Feasibility Study of the Treatment of Acute Ischemic Stroke Using the NOVIS Transcarotid Neuroprotection System In Transcarotid Embolectomy
Phase: NA
Conditions: Acute Ischemic Stroke
Sponsor: Silk Road Medical

CP00015_ SRM-2019-01_NITE 1 Study Protocol_ Rev E 
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Feasibility Study of the treatment of Acute Ischemic Stroke using the 
NOVIS Transcarotid Neuroprotection System In Transcarotid 
Embolectomy. 
The NITE 1 Study 
Clinical Protocol 
SRM–2019-01 
Version 
E 
Version Date 
May 15, 2023 
 
 
Sponsored by: 
Silk Road Medical, Inc. 
1213 Innsbruck Drive 
Sunnyvale, CA  94089 
United States of America 
Phone: +1 (408) 720-9002 
Fax: +1 (408) 720 9013 
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CLINICAL INVESTIGATIONAL PLAN
NCT Number: 04881162
ClinicalTrials.gov Cover Page

 
  
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Feasibility Study of the treatment of Acute Ischemic Stroke using the 
NOVIS Transcarotid Neuroprotection System In Transcarotid 
Embolectomy. 
 
 
The NITE 1 Study 
 
 
 
Clinical Protocol 
SRM–2019-01 
Version 
E 
Version Date 
May 15, 2023 
 
 
 
 
 
 
Sponsored by: 
 
Silk Road Medical, Inc. 
1213 Innsbruck Drive 
Sunnyvale, CA  94089 
United States of America 
Phone: +1 (408) 720-9002 
Fax: +1 (408) 720 9013 
 
 
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_____________________________________________________________________________________________________________________________________________________ 
 
 
PROTOCOL SIGNATURE PAGE 
 
Feasibility Study of the treatment of Acute Ischemic Stroke using the NOVIS Transcarotid 
Neuroprotection System In Transcarotid Embolectomy.  
The NITE 1 Study 
 
Clinical Protocol:   
SRM-2019-01 
Version: 
 
E 
Version Date:   
May 15, 2023 
 
 
 
 
 
 
 
I have read this protocol and agree to adhere to the requirements.  The protocol, other study 
documents and all necessary information will be made available to trained study staff 
(Investigators, Neurologists, Coordinators, etc.).  As required, will discuss this material with them 
and ensure they are fully informed regarding the study device and protocol.  The study will be 
conducted in compliance with the protocol, Good Clinical Practice (GCP), ISO 14155, Declaration 
of Helsinki, and all applicable regulatory requirements, and to the Institutional Review Board (IRB) 
requirements. 
 
 
 
 
 
 
 
 
Study Site Name 
 
Site Location (City, State) 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
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Table of Contents 
1 
Protocol Summary ............................................................................................................... 6 
2 
Principal Contacts ................................................................................................................ 7 
3 
Introduction ......................................................................................................................... 7 
3.1 
Background .............................................................................................................. 7 
3.2 
Summary of Relevant Publications and Clinical Studies for the Transcarotid 
Approach for AIS ............................................................................................................. 10 
3.2.1 
Transcarotid Artery Revascularization (TCAR) ................................................... 11 
3.2.2 
ROADSTER Study .............................................................................................. 12 
3.2.3 
ROADSTER 2 Study ........................................................................................... 14 
3.2.4 
Procedural Times ............................................................................................. 14 
3.2.5 
Anticoagulation................................................................................................ 14 
4 
Investigational Study Plan .................................................................................................. 15 
4.1 
Objectives .............................................................................................................. 15 
5 
Device Overview ................................................................................................................ 15 
5.1 
Device Description ................................................................................................. 15 
5.2 
Transcarotid Arterial Sheath ................................................................................... 17 
5.3 
Venous Return Sheath ............................................................................................ 17 
5.3.1 
Flow Controller ................................................................................................ 18 
5.4 
Intended Use.......................................................................................................... 19 
6 
Study Design ...................................................................................................................... 20 
7 
Outcomes ........................................................................................................................... 20 
7.1 
Primary Outcomes ................................................................................................. 20 
7.2 
Secondary Outcomes ............................................................................................. 20 
8 
Study Population................................................................................................................ 21 
8.1 
Selection of Patients............................................................................................... 21 
8.2 
Patient Eligibility .................................................................................................... 21 
8.3 
Inclusion Criteria .................................................................................................... 21 
8.4 
Exclusion Criteria.................................................................................................... 22 
9 
Patient Enrollment ............................................................................................................. 22 
9.1 
Patient numbering ................................................................................................. 23 
9.2 
Patient discontinuation .......................................................................................... 23 
10 Study Procedures ............................................................................................................... 23 
10.1 Informed Consent .................................................................................................. 23 
10.2 Pre-Procedure ........................................................................................................ 24 
10.2.1 Pre-Procedure Imaging .................................................................................... 24 
10.3 Transcarotid Endovascular Therapy Procedure ....................................................... 24 
10.3.1 Intra-Procedural Medications........................................................................... 24 
10.3.2 Failed Transfemoral Therapy ............................................................................ 24 
10.3.3 Establishment of Transcarotid Flow Reversal ................................................... 24 
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10.3.4 Endovascular Therapy ...................................................................................... 25 
10.3.5 Procedural Angiography ................................................................................... 25 
10.4 Post-Procedure Medications .................................................................................. 26 
10.5 Post-Procedure Surgical Wound Management ....................................................... 26 
11 Post-Procedure Evaluations ............................................................................................... 26 
11.1 24 Hours Post-op.................................................................................................... 26 
11.2 Day 5-7 or Discharge .............................................................................................. 26 
11.3 Clinical Follow-up ................................................................................................... 27 
11.3.1 30 Days ............................................................................................................ 27 
11.3.2 90 Days ............................................................................................................ 28 
11.4 Patient Flow Diagram ............................................................................................. 29 
12 Adverse Events................................................................................................................... 29 
12.1 Severity .................................................................................................................. 30 
12.2 Serious Adverse Events .......................................................................................... 30 
12.3 Serious Adverse Device Event ................................................................................. 30 
12.4 Unanticipated Adverse Device Effects .................................................................... 30 
12.5 Relatedness............................................................................................................ 31 
12.6 Device Failures, Malfunctions and Nonconformities ............................................... 31 
13 Safety Monitoring .............................................................................................................. 32 
13.1 Data Safety Monitoring Board ................................................................................ 32 
13.2 Clinical Events Committee (CEC) ............................................................................. 32 
13.3 Core Lab ................................................................................................................. 33 
14 Statistical Methods and Sample Size .................................................................................. 33 
14.1 Populations for Analysis ......................................................................................... 33 
14.2 Sample Size ............................................................................................................ 33 
14.3 Endpoint Analyses and Hypothesis Testing ............................................................. 33 
15 Data Collection ................................................................................................................... 34 
15.1 Required Data ........................................................................................................ 34 
15.2 Source Documentation........................................................................................... 34 
15.3 Record Retention ................................................................................................... 35 
15.4 Confidentiality........................................................................................................ 35 
15.5 Release of Data/ ClinicalTrials.gov .......................................................................... 35 
16 Site Responsibilities ........................................................................................................... 35 
16.1 Investigator Responsibilities ................................................................................... 35 
17 Device Accountability ........................................................................................................ 36 
17.1 Device Returns ....................................................................................................... 36 
18 Sponsor Responsibilities .................................................................................................... 36 
18.1 Selection of Clinical Investigators and Sites ............................................................ 36 
18.2 Training of Investigators and Site Personnel ........................................................... 37 
19 Study Monitoring ............................................................................................................... 38 
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19.1 On-Site Audits ........................................................................................................ 38 
20 COVID-19 ........................................................................................................................... 38 
20.1 ICF Process or Patient Impact ................................................................................. 38 
20.2 Visits/Procedures ................................................................................................... 39 
20.3 Protocol Deviations ................................................................................................ 39 
20.4 AE Collection and Reporting ................................................................................... 39 
20.5 On-site Monitoring ................................................................................................. 39 
20.6 Study Personnel Turnover ...................................................................................... 39 
21 Protocol Amendments ....................................................................................................... 39 
22 Protocol Deviations ............................................................................................................ 40 
23 Risk Benefit Analysis .......................................................................................................... 40 
23.1 CT Imaging ............................................................................................................. 40 
23.2 Diagnostic Angiograms or Fluoroscopy ................................................................... 41 
23.3 Risk Analysis for Endovascular Therapy .................................................................. 41 
23.4 Risk Analysis for Transcarotid Access with Reverse Flow ......................................... 42 
23.5 Potential Benefits ................................................................................................... 43 
23.6 Minimization of Risks ............................................................................................. 43 
24 Non-Protocol Research ...................................................................................................... 44 
25 Use of Information and Publication ................................................................................... 44 
26 Study Termination ............................................................................................................. 45 
Appendix 1.  Schedule of Events............................................................................................... 46 
Appendix 2.  Neurological Assessments/Scoring ...................................................................... 47 
Appendix 3. Abbreviations ....................................................................................................... 49 
Appendix 4.  Definitions ........................................................................................................... 51 
Appendix 5. Patient Flow Diagram ........................................................................................... 54 
Appendix 6. References ............................................................................................................ 55 
 
