function 
 Required in-patient hospitalization or prolongation of existing hospitalization 
 Resulted in medical or surgical intervention to arrest permanent impairment to 
body structure or a body function 
 Led to fetal distress, fetal death or a congenital abnormality or birth defect 
 
An Unanticipated Adverse Device Event is an event that has an Adverse Device 
Effect, the specificity or severity of which is not consistent with the current 
investigator brochure; or, if an investigator brochure is not required or available, 
the specificity or severity of which is not consistent with the risk information 
described in the Instruction for Use or the clinical protocol.  
 
Minimum requirements of data to be recorded are: type of event, duration of 
adverse event or adverse device effects (start through end), severity, seriousness, 
action taken, outcome and, if appropriate, causality. 
 

 
 
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The Investigator will report any serious adverse event or adverse device effect to 
the Sponsor or its designee as soon as possible, but no later than 24 hours after the 
event occurred. All serious adverse events or serious device effects must be 
documented on the Serious Adverse Events form along with an explanation of any 
medical treatment administered. The form must be completed, signed, and sent by 
fax or overnight courier to the Sponsor or its designee within five working days.  
This report must be followed by full written documentation. 
 
An adverse event need not be reported as a serious adverse event if it represents 
only a relapse or an expected change or progression of the condition that was the 
cause of treatment without any symptoms and signs other than those present 
before procedure. This type of event only needs to be reported as an adverse 
event.  The competent IRB/EC must be informed by the investigator about serious 
adverse events or device effects associated with the use of the product. 
 
5.4 
Adherence to Protocol/Amendments 
 
The investigator shall approve and adhere to this protocol and any amendments 
that arise during the course of the study.  Any deviations to the protocol shall be 
discussed with Penumbra prior to implementation, where possible, and shall be 
documented on the appropriate case report form.  The investigator shall permit the 
Penumbra System to be used only under his/her supervision. 
 
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 the confidentiality statement. 
 
The investigator will report to the Sponsor or designee immediately if, for any 
reason, the approval to conduct the investigation is withdrawn by the IRB/EC or 
Competent Authority. The report will include a complete description of the 
reason(s) for which approval was withdrawn 
 
5.5 
Case Report Form Completion 
 
The investigator and study staff shall complete the case report forms associated 
with this study. Patient numbers shall be used to identify individual patients in 
this study. The Case Report Forms (CRFs) should be a complete and accurate 
record of patient data collected during the study according to ISO 14155 and 
Good Clinical Practices (GCP) requirements. It is the investigator's responsibility 
to ensure the quality of the data collected and recorded. 
 
5.6 
Administration of Neurological Exams and Stroke Scales 
 
The principal investigator at each investigative site is responsible for the 
administration of the neurological examinations and grading of patients on the 
stroke scales (i.e., NIHSS, mRS). In cases where a designee is needed, the 
investigator must ensure that the designee is trained and has the appropriate 
qualifications to perform these functions. 

 
 
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5.7 
Device Inventory Requirements 
 
The investigator shall maintain records pertaining to device inventory. These 
records shall include: 
 
 The disposition of each device including patient number and device lot 
number 
 The serial numbers for investigational devices 
 
The investigator will ensure that, for the purpose of this investigation, only trained 
physicians who are co-investigators in this study will use the Penumbra System.   
 
5.8 
 Reports 
 
The investigator shall submit all reports in a timely manner. 
 
5.9 
Records Retention 
 
The investigator shall maintain the records associated with this study for a period 
of at least two years after either the date on which the investigation is completed 
or the date that the records are no longer required for supporting a premarket 
approval/notification submission, whichever is later. These records include the 
following: 
 
 Correspondence with the Sponsor or designee, the Medical Monitor, and other 
investigators 
 Accountability records of receipt, use, and disposition of all investigational 
devices and other study materials, including the following information: 
 The type and quantity of the device, the dates of receipt, and the study 
tracking number 
 The names of all persons who received, used, or disposed of each device 
 The number of devices that have been returned to Penumbra, discarded, or 
otherwise disposed of, and the reason for such action 
 Patient Records, including Informed Consent Forms, copies of all completed 
CRFs, and supporting documents (laboratory reports and reports of diagnostic 
tests, medical records, etc.) 
 Current study protocol with dates and details of reasons for any deviations 
from the protocol that could affect the scientific quality of the study or the 
rights, safety, or welfare of the patients 
 Instructions for Use 
 Reports of any serious adverse event or serious device effects 
 A copy of all approvals related to the clinical investigation 
 The approved, blank, informed consent form and blank CRFs 
 Certification that the investigational plan has been approved by the IRB/EC 
 Signed Investigator Agreements and current signed and dated curriculum 
vitae of the Principal Investigator and all participating co-investigators 

 
 
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6. 
Sponsor Responsibilities 
 
6.1 
Training 
 
During study initiation, the Sponsor will train the investigator and study staff on 
use of the Penumbra System. Training will also be performed to ensure the study 
staff understands their obligations under ISO 14155.  
 