 
 
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1 
Protocol Summary 
Title 
Feasibility Study of the treatment of Acute Ischemic Stroke using the 
NOVIS Transcarotid Neuroprotection System In Transcarotid 
Embolectomy. (The NITE 1 Study) 
Study Objective 
 
To establish the feasibility and safety of the NOVIS Transcarotid 
Neuroprotection System when used for the transcarotid intervention 
of patients that have a failed transfemoral endovascular therapy in 
the case of anterior circulation strokes due to large vessel embolic 
occlusions. 
Study Design 
A prospective, multi-center, single arm feasibility study for the 
endovascular treatment of patients with acute ischemic anterior 
circulation strokes due to large vessel embolic occlusions using the 
transcarotid approach with flow reversal. Patients enrolled into the NITE 
1 Study will have failed transfemoral therapy and will be followed 
immediately from post-op to 90 days.   
Enrollment 
A minimum of 30 and a maximum of 40 study patients will be enrolled 
into the per protocol population (reference Section 14.1 for definition). 
Investigation Site 
Locations 
Up to 8 sites in the United States of America. 
Primary Outcomes 
• 
Device-related Serious Adverse Events – vascular complications 
including dissection, pseudoaneurysm, hematoma, arteriovenous 
fistula, thrombus formation, embolization and any vascular 
complication that may be attributed to the device AND requires 
surgical repair, surgical wound revision, transfusion, etc.  
• 
Other Serious Adverse Events – permanent cranial nerve injury, 
new symptomatic ipsilateral hemorrhage and dissections related to 
ancillary devices. 
• 
Functional independence measured at 90-day mRS (proportion 
with mRS score 0-2) 
Secondary Outcomes 
• 
Carotid access time  
• 
Time to final revascularization 
• 
Device-related complications 
• 
Neurologic assessment at 90 days (proportion of patients with a 
nondisabling or disabling stroke according to NIHSS) 
• 
Technical success rates  
• 
Rates of revascularization success (mTICI ≥ 2b) 
Patient Population 
Patients with acute ischemic anterior circulation stroke due to large 
vessel embolic occlusion who are candidates for endovascular therapy 
and in whom transfemoral therapy failed. 
Planned Schedule 
Commence Enrollment: 
Q3 2021 
Complete Enrollment: 
Q3 2022 (estimated)  
Complete 90-day Follow-Up:    90 days following last enrollment 
Issue FDA Final Report:           Q4 2022 (estimated) 
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2 
Principal Contacts 
Sponsor 
Silk Road Medical, Inc. 
1213 Innsbruck Drive 
Sunnyvale, CA 94089 
Study Monitor 
Fred Mosqueda, CRA II 
Silk Road Medical, Inc. 
1213 Innsbruck Drive 
Sunnyvale, CA 94089 
National Principal Investigator 
Charles Matouk, MD 
Yale University School of Medicine 
333 Cedar Street 
New Haven, CT 06510 
Data Coordinating Center 
MedNet, Inc. 
110 Cheshire Lane, Suite 300  
Minnetonka, MN 55305  
Imaging Core Lab 
David S. Liebeskind, MD, FAAN, FAA, FANA, FSVIN, FWSO 
Neurovascular Imaging Research Core 
635 Charles E Young Drive South, Suite 225 
Los Angeles, CA 90095-7334 
3 
Introduction 
3.1 
Background  
Nearly 800,000 strokes occur in the United States each year.  Of these, approximately 87% are 
considered ischemic strokes (Benjamin et al. 2019). About three-quarters of all strokes occur in 
persons aged ≥65 years. Age remains the most non-modifiable risk factor for stroke, and the risk 
continues to double every 10 years after the age of 55 (Yousufuddin et al. 2019). Although stroke 
mortality during the past 10 years has declined, it is still the fifth leading cause of death. Stroke is 
the leading cause of permanent disability and one of the most frequent causes of vascular 
dementia in the developed world (Benjamin et al. 2019). Large vessel occlusions (LVOs) are 
ischemic strokes that result from a blockage in one of the major proximal arteries of the brain. 
These large vessels include the basilar artery, carotid terminus and middle cerebral artery, and 
occlusions therein cause loss of blood flow to significant portions of the brain. 
 
Since the 1990s, the only proven treatment of acute ischemic stroke (AIS) was intravenous 
thrombolysis (IVT) with tissue-type plasminogen activator (tPA). However, its use is limited by 
several factors like the narrow time window after stroke onset during which it has been found to 
be safe and effective from randomized trials and the fact that its use is associated with only a 
moderate recanalization rate, especially in the larger proximal cerebral arteries (Papanagiotou 
MD et al. 2018). Major breakthroughs in endovascular treatment of acute stroke occurred in 2015, 
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when endovascular therapy/thrombectomy became the standard of care after 5 prospective 
randomized trials demonstrated consistent benefit in selected patients with AIS (Hasan et al. 
2018). These trials concluded convincingly that endovascular thrombectomy dramatically 
improves the 90-day functional outcomes of eligible patients. MR CLEAN was the first 
randomized control trial to report beneficial results for endovascular therapy (EVT) in acute 
ischemic stroke. This study was followed by additional positive trials EXTEND-IA, ESCAPE, 
SWIFT PRIME, and REVASCAT with consistent outcome benefit for EVT. These trials 
established EVT for patients presenting 0-8 hours after symptom onset (Papanagiotou MD et al. 
2018). 
The most recent paradigm shift in AIS care for patients with LVOs was seen in 2018 with the 
completion of the DAWN and DEFUSE 3 trials. These studies established EVT for patients with 
emergent large vessel occlusions presenting 6 to 24 hours after symptom onset. As a result, 
current American Heart Association guidelines recommend EVT for patients with AIS within 6-16 
hours and is considered reasonable for 16-24 hours (Powers et al. 2019). This shift 
was attributable partly to the efficacy of stentrievers in clot extraction, but largely to 
the appropriate selection of patients with salvageable brain tissue, based on multimodal 
imaging and limiting inclusion to strokes with small infarct cores(Dolia et al. 2019).  
In a 2018 meta-analysis of patient-level data from MR CLEAN, ESCAPE, EXTEND-IA, SWIFT 
PRIME, REVASCAT, THRACE, and PISTE , the HERMES collaboration reported that 
endovascular therapy achieves better outcomes at 90 days than standard medical therapy across 
a broad range of imaging categories including ASPECTS <6 (San Román et al. 2018).  
Direct suction aspiration of the thrombus also has been developed as an alternative technique to 
the use of stentrievers. Randomized trials such as ASTER and COMPASS have shown no 
difference between suction aspiration and stentrievers as a first-line strategy on any 
angiographic, clinical or safety outcome(Zhu et al. 2018). New aspiration systems have 
continually developed, resulting in larger inner diameters of the aspiration catheters. The 
aspiration technique is used in some centers as a primary approach for treating intracranial large 
vessel occlusions (Papanagiotou MD et al. 2018). Recently developed techniques simultaneously 
use the stentrievers and the aspiration catheter at once to enhance the efficacy of recanalization. 
Combined therapies, commonly referred to as the SOLUMBRA technique, are being evaluated in 
trials such as ASTER 2 (Zhu et al. 2018). 
EVT for acute ischemic stroke is most commonly performed through transfemoral access. The 
preference for this approach is related to the compressibility of the common femoral artery, to the 
fact that via this approach all great vessels from the aortic arch can be catheterized and in 
addition, selective catheterization of the great vessel branches (internal carotid arteries for 
example etc.) can be performed and thus multiple potential sites of occlusion can be accessed 
(Jadhav et al. 2014). It should be appreciated that almost all endovascular devices were originally 
formulated to be inserted via a transfemoral access point in the era of coronary catheterization 
and angioplasty (percutaneous coronary intervention; PCI). Barriers to great 
vessel/carotid/vertebral/intracranial vessel access and inadequate guide catheter support can 
impede or prevent device delivery to the face of the thrombus. Significant peripheral vascular 
disease can make traditional femoral artery access either time consuming or impossible, 
necessitating alternative approaches or causing early termination of the thrombectomy 
procedure, risking a poor clinical outcome. Similarly, in patients with certain aortic arch 
configurations (e.g., type III or “bovine”) or with significant cervical vascular tortuosity, 
catheterization may be significantly delayed, and placement of large-bore guide catheters may be 
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impossible (Yoo et al. 2017). The presence of significant arch atheroma burden (which increases 
with age) renders transfemoral access risky in terms of embolization from the arch during 
catheter/guidewire manipulations. 
Ribo et al. performed an analysis of 130 patients undergoing endovascular procedures for acute 
stroke which showed that 5.4% of the patients could not be successfully catheterized via 
transfemoral access. A negative correlation was found between time to carotid access and final 
recanalization; patients with difficult access had a lower rate of recanalization. Moreover, patients 
with difficult catheter access also had a significantly longer procedure time but similar time from 
symptom onset to final recanalization meaning that catheterization of the arch and great vessel 
origins from a transfemoral approach is the rate limiting step. Based on this study, patients with 
difficult catheter access had longer procedures, lower recanalization rates and poorer outcomes 
at 90 days(Ribo et al. 2012). 
In AIS from LVO, timely recanalization of proximal intracerebral vessels can minimize long term 
disability by salvaging the at-risk ischemic penumbra around the infarct core and, consequently, 
reducing the associated morbidity and mortality (Papanagiotou MD et al. 2018). Several studies 
have emphasized that procedure time in stroke patients undergoing endovascular intervention 
(vascular access to recanalization) is a critical determinant of long-term outcomes. Difficult 
catheter access, which may contribute to delays in revascularization, has been associated with 
lower recanalization rates and poor clinical outcomes. Prolonged groin to reperfusion time due to 
technical difficulties in catheterizing proximal supraaortic vessels leading to termination of EVT 
are also associated with higher severity of poststroke disability and reduced rate of functional 
independence (Jadhav et al. 2014). 
Every hour of delay has been shown to result in an absolute 6.4% decrease in the probability of a 
good outcome by EVT, measured as the risk difference between intervention and control (Ribo et 
al. 2012). Ribo et al. showed that failure of transfemoral catheterization occurred in up to 5% of 
patients and that this was associated with a delay of more than 30 minutes until vessel 
recanalization, thereby worsening clinical outcomes. 
Patients with difficult catheter access also had a significantly longer procedure time (groin 
puncture to recanalization) but similar time from symptom onset to final recanalization. Ribo et al. 
created a risk factor-based scoring system to calculate the chances of difficult femoral access in 
advance of the procedure. The scoring system focuses on four variables that individually and in 
combination are significantly associated with difficult access, primarily due to elongated and 
tortuous vessel anatomy: age >75 years, hypertension, dyslipidemia and left carotid access. A 
point is added for every risk criterion that the subject is associated with and a score of >2 was 
found to be predictive of difficult catheter access with 84% sensitivity and 74% specificity (Ribo et 
al. 2012).  
In order to avoid the limitations posed by the transfemoral access, alternative access routes 
including transradial, transbrachial, transcervical vertebral and transcarotid approaches have 
been reported in order to treat acute ischemic stroke. While some have performed a 
percutaneous puncture of the common carotid artery, others have reported a direct (open) carotid 
approach preceded by surgical cutdown (Styczen et al. 2019). Published experiences of 
endovascular treatment of acute stroke via the transcarotid approach have shown that surgical 
carotid access for endovascular stroke treatment is feasible, with considerable advantages, in 
patients with expected problematic access or for whom transfemoral endovascular carotid access 
has failed (Wiesmann et al. 2016). As such, the current American Stroke Association (Powers et 
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al. 2019)  guidelines recommend that alternate routes, including transradial, transbrachial, and 
direct carotid puncture, are technically feasible and should be employed as necessary to obtain 
recanalization (Gandhi et al. 2018). However, there is an increased risk of arterial injury and 
postoperative arterial occlusion due to the smaller diameter of the brachial and radial arteries 
(Wiesmann et al. 2016). 
3.2 
Summary of Relevant Publications and Clinical Studies 
for the Transcarotid Approach for AIS 
In 2014, Jadhav et al. reported a series of seven cases in which access was achieved via 
percutaneous puncture of the carotid after initial attempts via the transfemoral artery were 
unsuccessful. A skin incision was necessary to both facilitate catheter advancement and permit 
the redundant cervical epidermis from being pulled into the arteriotomy. All patients achieved 
recanalization with 87.5% of patients achieving ≥50% reperfusion (Jadhav et al. 2014).   
 