6.2 
Investigator List 
 
The Sponsor shall keep a list of the names, addresses, and professional positions 
of the clinical investigators for the study.   
 
6.3 
Adverse Event Reporting 
 
The Sponsor shall evaluate adverse event reports received from the investigational 
sites and found during data monitoring and shall report them to the appropriate 
regulatory bodies and other investigational sites as necessary. 
 
6.4 
Data Monitoring 
 
Penumbra is responsible for ensuring that the study is conducted according to the 
appropriate regulations (US Food and Drug Administration 21 CFR §812, ISO 
14155). A Penumbra employee or designate will conduct the following site visits: 
 
 Site Qualification Visit 
 
Conducted to ensure the investigational site has the appropriate staff, facilities, 
and expertise to participate in the study. This requirement is waived if the site had 
recently participated in a similar trial sponsored by Penumbra.   
 
 Site Initiation Visit 
 
Conducted to train the investigational staff on use of the device, study 
requirements, and other relevant training. 
 
 Data Monitoring Site Visit 
 
Conducted as needed to ensure the investigational site is operating in compliance 
with this protocol, continues to have the appropriate staff and facilities, and is 
correctly completing the Case Report Forms (CRFs) (verify against source data).  
  
To 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 and 

 
 
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resolution of missing or inconsistent data and source document checks to ensure 
the accuracy of the reported data. CRFs for all enrolled patients will be made 
available to the Sponsor for review and collection as agreed with the investigator.  
The Sponsor will evaluate and summarize the results of each site visit in written 
reports, identifying repeated data problems with any investigator and specifying 
recommendations for resolution of noted deficiencies. 
 
 Study Close-Out Site Visit 
 
 
Conducted at the termination of the study to resolve any outstanding data queries, 
and to ensure that any remaining study materials are returned to the Sponsor. 
 
6.5 
Data Management 
 
All study data will be entered into an electronic data capture (EDC) system 
provided by a vendor. Study personnel will have individual login and password to 
access the clinical study information based upon each individual’s roles and 
responsibilities. For data security, the system operates within the Secure Socket 
Layer (SSL) 128-bit encryption protocol. This application is designed to fully 
support compliance with the following regulations and guidance documents: 
 
 Guidance for Industry 21 CFR Part 11; Electronic Records; Electronic 
 
Signatures; Scope and Application [FDA];  
 21CFR Part 820, also known as FDA Quality System Regulation (QSR); 
 Guidance for Industry; E6 Good Clinical Practice: Consolidated Guidance; 
 Guidance for Industry; Computerized Systems used in Clinical Investigations; 
 General Principles of Software Validation; Final Guidance for Industry and 
FDA Staff; 
 Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
 
Data entry will be performed at the investigational sites. Standardized electronic 
Case Report Forms (eCRFs) will be provided for use at all investigational sites. 
Investigators are responsible for completion and timely submission of the data to 
Penumbra, Inc. This EDC system requires no on-site software installation or 
specific hardware to operate. Investigators, clinical coordinators, data managers, 
and Penumbra clinical personnel access project information and study data 
centrally via a Web browser. Incoming data are to be reviewed for quality and 
consistency before being locked for data export. Questions or problems with 
submitted data will be addressed with the principal investigator via an electronic 
querying system, or through direct contact.  
 
All hard copy forms and data files will be secured to ensure confidentiality. 
Investigators are required to maintain source documents required by the protocol, 
including laboratory results, patient report forms, supporting medical records, and 
Informed Consent Forms. The source documents will be used during the regular 
monitoring visits to verify information submitted on the CRFs. 
 

 
 
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7. 
Contact Information 
 
The address of Penumbra Incorporated is: 
 
Penumbra Incorporated  
1351 Harbor Bay Parkway 
Alameda, CA 94577 
Tel.  (510) 748-3200  
Fax  (510) 814-8305 
 
Key contacts at the company include: 
 
Elan Mualem   
Clinical Research Associate 510-748-3254 
Siu Po Sit, Ph.D. 
VP, Clinical Affairs     
510-748-3221 
Arani Bose, M.D. 
Medical Monitor 
 
510-748-3200   
Adam Elsesser 
CEO  
 
 
510-748-3222 
 
8. 
Ethical Requirements 
 
8.1 
Declaration of Helsinki 
 
The study will be performed in accordance with 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/Ethics Committee (IRB/EC) and to keep the 
IRB/EC informed of any serious adverse event, serious adverse device effects, 
and amendments to the protocol. All correspondence with the IRB/EC should be 
filed by the investigator and copies sent to the Sponsor or its designee. 
 
8.2 
Patient Information and Consent 
 
It is the responsibility of the investigator to give each patient full and adequate 
verbal and written information regarding the objective and procedure of the study 
and the possible risks involved and to obtain signed informed consent from all 
patients prior to inclusion in the study unless the patient's health condition does 
not allow informed consent, in which case the local hospital, state, and FDA 
procedures will be applied. The original, signed consent is filed with the patient 
study records, and a copy is provided to the patient. 
 
8.3 
Patient Data Protection 
 
The patients will be identified in the CRFs with patient number and initials. The 
patient must be informed that the data will be stored and analyzed by computer, 
that national regulations for handling of computerized data will be followed, and 
that only the investigator and the Sponsor or designee will have access to 
individual patient data. Furthermore, the patients should be informed about the 
possibility of inspection of relevant parts of the hospital records by the Sponsor or 
other Health Authorities including the FDA. 

 
 
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8.4 
Clinical Trial Termination 
 
A patient’s participation in the clinical trial 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 trial requirements. The patient may also decide to 
withdraw from the clinical trial at any time and terminate participation. 
Penumbra, the Competent Health Authorities, or FDA may decide to interrupt or 
terminate this clinical trial if they believe that this is necessary.   
 
9. 
Statistical Procedures 
 
9.1 
Sample Size Justification 
 
The sample size calculations assume that 80% of the standard Penumbra System 
patients experience success (TICI of 2 to 3) and 80% of the Penumbra System 
with Separator 3D patients experience success.  Based on a binomial non-
inferiority analysis with a non-inferiority margin of 15%, a study of 103 patients 
per group will have 85% power with a one-sided alpha of 0.05.  The sample size 
was adjusted to 115 patients per group to account for up to10% attrition rate. 
Assuming that both the 3D arm and the control arm observe a rate of 80% 
(82/103), the 95% confidence interval for the difference between groups is (-
11.0%, 11.0%). 
 
 
 
9.2 
Statistical Analysis 
 
The objective of the statistical analyses is to support the demonstration of the 
safety and effectiveness of the Penumbra System with Separator 3D. The efficacy 
analysis will be conducted in the intent-to-treat (ITT) and per protocol (PP) 
populations and the safety analysis will be conducted in the safety population.  
The specific details of the statistical analyses will be described completely in the 
statistical analysis plan.  The statistical analysis plan will be finalized prior to 
database lock.  
 
Descriptive statistics will be provided.  This includes the number of observations, 
mean, median, standard deviation, minimum and maximum for continuous 
variables and counts and percents for discrete variables.  Analyses will be 
conducted using SAS (SAS Institute, Cary, NC).24 
 
Results collected at multiple visits will be summarized at each visit for which they 
are collected as described in Table 7.  Summaries for all measures will include all 
observed data for each visit. 
 
9.3 
Effectiveness 
 
9.3.1 Primary Endpoint 
 

 
 
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The primary effectiveness variable is the proportion of patients with a post 
procedure TICI score of 2 to 3. The proportion of patients in each group who are 
successful based on these criteria will be calculated. The Core Laboratory data 
supersede the investigator-reported data in all analyses of TICI scoring. 
 
The primary effectiveness analysis will be the difference between the Penumbra 
System only group (control) and the Penumbra System with the Separator 3D 
group. A binomial comparison will be used to test the null hypothesis that the 
difference in proportions is less than or equal to -.15 (H0: P3D - PControl   ≤ -.15) vs. 
the one-sided alternative (H1: P3D - PControl   > -.15). This is equivalent to 
evaluating that the lower bound of the 90% confidence interval for the difference 
is above -15%. 
 
9.3.2 Secondary Effectiveness Endpoints 
 
The secondary effectiveness variables: 
 
 Good clinical outcome at 30 days post-procedure. Patients meeting one of the 
following are evaluated as having good clinical outcome: 10 points or more 
improvement in the NIHSS at Discharge; a NIHSS score of 0-1 at Discharge; 
30-day mRS score of 0-2. 
 Good neurological outcome at 90 days post-procedure. Patients meeting one 
of the following are evaluated as have a good neurological outcome at 90 
days:  
o mRS score ≤ 2 at 90 days  
o mRs score at 90 days equal to the pre-stroke mRS score (if the pre-
stroke mRS score was higher than 2) 
o 10 or more points improvement on the NIHSS score at 90 days 
 The proportion of patients with a modified Rankin Scale (mRS) of ≤ 2 at 90 
days post procedure. 
 