Mokin et al. reported two cases in which a direct, percutaneous carotid approach was used for 
endovascular stroke treatment with favorable results. In one of these two patients, reperfusion 
with good clinical outcome was achieved in 25 minutes (Mokin et al. 2015). 
 
In 2016, Wiesmann reported a retrospective analysis of six cases that used surgical access to the 
carotid artery and consecutive transcarotid endovascular thrombectomy in patients with acute 
ischemic stroke with all patients achieving intracranial recanalization. There was one small 
hematoma reported due to post-operative oozing, but no other access-related or endovascular 
therapy related events were reported (Wiesmann et al. 2016). 
Larrazabal performed a carotid cutdown and direct, controlled puncture of the carotid artery for 
the treatment of intracranial aneurysms and carotid artery stenosis in four patients. The carotid 
artery access was also repaired surgically under direct visualization. There were no access site 
related complications nor cardiac, systemic, or neurologic events. The authors concluded that 
transcarotid access with surgical exposure of the carotid artery for direct and controlled vascular 
puncture is an effective alternative for endovascular extracranial and intracranial procedures in 
patients in whom the femoral route cannot be used (Larrazabal et al. 2010). 
Cord et al. reported a retrospective analysis of 352 mechanical thrombectomy (MT) procedures 
attempted mostly via transfemoral approach between 2015 and 2018, of which 37 cases were 
deemed to have prohibitive vascular access and divided into two groups. One subset included 
aborted MT attempts (n=17) that failed transfemoral access due to the inability to reach the clot. 
The second subset included direct carotid puncture cases (n=20) that were attempted either as a 
salvage technique following a failed transfemoral MT attempt or failed transfemoral MT due to 
operator discretion following review of the preintervention CTA. In the direct carotid puncture 
subset, successful reperfusion was achieved in 84% of cases, and complications included 
inability to catheterize the carotid artery in one patient, neck hematomas in four patients, non–
flow-limiting common carotid artery (CCA) dissections in two patients, and a delayed, fatal carotid 
blowout in one patient. When comparing the two subsets, patients in the direct carotid puncture 
group had smaller infarct volumes (11 vs. 48 mL, p = 0.04), a greater reduction in NIHSS score 
(−4 vs. +2.9, p = 0.03), and better functional outcome (shift analysis for 3-month modified Rankin 
Scale score: adjusted OR 5.2, 95% CI 1.02–24.5; p = 0.048), advocating for the use of direct 
carotid puncture among emergency MT patients with anterior circulation AIS-LVO and prohibitive 
vascular access  (Cord et al. 2020).    
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While recanalization can be achieved using the percutaneous carotid approach, closure of the 
carotid puncture site remains an unsolved problem, as none of the available closure devices used 
for transfemoral closure have been approved for carotid closure. Local puncture-related 
complications (dissections and local hematomas) after percutaneous carotid puncture have been 
reported in 2.4–10.7% of cases in a large series (Wiesmann et al. 2016). Mokin also reported that 
percutaneous puncture of the carotid artery without direct visualization could result in 
perpendicular placement of the sheath into the carotid artery causing kinking of the sheath, which 
made subsequent aspiration catheter delivery and aspiration thrombectomy less efficient (Mokin 
et al. 2015). This may suggest that surgical cutdown of the carotid artery may facilitate placement 
of the sheath. Carotid access enabled by direct neck exposure also allows for the use of a large-
caliber catheter and the access site can be safely closed under direct visualization while checking 
for bleeding, dissection and subsequent hematomas (Lee et al. 2018). 
 
Given the overall smaller risk of local complications of surgical cutdowns compared with 
percutaneous puncture, various authors strongly recommended surgical cutdown instead of 
percutaneous puncture of the carotid artery in order to reduce the risk of vessel injuries, in 
particular when patients have vascular fragility (Wiesmann et al. 2016).  
Regarding alternative vascular access, regardless of a percutaneous or surgical approach, the 
inability to safely place the guiding catheter, which is the main cause of technical failure in 
transfemoral neurointerventions, is overcome with a direct carotid approach. The direct carotid 
approach also offers a short access route, which represents both a mechanical and temporal 
advantage because it renders the endovascular navigation quicker and easier (Larrazabal et al. 
2010).  
 