Frequency counts and percentage of patients within each category will be 
provided for categorical data. Estimates of the treatment differences and their 
95% confidence intervals will be calculated. Patient rates will be compared 
between treatment groups with Fisher's exact test. 
 
9.3.3 Effectiveness Subgroup Analysis 
  
To evaluate the impact of baseline conditions on treatment effect, subgroup 
analyses will be performed for the primary efficacy variable, TICI 2-3, the 
secondary effectiveness variables, (good clinical outcome at 30 days, good 
neurological outcome at 90 days and 90-day mRS 0-2). The subgroups below will 
be used for these analyses: 
 
 Age (< 65, or >= 65)  
 Baseline NIHSS  (< 20, or >= 20) 
 Site of occlusion. 

 
 
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9.4 
Safety 
 
The denominator for the safety analyses is all enrolled patients who received the 
assigned treatment in the target vessel. 
 
9.4.1 Primary Safety Analysis 
 Analysis of device or procedure related SAE within 24 hours post procedure:  
The proportion of patients in each group who experience a device or 
procedure related SAE within 24 post procedure will be calculated. The 
CEC/DSMB data supersede the investigator-reported data in all analyses 
Adverse Events. Frequency counts and percentage of patients within each 
category will be provided. Estimates of the treatment differences and their 
95% confidence intervals will be calculated. Subject rates will be compared 
between treatment groups with Fisher's exact test. 
 
9.4.2 Secondary Safety Analysis 
 
 Analysis of symptomatic ICH: 
Rates of symptomatic and asymptomatic hemorrhage will additionally be 
provided. Frequency counts and percentage of subjects within each category 
will be provided for categorical data. Estimates of the treatment differences 
and their 95% confidence intervals will be calculated. Patient rates will be 
compared between treatment groups with Fisher's exact test. 
 
 Analysis of Deaths: 
The Kaplan-Meier product-limit method will be the primary method utilized 
to assess the mortality rate. With the date of randomization set at Day 0, any 
death occurring on or before calendar day 90 will be counted as a death. If 
clinical assessment is missing for a patient who has not died, the patient will 
be censored at the last follow-up date. Patients who are alive at day 90 will be 
censored at day 90. The log-rank test will be used to compare the groups.  
This comparison weights earlier and later differences equally. Additionally, 
the death data will be presented as 90 Day binary deaths.  The number of 
deaths will be presented for each group. 
 
9.5 
Adverse Event Analysis 
 
All adverse events will be summarized by showing the number and percent of 
patients which report the event.  Events will also be reported by relationship to the 
procedure or device. Causality of adverse events will be adjudicated by a Clinical 
Events Committee/Data Safety Monitoring Board (CEC/DSMB).  Operations of 
the CEC/DSMB is governed by the CEC/DSMB Charter for this study. The 
CEC/DSMB data supersede the investigator-reported data in all analyses of 
adverse events. 
 
9.6 
Interim Analysis 
 

 
 
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There will be no interim analysis for this study. 
 
10. 
Publication of Information 
 
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 test device and 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. 
 
 

 
 
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11. 
References 
     
11.1 
Schematic of Study Design 
 
 
1 month Follow-up 
1 month Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients who present with symptoms consistent with an acute 
ischemic stroke and are ineligible or refractory for IV rtPA 
therapy 
Signed Informed Consent  
Screen medical history, perform clinical/neuro exam, 
lab work and imaging to determine if patient is eligible. 
Enrollment is randomized 1:1 to the Separator 3D with the 
Penumbra System arm or the Penumbra System only arm  
Separator 3D with the 
Penumbra System 
If NO, do not enroll 
patient.  Record reasons in 
screening log. 
Penumbra System only 
24-Hr, and Discharge/7-Day 
Assessments 
24-Hr, and Discharge/7-Day 
Assessments 
3 month Follow-up 
3 month Follow-up 
1 month Follow-up 
 
1 month Follow-up 
 

 
 
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11.2 
Acronyms 
 
 
Acronym 
Definition 
AHA 
American Heart Association 
ADE 
adverse device effect 
AE 
adverse event 
ASA 
acetylsalicylic acid (aspirin) 
BID 
twice daily 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CEC/DSMB 
Clinical Events Committee/Data Safety Monitoring Board 
CRA 
clinical research associate 
CRF 
case report form 
CTA 
computed tomography angiography 
CVA 
cerebrovascular accident 
DSA 
digital subtraction angiography 
EC 
Ethics Committee 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
IA 
Intra-arterial 
ICH 
intracranial hemorrhage 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVRS 
interactive voice response system 
MI 
myocardial infarction 
 