3.2.1 Transcarotid Artery Revascularization (TCAR) 
Since its introduction in the 1950s, carotid endarterectomy (CEA) has been the gold standard for 
stroke prevention in patients presenting with neurological deficits secondary to embolization from 
the internal carotid artery and in patients incidentally found to have high grade asymptomatic 
extracranial internal carotid artery stenoses. Transfemoral carotid stenting was introduced as a 
less invasive alternative to carotid endarterectomy in 1996 to decrease perioperative morbidity 
and mortality. While this alternative has been associated with a lower perioperative risk of 
myocardial infarction and cranial nerve injury compared to CEA, several randomized controlled 
trials have found significantly higher risk of perioperative stroke/death. 
TCAR was developed to address several areas of concern with transfemoral carotid stenting: 
first, iatrogenic embolization from manipulation of the aortic arch when attempting to cannulate 
the carotid artery; second, use of long sheaths and catheters to reach the carotid lesion; third, 
embolization during unprotected crossing of the carotid lesion to deploy a distal  embolic filter-
type protection device; and finally, embolization around an incompletely apposed filter or through 
the micropores of the filter (filter peri-flow and through-flow).  
In 2009, Silk Road Medical, Inc., initiated a first-in-human trial to evaluate the safety and 
performance of a dedicated system that facilitates carotid revascularization via the transcarotid 
approach using flow reversal as the embolic protection mechanism. The device was later 
evaluated in 2 separate clinical studies as described below.  
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Briefly described, for the ENROUTE NPS TCAR procedure, an arterial sheath is placed under 
direct surgical visualization into the common carotid artery proximal to the carotid bifurcation and 
a venous return sheath is placed percutaneously in the femoral vein.  The two sheaths are 
connected by a flow controller line and filter creating an arteriovenous shunt. Once the systems 
are in place, the common carotid artery is clamped just proximal to the arterial sheath insertion 
site. Once antegrade flow is obstructed, the differential in the arterial and venous pressures 
causes the blood flow to reverse from the brain, entraining oxygenated blood across the Circle of 
Willis from unclamped territories, out through the external flow line with the blood returned to the 
femoral vein after passing through an external 200 micron filter. With the protection of flow 
reversal initiated, the EVT can be performed while emboli are directed away from the brain. The 
NOVIS NPS NITE (Neuroprotection in Transcarotid Embolectomy) procedure is slightly modified 
from the ENROUTE NPS TCAR procedure, since EVT is focused on the removal of an anterior 
circulation LVO vs. balloon angioplasty and stenting a carotid bifurcation. However, both 
procedures establish flow reversal as a protection mechanism before initiating EVT.  
3.2.2 ROADSTER Study 
In 2012, Silk Road Medical initiated the ROADSTER study, a multicenter trial of 219 patients to 
evaluate the safety and effectiveness of the ENROUTE Transcarotid Neuroprotection System 
(ENROUTE NPS) with all FDA-approved carotid artery stent systems. The ROADSTER study 
showed a low overall 30-day stroke/death rate of 2.8% and a 30-day stroke rate of 1.4%. It was 
the lowest reported stroke rate of any multicenter trial of carotid revascularization with 
independent adjudication. The ROADSTER study supported 510(k) clearance of the ENROUTE 
NPS in 2015. 
The rate of serious arterial dissections (those requiring treatment) in the ROADSTER study was 
1.8% (4/219). The rates of arterial dissection deemed to be serious in nature vary across 
contemporaneous studies of carotid artery stenting and embolic protection devices as shown in 
Table 1. 
 
Table 1. Rates of Serious Dissection and Hematomas 
 
ROADSTER 
Abbott 
Acculink 
(ARCHeR) 
P040012 1 
Abbott Xact 
(SECuRITY) 
P040038 
Boston 
Scientific 
Wallstent 
(BEACH) 
P050019 
Covidien 
Protégé 
(CREATE) 
P060001 
Cordis 
Precise 
(SAPPHIRE) 
P030047 
Serious 
Dissection 
Rate 
1.8% 
0.0%,  
0.72%, 
2.07% 
3.28% 
0.4% 
1.2% 
Not Reported 
Serious 
Wound/Groin 
Hematoma 
2.3% 
Not Reported 
Not Reported 
2.1% 
Not Reported 
Not Reported 
As these results show, the rate of serious dissection in the ROADSTER study is within the range 
reported in other pivotal carotid artery stenting and embolic protection device trials (0.0%-3.28%). 
The rate of serious wound hematoma (defined as non-arterial surgical wound hematomas 
requiring treatment) was 2.3% (5/219) in the combined population (pivotal and extended 
enrollment). There were no serious groin hematomas (defined as femoral vein access site 
hematomas) in the ROADSTER study.  Wound/groin hematoma rates are rarely reported in other 
contemporaneous CAS and EPD studies and thus reports of this event are under-reported in TF-
 
1 Rates include ARCHeR 1, 2 and 3 respectively 
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CAS studies. As a result, direct comparisons against TCAR may not be valid. The BEACH study 
(Boston Scientific Carotid Wallstent) reported a discreet hematoma rate of 2.1%, and the 
ROADSTER serious wound hematoma rate is comparable to this rate. The variable definitions 
and reporting standards for local complications make direct comparisons complex. 
While wound/groin/access site hematomas are rarely reported separately, most 
contemporaneous carotid artery stenting and embolic protection device studies do report on 
serious access site complications or serious vascular complications, which represent varying 
composites of bruising, hematoma, bleeding and vascular injury. However, there is no apparent 
harmonization of the definitions and it is difficult to discern how each of the individual elements of 
the composite contribute to the overall rates of occurrence.  That said, the following table 
presents the rates of serious access site complications from contemporaneous carotid artery 
stenting and embolic protection device studies that are incremental to the wound hematoma and 
dissection rates tabulated above, unless they were otherwise not reported. Data for the pivotal 
stent trials are reported in the respective Summaries of Safety and Efficacy Data on the FDA 
website. 
Table 2. Rates of Serious Access Site Complications 
 
ROADSTER 
Abbott 
Acculink 
(ARCHeR) 
P040012 2 
Abbott Xact 
(SECuRITY) 
P040038 
Boston 
Scientific 
Wallstent 
(BEACH) 
P050019 
Covidien 
Protégé 
(CREATE) 
P060001 
Cordis 
Precise 
(SAPPHIRE) 
P030047 3 
Serious  
Access Site 
Complications 
2.3% 
5.70%, 
4.68%, 
2.76% 
2.62% 
NR 
2.6% 
5.4%, 
2.5% 
For the ROADSTER study, access site complications were a secondary endpoint as reported 
above with a tabulation that is redundant to separately reported adverse events and serious 
adverse events. The five (5) events reported in this tabulation of serious access site 
complications (Table 2) are the same events reported in the serious wound hematoma tabulation 
and discussion above. 
There were no serious or non-serious pseudoaneurysms reported in the ROADSTER study. In 
comparison, the rate of pseudoaneurysm has been reported to be 0.4% in the BEACH study 
(Boston Scientific Carotid Wallstent). Data from the ROADSTER study show that direct carotid 
access for extracranial carotid revascularization in patients with significant anticoagulation (to an 
ACT of ≥ 250 seconds) and dual antiplatelet medications is safe and effective. 
The secondary endpoints demonstrate that the device has a high rate of acute, technical and 
procedural success (99.3%, 99.3%, and 95.7% respectively) and low rate of serious access site 
complications (0.7%). Furthermore, the non-hierarchical rates of events for all death (1.4%) and 
all stroke (1.4%) are equivalent to the hierarchical event rates for death and stroke respectively, 
meaning that there were no stroke related deaths. There were no major or hemorrhagic strokes in 
the ITT population. There was one cardiac death (0.7%) and one death due to sequelae from 
respiratory failure (0.7%). 
 
2 Rates include ARCHeR 1, 2 and 3 respectively 
3 Rates include randomized and non-randomized arms respectively 
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3.2.3 ROADSTER 2 Study 
In October 2015, Silk Road Medical initiated the ROADSTER 2 Post-Approval Study, a 
multicenter study of 692 patients. Results of this study were submitted to FDA on November 25, 
2019 via P140026/R013. The primary endpoint was the rate of procedural success at 30 days 
following the index procedure. Procedural success is defined as acute device success 
(successful insertion of the ENROUTE NPS and establishment of flow reversal), technical 
success (deployment of interventional tools) and the absence of a major adverse events 
(hierarchical stroke/death/myocardial infarction) through 30 days. This study demonstrated a high 
procedural success rate of 97.9%. High rates of acute device and technical success were 
demonstrated at 99.7% for both.  
The hierarchical major adverse event rate (stroke/death/myocardial infarction) in ROADSTER 2 
was 1.7%. The incidence of combined stroke/death was 0.8%. There was one (1) death (0.2%) 
which was unrelated to both the study device and procedure. That patient expired from a ruptured 
abdominal aortic aneurysm approximately two weeks following treatment in ROADSTER 2.   
There were ten (10) acute cranial nerve injuries reported in the ITT population of ROADSTER 2 
(1.4%). Six (6) of ten (10) patients returned for extended follow-up and all cranial nerve injuries 
had resolved. The resolution of cranial nerve injuries for four (4) patients is unknown, since these 
patients did not consent to additional follow-up.   
There were eight (8) adverse events that were attributed to the study devices (1.3%) including 
seven (7) arterial dissections (1.1%) and one (1) thrombosed stent (0.2%).  The arterial dissection 
rate in ROADSTER 2 was lower than that of ROADSTER, as ROADSTER 2 used a second-
generation device designed to be more atraumatic.  In a recent publication comparing TCAR to 
transfemoral CAS, TCAR was associated with a lower rate of technical failure compared to 
transfemoral CAS (0.5% vs 1.2%; p<.001)(Schermerhorn et al. 2019). 
There were no reports of unanticipated adverse device effects in ROADSTER 2. 
TCAR with reverse flow has proven to be a safe and effective treatment for carotid 
revascularization. With over 20,000 procedures performed worldwide, physician utilization of 
TCAR has started to evolve into other therapeutic areas for the benefits of the access and the 
protective aspects of reverse flow. 
 
3.2.4 Procedural Times 
 
The average time from skin incision to cannulation of the common carotid artery (CCA) was 13 
minutes in the ROADSTER study population (excluding aborted cases). In ROADSTER 2, mean 
procedure time was 74.8 minutes (skin incision to skin closure). This is comparable to the mean 
procedure time for transfemoral CAS of 69 minutes as reported in the CREST study(Vilain et al. 
2012). Procedure time was not defined in the CREST study. 
   
3.2.5  Anticoagulation 
Several studies have been conducted to evaluate the safety of intraprocedural anticoagulation in 
the acute ischemic stroke (AIS) patient population. A few representative studies are summarized 
below, which largely demonstrate no difference in functional outcomes and rates of symptomatic 
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intracranial hemorrhage (sICH) among patients who receive intraprocedural anticoagulation and 
those who do not.  
The TREVO 2 trial (Winningham et al. 2018) evaluated 173 AIS patients who underwent clot 
retrieval using the Merci coil retriever and Trevo stent retriever. The mRS at 90-days was 
independently associated with patients who received a heparin bolus, and the rate of TICI 2b/3 
reperfusion and intracranial hemorrhages were similar between those who received and did not 
receive intraprocedural heparin. Another study (Farook et al. 2016) stratified the use of intra-
procedural heparin among 76 AIS patients with MCA M1- or ICA-T occlusion and found 
significantly lower rates of hemorrhage among the heparin group (p=0.02). Finally the MR CLEAN 
registry, a multi-center prospective registry(Van De Graaf et al. 2019), presented data on 1,488 
patients with ICA, ICA-T, MCA-M1, MCA-M2, ACA-A1 or ACA-M2 occlusions demonstrating no 
significant difference among patients treated with intravenous heparin and those without in 
functional outcomes (adjusted common odds ratio, 1.17; 95% CI, 0.87–1.56), successful 
recanalization (adjusted odds ratio, 1.24; 95% CI, 0.89–1.71), sICH (adjusted odds ratio, 1.13; 
95% CI, 0.65–1.99), or mortality (adjusted odds ratio, 0.95; 95% CI, 0.66–1.38). However, site 
level analysis showed sites that used heparin more often, also had better functional outcomes 
(adjusted common odds ratio, 1.07 per 10% more heparin, 95% CI, 1.01–1.13). On the other 
hand, a Chinese study (Yang et al. 2019), presented an analysis on 619/917 patients from the 
ANGEL registry, which showed an increased risk for sICH and embolization and lower functional 
independence with heparinization (9.3 vs. 5.1%, adjusted p = 0.02; 7.1 vs. 3.1%, adjusted p = 
0.04, respectively), although recanalization rates, total ICH, and long-term mortality did not differ 
between the heparinized and non-heparinized groups (adjusted p > 0.05 for all). In conclusion, 
the summary of these multiple data sets demonstrates comparable outcomes among patients 
who do and do not receive intraprocedural anticoagulation across functional outcome, sICH, and 
mortality. 
As a result, the sponsor does not believe patients are at any additional risk based on who has or 
has not received anti-coagulants during the procedure. With the exception of the required use of 
the pressurized, heparinized saline bag in section 10.3.3, the use of procedural anticoagulation 
has been carefully considered and will be left to the discretion of the operator. 
4 
Investigational Study Plan 
4.1 
Objectives 
The objective of this study is to demonstrate the feasibility and safety of the NOVIS Transcarotid 
NPS when used for the transcarotid intervention of patients that have failed transfemoral 
endovascular therapy in the case of anterior circulation strokes due to large vessel embolic 
occlusions. 
5 
Device Overview  
5.1 
Device Description 
The NOVIS Transcarotid Neuroprotection System (NPS) 
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The NOVIS Transcarotid Neuroprotection System is a modified version of the ENROUTE NPS. 
The NOVIS Transcarotid NPS consists of four primary components: 
• 
Transcarotid Arterial Sheath with Arterial Dilator 
• 
Venous Return Sheath with Venous Dilator 
• 
Flow Controller with Filter 
• 
0.035” Extra Support, J-Tip Guidewire 
When assembled, the NOVIS Transcarotid NPS creates an arteriovenous shunt that can 
reverse the flow of blood in the carotid artery from antegrade to retrograde, shunting embolic 
particles away from the cerebral circulation during endovascular interventions (see Figure 1 
below). The NOVIS NPS is intended to provide vascular access and embolic protection during 
treatment with neurothrombectomy devices; it is not intended to aspirate the carotid artery and 
its branches or to perform mechanical neurothrombectomy at a distance from the site of 
occlusion. 
 
Figure 1. NOVIS Transcarotid Neuroprotection System 
 
Key dimensions of the NOVIS Transcarotid NPS are listed in Table 3 and include lengths and 
diameters of each component. 
 