MRA 
magnetic resonance angiography 
mRS 
modified Rankin Scale 
NCCT 
nonenhanced CT (without contrast) 
NHLBI 
National Heart, Lung, and Blood Institute 
NIHSS 
National Institute of Health Stroke Scale 
NINDS 
National Institute of Neurological Disorders and Stroke 
p.o. 
per os; by mouth 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 
rtPA 
recombinant human tissue plasminogen activator 
SAE 
serious adverse event 
 
TIA 
transient ischemic attack  
TICI 
thrombolysis in cerebral infarction 
TIMI 
thrombolysis in myocardial infarction 
UADE 
unanticipated adverse device effect 
 

 
 
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11.3 
Definitions 
 
ADVERSE EVENT  
Any undesirable clinical event occurring in a patient during a clinical trial, whether or not 
it is considered related to the investigational product.  This includes a change in a 
patient's condition or laboratory results that has or could have a deleterious effect on the 
patient's health or well-being. 
 
ADVERSE DEVICE EFFECT  
Any adverse event related to the investigational device. 
 
CASE REPORT FORM 
A record of the data and other information on each patient in the study often abbreviated 
as CRF 
 
COMPLICATION (ANGIOGRAPHIC OR CLINICAL) 
An undesirable clinical event that results in death, injury, or invasive intervention.  
Complications may include, but are not limited to acute occlusion, air embolism, 
arteriovenous fistula, death, distal embolization, emboli, false aneurysm formation, 
hematoma or hemorrhage at access site, infection, intracranial hemorrhage, ischemia, 
neurological deficits including stroke, vessel spasm, thrombosis, dissection, or 
perforation.  Complications may or may not be related to the investigational product(s). 
 
CEREBRAL ARTERY VASOSPASM 
Spasm of the intracranial arteries, resulting in decrease in lumen diameter.  Also known 
as cerebral vasospasm.  May occur distal to the treatment site and is generally reversed 
with administration of vasodilator agents or with adjunct balloon dilatation. 
 
DISSECTION 
Angiographic evidence of a tear in the arterial wall as defined by the occurrence of 
intramural hematoma 
 
DISTAL EMBOLIZATION 
Migration of a filling defect or thrombus to distally occlude the target vessel or one of its 
branches 
 
EMBOLI 
Blood clots or thrombi transported by blood from a distant source 
 
HYPERTENSION 
Persistently high arterial blood pressure.  Various criteria for its threshold have been 
suggested, ranging from 140 mm Hg systolic and 90 mm Hg diastolic to as high as 
220 mm Hg systolic and 110 mm Hg diastolic.  Hypertension may have no known cause 
or be associated with other primary diseases. 

 
 
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HYPOTENSION 
Sustained Hypotension: Systolic blood pressure less than 80 mm Hg lasting more than 
30 minutes or requiring intervention (e.g. pacing, intra aortic balloon pump (IABP), 
intravenous vasopressors to sustain systolic blood pressure). This excludes transient 
hypotension or vagal reactions, which are self limited or readily reversible. 
 
INTIMAL FLAP 
An extension of the vessel wall into the arterial lumen 
 
INTRACRANIAL HEMORRHAGE 
Bleeding in the cranium of the brain. 
 
ISCHEMIA 
The deficiency, or a lack of blood flow to an organ resulting in an imbalance between the 
supply and demand of oxygen (or other nutrients) leading to cell damage or death 
 
LEUKOPENIA 
A leukocyte count of <3.5 x109/liter for more than 3 days 
 
NEOINTIMAL HYPERPLASIA  
Thickening of the neointima due to intimal cell accumulation 
 
NEUTROPENIA 
A decrease in the number of neutrophilic leukocytes in blood to <1,000 mm3 
 
OCCLUSION  
The cessation of blood flow in an artery due to the presence of a clot or thrombus 
 
OCCLUSION LOCATION 
Location according to specific cerebral artery; a standard code will be provided in the 
CRF to use for location descriptions 
 
PERFORATION 
The piercing or rupturing of a blood vessel; perforations can be detected or observed 
angiographically 
 
PROCEDURAL SERIOUS ADVERSE EVENTS 
Serious adverse events that occurred within 24 hours of the procedure 
 

 
 
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SERIOUS ADVERSE EVENT 
Any undesirable clinical event or serious device effect that results in death, is life-
threatening, causes persistent or significant disability/incapacity, requires or prolongs 
hospitalization, requires intervention, results in congenital abnormality, or led to a serious 
deterioration in the health of the patient that resulted in life-threatening illness or injury, 
resulted in permanent impairment of a body structure or a body function, resulted in 
medical or surgical intervention to arrest permanent impairment to body structure or a 
body function, or led to fetal distress, fetal death or a congenital abnormality or birth 
defect 
 
STROKE 
A new focal neurological deficit of presumed vascular origin persisting more than 
24 hours and with a neuro-imaging study that does not indicate a different etiology.  The 
24-hour criterion is excluded if the patient undergoes cerebrovascular surgery or dies 
during the first 24 hours.  It includes patients presenting with clinical signs and symptoms 
suggestive of subarachnoid hemorrhage, intracerebral hemorrhage, or cerebral infarction.  
It does not include stroke events in cases of blood disorders such as leukemia, and it 
excludes patients with a history of stroke secondary to trauma. 
 