Table 3. Key Dimensions of the NOVIS Transcarotid Neuroprotection System 
Attribute 
Transcarotid Arterial 
Sheath 
Venous Return Sheath 
Arteriovenous 
Shunt** 
Working Length 
11 cm (4.3 in) 
11 cm (4.3 in) 
 
Total Length 
33.2 cm (13.1 in) 
13.6 cm (5.4 in) 
102 cm (40.2 in) 
Inner Diameter 
Sheath Tip ID: 8 Fr 
(2.7 mm/0.105 in) 
Sheath Tip ID: 8 Fr 
(2.7 mm/0.105 in)  
 
Outer Diameter 
10.5 Fr  
10.5 Fr 
 
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Attribute 
Transcarotid Arterial 
Sheath 
Venous Return Sheath 
Arteriovenous 
Shunt** 
(3.5 mm/ 0.136 in) 
(3.5 mm/ 0.136 in) 
** The Arteriovenous Shunt total length includes the large diameter tubing from the Arterial Sheath to the 
Venous Return Sheath. 
Each component of the NOVIS Transcarotid NPS is described in the following sections. 
5.2 
Transcarotid Arterial Sheath  
The NOVIS Transcarotid Arterial Sheath with Uber-Flex™ Tip consists of an 8 Fr. Arterial Sheath 
and an Arterial Dilator (see Figure 2). The Transcarotid Arterial Sheath permits access to the 
common carotid artery (CCA), and includes the following features: 
 
A radiopaque tip which allows visualization of the sheath tip under fluoroscopy. 
 
Printed centimeter markers to measure sheath insertion depth. 
 
An extension tube which extends the proximal end of the Arterial Sheath away from the 
radiation field. 
 
A female luer connection on the proximal end of the extension tube for the attachment of a 
Rotating Hemostasis Valve (RHV). The RHV (not included) will provide hemostasis after 
Dilator removal, allow introduction of interventional devices into the Arterial Sheath and 
enable continuous heparinized saline flush. 
 
Suture Eyelets for securement of the Arterial Sheath. 
 
An Arterial Stopcock which connects the Arterial Sheath to the Flow Controller via a “quick 
connect” type fitting.  The handle on the Arterial Stopcock is used to shunt flow once the 
Arterial Sheath is connected to the Flow Controller. 
  
Figure 2. NOVIS Transcarotid Arterial Sheath and Dilator 
5.3 
Venous Return Sheath  
The NOVIS Venous Return Sheath consists of an 8 Fr. Venous Sheath and a Venous Dilator (see 
Figure 3).  The Venous Return Sheath is used to gain femoral vein access, and includes the 
following features: 
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 
A radiopaque tip which allows visualization of the sheath tip under fluoroscopy. 
 
A Hemostasis Valve on the proximal end of the Sheath to provide hemostasis after removal 
of the Dilator. 
 
Suture Eyelets for securement of the Venous Return Sheath. 
 
A Venous Flow Line and Stopcock which connects the Venous Return Sheath to the Flow 
Controller via a “quick connect” type fitting.  The Venous Stopcock also permits saline prep, 
saline and contrast injections, and aspiration. 
 
 
Figure 3. NOVIS Venous Return Sheath 
5.3.1 Flow Controller 
The NOVIS Flow Controller (see Figure 4) connects the Transcarotid Arterial Sheath to the 
Venous Return Sheath and includes the following features: 
 
A Flow Controller which regulates the rate of reverse flow via the High/Low Switch and which 
allows temporary shut off of the Controller/Filter Line during contrast injections via the Flow 
“Stop” Button (detail in Figure 5).  Pressing the switch towards “Low” sets the flow setting to 
low flow and pressing the switch towards “High” sets the flow setting to high flow. 
 
An in-line Filter which captures embolic debris from the blood flow through the shunt. 
 
An in-line Check Valve which prevents inadvertent flow or injection of blood or fluid through 
the shunt in the arterial direction. 
 
“Quick-Connect” type connections to the Transcarotid Arterial Sheath and Venous Return 
Sheath. 
 
A “Pull to Prep” Toggle Loop that is removed and discarded prior to system prep and usage.  
 
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Figure 4. NOVIS Flow Controller 
 
 
Figure 5. Flow Controller Detail 
 
The Flow Controller has two functions.  The first is to enable the user to switch between Low and 
High flow modes via the use of the High/Low switch to modulate reverse flow.  This is 
accomplished by providing two parallel flow paths through the Controller Line: one with a low 
resistance flow path and the other with a high resistance flow path.  When the switch is on Low, 
the low resistance flow path is pinched off, requiring all the blood flow to go through the high 
resistance path.  When the switch is set to High, both paths are open and the blood flows through 
both paths in parallel, which in combination form a low resistance flow path.   
The second function of the Flow Controller is to momentarily block the flow of blood through the 
Controller Line via a Flow Stop Button.  This button is spring-loaded to be normally open and is 
designed to be used during injection of contrast through the arterial sheath into the carotid 
vasculature.  By shutting off the arteriovenous shunt flow line during contrast injection, the 
contrast solution is prevented from immediately filling the shunt line rather than entering the 
artery.  The normally open configuration of the button prevents the user from neglecting to re-
open the shunt line (and thereby re-establishing reverse flow) after a contrast injection. 
5.4 
Intended Use 
The NOVIS Transcarotid Neuroprotection System (NPS) is intended to provide transcarotid 
vascular access and embolic protection for the introduction of diagnostic agents and therapeutic 
devices during treatment of acute ischemic stroke (large vessel occlusion in the anterior 
circulation) in patients with distal ICA, MCA M1, proximal MCA M2, single-vessel MCA M2, 
dominant MCA M2, or co-dominant MCA M2 occlusions, within 24 hours of time last known well. 
Appropriate patients will have undergone a failed transfemoral attempt (as defined in Appendix 4) 
and have appropriate anatomy described below: 
 