TARGET OCCLUSION 
The occlusion treated or attempted to be treated during the index procedure 
 
TARGET VESSEL 
The intracranial vessel containing a target occlusion 
 
THROMBUS 
Discrete, mobile intraluminal filling with defined borders with or without associated 
contrast straining; these are classified as either absent or present. 
 
THROMBOCYTOPENIA 
A platelet count of <100,000 mm3 
 
TOTAL OCCLUSIONS 
An occlusion with no flow (TIMI/TICI 0) 
 
TRANSIENT ISCHEMIC ATTACK (TIA) 
A focal ischemic neurological deficit of abrupt onset and of presumed vascular etiology 
that resolves completely within 24 hours of onset 
 
UNANTICIPATED ADVERSE DEVICE EVENT  
An event that has an Adverse Device Effect, the specificity or severity of which is not 
consistent with the current investigator brochure; or, if an investigator brochure is not 
required or available, the specificity or severity of which is not consistent with the risk 
information described in the Instruction for Use or the clinical protocol.  
 
 
 

 
 
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11.4 
Modified Rankin Scale 
 
0 
No Symptoms 
1 
No significant disability, despite symptoms; able to perform all 
usual duties and activities 
2 
Slight disability; unable to perform all previous activities but 
able to look after own affairs without assistance 
3 
Moderate disability; requires some help, but able to walk 
without assistance 
4 
Moderately severe disability; unable to walk without assistance 
and unable to attend to own bodily needs without assistance  
5 
Severe disability; bedridden; incontinent, and requires 
constant nursing care and attention 
From Sulter, G, Steen C, De Keyser, J.  “Use of the Barthel Index and Modified Rankin Scale in acute 
stroke trials.”  Stroke.  1999;30:1538-1541.    
 
 
 
 
 
 
 

 
 
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11.5 
National Institute of Health Stroke Scale 
 
NIH STROKE SCALE 
Instructions 
Scale Definition 
Score 
1a.  Level of Consciousness:  The investigator must choose a 
response, even if a full evaluation is prevented by such obstacles as 
an endotracheal tube, language barrier, orotracheal trauma/bandages.  
A 3 is scored only if the patient makes no movement (other than 
reflexive posturing) in response to noxious stimulation. 
 
0 = Alert: keenly responsive. 
1 = Not alert, but arousable by minor stimulation to obey, 
answer, or respond. 
2 = Not alert, requires repeated stimulation to attend, or is 
obtunded and requires strong or painful stimulation to 
make movements (not stereotyped). 
3 = Responds only with reflex motor autonomic effects or 
totally unresponsive, flaccid, and flexic. 
____ 
1b.  LOC Questions:  The patient is asked the month and his/her age.  
The answer must be correct – there is no partial credit for being close.  
Aphasic and stuporous patients who do not comprehend the questions 
will score 2.  Patients unable to speak because of endotracheal 
intubation, orotracheal trauma, severe dysarthria from any cause, 
language barrier or any other problem not secondary to aphasia are 
given a 1.  It is important that only the initial answer be graded and 
that the examiner not “help” the patient with verbal or non-verbal cues. 
0 = Answers both questions correctly. 
 
1 = Answers one question correctly. 
 
2 = Answers neither question correctly. 
____ 
1c.  LOC Commands:  The patient is asked to open and close the 
eyes and then to grip and release the non-paretic hand.  Substitute 
another one step command if the hands cannot be used.  Credit is 
given if an unequivocal attempt is made but not completed due to 
weakness.  If the patient does not respond to command, the task 
should be demonstrated to him/her (pantomime) and score the result 
(i.e., follows none, one or two commands).  Patients with trauma, 
amputation, or other physical impediments should be given suitable 
one-step commands.  Only the first attempt is scored. 
0 = Performs both tasks correctly. 
 
1 = Performs one task correctly. 
 
2 = Performs neither task correctly. 
____ 
2.  Best Gaze:  Only horizontal eye movements will be tested.  
Voluntary or reflexive (oculocephalic) eye movements will be scored 
but caloric testing is not done.  If the patient has a conjugate deviation 
of the eyes that can be overcome by voluntary or reflexive activity, the 
score will be 1.  If  a patient has an isolated peripheral nerve paresis 
(CN III, IV or VI) score a 1.  Gaze is testable in all aphasic patients.  
Patients with ocular trauma, bandages, pre-existing blindness or other 
disorder of visual acuity or fields should be tested with reflexive 
movements and a choice made by the investigator.  Establishing eye 
contact and then moving about the patient from side to side will 
occasionally clarify the presence of a partial gaze palsy. 
0 = Normal. 
 
1 = Partial gaze palsy; gaze is abnormal in one or both eyes, 
but forced deviation or total gaze paresis is not present. 
 
2 = Forced deviation, or total gaze paresis not overcome by 
the oculocephalic maneuver. 
____ 
3.  Visual:  Visual fields (upper and lower quadrants) are tested by 
confrontation, using finger counting or visual threat as appropriate.  
Patient may be encouraged, but if they look at the side of the moving 
fingers appropriately, this can be scored as normal.  If there is 
unilateral blindness or enucleation, visual fields in the remaining eye 
are scored.  Score 1 only if a clear-cut asymmetry, including 
quadrantanopia is found.  If patient is blind from any cause, score 3.  
Double simultaneous stimulation is performed at this point.  If there is 
extinction, patient receives a 1, and the results are used to answer 
item 11. 
0 = No visual loss. 
 
1 = Partial hemianopia. 
 
2 = Complete hemianopia. 
 
3 = Bilateral hemianopia (blind including cortical blindness). 
____ 
4.  Facial Palsy:  Ask, or use pantomime to encourage the patient to 
show teeth or raise eyebrows and close eyes.  Score symmetry of 
grimace in response to noxious stimuli in the poorly responsive or non-
comprehending patient.  If facial trauma/bandages, orotracheal tube, 
tape or other physical barrier obscures the face, these should be 
removed to the extent possible. 
0 = Normal symmetrical movement. 
1 = Minor paralysis (flattened nasolabial fold, asymmetry on 
smiling). 
2 = Partial paralysis (total or near total paralysis of lower 
face). 
3 = Complete paralysis of one or both sides   (absence of 
facial movement in the upper and lower face). 
____ 

 
 
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NIH STROKE SCALE 
Instructions 
Scale Definition 
Score 
5.   Motor Arm:  The limb is placed in the appropriate position: extend 
the arms (palms down) 90 degrees (if sitting) or 45 degrees (if supine).  
Drift is scored if the arm falls before 10 seconds.  The aphasic patient 
is encouraged using urgency in the voice and pantomime, but not 
noxious stimulation.  Each limb is tested in turn, beginning with the 
non-paretic arm.  Only in the case of amputation or joint fusion at the 
shoulder, the examiner should record the score as untestable (UN), 
and clearly write the explanation for this choice. 
0 = No drift; limb holds 90 (or 45) degrees for full 10 
seconds. 
1 = Drift; Limb holds 90 (or 45) degrees, but drifts down 
before full 10 seconds: does not hit bed or other support. 
2 = Some effort against gravity; limb cannot get to or 
maintain (if cued) 90 (or 45) degrees, drifts down to bed, 
but has some effort against gravity. 
3 = No effort against gravity; limb falls. 
4 = No movement. 
UN = Amputation or joint fusion, explain: ________________ 
____ 
5a.  Left Arm 
5b.  Right Arm 
____ 
6. Motor Leg:  The limb is placed in the appropriate position: hold the 
leg at 30 degrees (always tested supine).  Drift is scored if the leg falls 
before 5 seconds.  The aphasic patient is encouraged using urgency 
in the voice and pantomime, but not noxious stimulation.  Each limb is 
tested in turn, beginning with the non-paretic leg.  Only in the case of 
amputation or joint fusion at the hip, the examiner should record the 
score as untestable (UN), and clearly write the explanation for this 
choice. 
0 = No drift; leg holds 30 degrees position for full 5 seconds 
1 = Drift; leg falls by the end of the 5 second period but does 
not hit bed 
2 = Some effort against gravity; leg falls to bed by 5 seconds, 
but has some effort against gravity 
3 = No effort against gravity; leg falls to bed immediately 
4 = No movement 
UN = Amputation or joint fusion, explain: ________________ 
____ 
6a. Left Leg      
6b. Right Leg 
____ 
7. Limb Ataxia:  This item is aimed at finding evidence of a unilateral 
cerebellar lesion.  Test with eyes open.  In case of visual defect, 
ensure testing is done in intact visual field.  The finger-nose-finger and 
heel-shin tests are performed on both sides, and ataxia is scored only 
if present out of proportion to weakness.  Ataxia is absent in the 
patient who cannot understand or is paralyzed.  Only in the case of 
amputation or joint fusion may the item be scored “UN” and the 
examiner must clearly write the explanation for not scoring.  In case of 
blindness test by touching nose from extended arm position.   
0 = Absent. 
 
1 = Present in one limb. 
 
2 = Present in two limbs. 
 
UN = Amputation or joint fusion, explain: ________________ 
____ 
8.  Sensory:  Sensation or grimace to pin prick when tested, or 
withdrawal from noxious stimulus in the obtunded or aphasic patient.  
Only sensory loss attributed to stroke is scored as abnormal and the 
examiner should test as many body areas [arms (not hands), legs, 
trunk, face] as needed to accurately check for hemisensory loss.  A 
score of 2, “severe or total sensory loss,” should only be given when a 
severe or total loss of sensation can be clearly demonstrated.  
Stuporous and aphasic patients will therefore probably score 1 or 0.  
The patient with brainstem stroke who has bilateral loss of sensation is 
scored 2.  If the patient does not respond and is quadriplegic score 2.  
Patients in coma (item 1a=3) are automatically given a 2 on this item. 
0 = Normal; no sensory loss. 
 
1 = Mild to moderate sensory loss; patient feels pinprick is 
less sharp or is dull on the affected side; or there is a loss 
of superficial pain with pinprick but patient is aware 
he/she is being touched. 
 
2 = Severe to total sensory loss; patient is not aware of being 
touched in the face, arm, and leg. 
____ 
9.  Best Language:  A great deal of information about comprehension 
will be obtained during the preceding sections of the examination.  The 
patient is asked to describe what is happening in the attached picture, 
to name the items on the attached naming sheet, and to read from the 
attached list of sentences.  Comprehension is judged from responses 
here as well as to all of the commands in the preceding general 
neurological exam.  If visual loss interferes with the tests, ask the 
patient to identify objects placed in the hand, repeat, and produce 
speech.  The intubated patient should be asked to write.  The patient 
in coma (item 1a=3) will automatically score 3 on this item.  The 
examiner must choose a score for the patient with stupor or limited 
cooperation, but a score of 3 should be used only if the patient is mute 
and follows no one-step commands. 
0 = No aphasia, normal. 
1 = Mild to moderate aphasia; some obvious loss of fluency 
or facility of comprehension, without significant limitation 
on ideas expressed or form of expression.  Reduction of 
speech and/or comprehension, however, makes 
conversation about provided material difficult or 
impossible.  For example, in conversation about provided 
materials, examiner can identify picture or naming card 
content from patient’s response. 
2 = Severe aphasia; all communication is through 
fragmentary expression; great need for inference, 
questioning, and guessing by the listener.  Range of 
information that can be exchanged is limited; listener 
carries burden of communication.  Examiner cannot 
identify materials provided from patient response. 
3 = Mute, global aphasia; no usable speech or auditory 
comprehension. 
____ 

 
 
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CLP 4853.D 
NIH STROKE SCALE 
Instructions 
Scale Definition 
Score 
10.  Dysarthria:  If patient is thought to be normal, an adequate 
sample of speech must be obtained by asking patient to read or repeat 
words from the attached list.  If the patient has severe aphasia, the 
clarity of articulation of spontaneous speech can be rated.  Only if the 
patient is intubated or has other physical barrier to producing speech, 
may the item be scored as untestable (UN), and clearly write an 
explanation for this choice.  Do not tell the patient why (s)he is being 
tested.   
0 = Normal. 
1 = Mild to moderate dysarthria; patient slurs at least some 
words and, at worst, can be understood with some 
difficulty. 
2 = Severe; patient’s speech is so slurred as to be 
unintelligible in the absence of or out of proportion to any 
dysphasia, or is mute/anarthric. 
3 = Intubated or other physical barrier, 
explain: _______________________________  
____ 
11. Extinction and Inattention (formerly Neglect):  Sufficient 
information to identify neglect may be obtained during the prior testing.  
If the patient has a severe visual loss preventing visual double 
simultaneous stimulation, and the cutaneous stimuli are normal, the 
score is normal.  If the patient has aphasia but does appear to attend 
to both sides, the score is normal.  The presence of visual spatial 
neglect or anosagnosia may also be taken as evidence of abnormality.  
Since the abnormality is scored only if present, the item is never 
untestable. 
0 = Normal abnormality. 
1 = Visual, tactile, auditory, spatial, or personal inattention or 
extinction to bilateral simultaneous stimulation in one of 
the sensory modalities. 
2 = Profound hemi-inattention or extinction to more than one 
modality; does not recognize own hand or orients to only 
one side of space.   
____ 
 

 
 
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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 
 
CATERPILLAR  
 

 
 
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12. 
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