• 
Adequate femoral venous access as assessed by ultrasound 
• 
Common carotid artery reference diameter of at least 6 mm 
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The NOVIS Transcarotid Neuroprotection System (NPS) is contraindicated for use in patients with 
significant disease of the ipsilateral common carotid artery. 
The benefits and risks of carotid stenting in AIS patients have not been investigated, thus carotid 
stenting is not allowed in the NITE 1 Study. 
6 
Study Design 
The NITE 1 Study is a prospective, single arm, multi-center feasibility study for the treatment of 
patients experiencing an acute ischemic anterior circulation stroke due to large vessel embolic 
occlusions of the intracranial ICA, MCA M1, proximal MCA M2, single-vessel MCA M2, 
dominant MCA M2, or co-dominant MCA M2 segments using the open-surgical transcarotid 
approach.  The NOVIS Transcarotid NPS will be used to facilitate the transcarotid approach in 
patients that have failed transfemoral therapy. 
7 
Outcomes 
7.1 
Primary Outcomes 
The following primary endpoints will be collected and evaluated in all enrolled patients: 
• 
Device-related Serious Adverse Events – vascular complications including dissection, 
pseudoaneurysm, hematoma, arteriovenous fistula, thrombus formation, embolization and 
any vascular complication that may be attributed to the device AND requires surgical 
repair, surgical wound revision, transfusion, etc. 
• 
Other Serious Adverse Events – permanent cranial nerve injury, new symptomatic 
ipsilateral hemorrhage and dissections related to ancillary devices 
• 
Functional independence at 90 days (proportion with mRS score 0-2)  
7.2 
Secondary Outcomes 
The following secondary outcomes will be collected and evaluated in all enrolled patients: 
• 
Carotid access time  
o 
Hospital arrival to neck incision 
o 
Neck incision to carotid exposure 
o 
Neck incision to carotid artery catheterization (includes securement of sheath) 
o 
Neck incision to femoral venous sheath access (includes securement of 
sheath) 
o 
Neck incision to initiation of reverse flow 
• 
Time to final revascularization  
o 
Hospital arrival to OR  
o 
Last known well to final revascularization 
o 
Admission to final revascularization 
o 
OR to final revascularization 
o 
Cutdown to final revascularization 
o 
Arterial introduction of interventional tools to final revascularization 
o 
Total reverse flow time (CCA clamp to CCA unclamp)  
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• 
Device-related complications 
• 
Neurologic assessment at 90 days (proportion of patients with a nondisabling or 
disabling stroke according to NIHSS) 
• 
Technical success rate – Successful introduction of endovascular tools through the 
NOVIS Transcarotid NPS.  
• 
Rates of revascularization success assessed by angiographic core lab (mTICI ≥ 2b) 
8 
Study Population 
8.1 
Selection of Patients 
Prospective study patients’ medical history will be reviewed for potential eligibility by an approved 
member of the site clinical research team.  Once eligibility is established, the research team 
should review the study follow-up requirements with the patient or patient’s legal authorized 
representative.  Patients who will not be able to return to the study site for the required follow-up 
visits should not be considered for enrollment. 
8.2 
Patient Eligibility 
Patients enrolled into this study will be comprised of male and female patients who have had an 
acute ischemic anterior circulation stroke due to large vessel embolic occlusion who are 
candidates for endovascular therapy and in whom transfemoral therapy has failed. 
Patients must meet ALL the inclusion criteria to be considered for the study. If ANY of the 
exclusion criteria are met, the patient cannot be enrolled in this study.  
8.3 
Inclusion Criteria  
1. Patients presenting with acute ischemic stroke of the anterior circulation with large vessel 
occlusions who are eligible for revascularization using endovascular therapies 
(stentrievers and/or aspiration devices) 
2. Occlusion of the intracranial ICA, MCA M1, proximal MCA M2, single-vessel MCA M2, 
dominant MCA M2, or co-dominant MCA M2 segments 
3. Patient has failed transfemoral therapy (see Appendix 4 for definition), and at least 15 
minutes have elapsed from groin puncture   
4. Patient must meet current NOVIS Transcarotid Neuroprotection labeling requirements 
a. Adequate femoral venous access as assessed by ultrasound 
b. CCA reference diameter of at least 6 mm 
5. Patient is ≥ 18 years of age 
6. Patient willing/able to return for protocol required follow up visits 
7. Patient or patient’s Legally Authorized Representative (LAR) has signed the study 
Informed Consent form 
8. Imaging requirement for patients presenting within 6 to 24 hours from last known well: 
a. < 1/3 MCA territory involvement, as evidenced by CT 
b. Clinical Imaging Mismatch defined as one of the following on CTP:  
i. 0-20 cc core infarct and NIHSS ≥ 10 (and age ≥ 80 years old) 
ii. 0-30 cc core infarct and NIHSS ≥ 10 (and age < 80 years old) 
iii. 31 cc to ≤ 50 cc core infarct and NIHSS ≥ 20 (and age <80 years old)   
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8.4 
Exclusion Criteria  
Each potential patient must be screened to ensure they do not meet any of the following 
exclusion criteria.  This screening is based on known medical history and data available at the 
time of eligibility determination and enrollment. 
1. Significant disease of the ipsilateral common carotid artery on routine CTA 
2. Presence of a cervical ICA loop or other high-risk anatomical features of the ICA on 
routine CTA, that may preclude the use of the NOVIS NPS 
3. Any active or recent hemorrhage within the past 30 days 
4. Embolectomy contraindications  
a. Pre-stroke mRS ≥2 
b. NIHSS ≤ 5 
c. ASPECTS ≤ 5 
5. IV tPA has been or is being administered  
6. Last known well > 24 hours ago 
7. Known history of severe head injury within past 90 days with residual neurological deficit, 
as determined by medical history 
8. Patient has an isolated hemisphere, defined as intracranial circulation that is fed only by 
the ipsilateral internal carotid artery and may be detected on prior CTA  
9. Known history of neurological or psychiatric disease that would confound the neurological 
or functional evaluations, e.g., dementia with prescribed anti-cholinesterase inhibitor 
(e.g., Aricept) 
10. Presumed septic embolus, suspicion of bacterial endocarditis or cerebral vasculitis 
11. Known history of ipsilateral severe intracranial atherosclerotic disease (≥ 70% stenosis) 
documented on prior imaging  
12. Patient is known to have an active COVID-19 infection 
13. Female who is pregnant or lactating at time of admission 
14. Current participation in another investigational drug or device study. 
15. Evidence of any other disease or condition expected to compromise survival or ability to 
complete the endovascular procedure or follow-up assessments during the 90-day follow-
up period (e.g. methamphetamine, cocaine, or other recreational drug use) 
16. Patient has recurrent or metastatic malignancy or cancer 
17. Known history of hemorrhagic diathesis or coagulation factor deficiency 
18. Known risks for paradoxical embolism, including intracardiac right-to left shunt (e.g., 
PFO, ASD, VSD) or history of pulmonary embolism or deep vein thrombosis 
19. Patients that have undergone a transradial or transbrachial mechanical thrombectomy 
attempt prior to enrollment  
9 
Patient Enrollment 
A patient is considered enrolled after:  
1) written informed consent is obtained,  
2) meeting all inclusion and none of the exclusion criteria, 
3)  failed transfemoral therapy 
Patients who are screened but do not meet all study criteria are considered screen failures and 
will not be enrolled and no further follow-up assessments will be conducted. 
 
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9.1 
Patient numbering 
Patients will be identified by a Patient Identification (ID) number, which is a combination of the 
specified site number and a sequential number assigned by the site.  The Patient ID will consist 
of a 3-digit number and will be consecutively assigned upon enrollment in the study. 
9.2 
Patient discontinuation 
Where possible, every effort should be made for a patient to remain in the study until completion 
of the required follow-up period. However, if needed the patient’s participation in the study may 
be discontinued at any time during the study.  If this occurs, the reason for discontinuation should 
be documented in the source documentation, and the appropriate Case Report Form (CRF) must 
be completed.  Factors leading to patient discontinuation may include, but are not limited to the 
following: 
• 
Patient Withdrawal:  Patient participation in a clinical trial is voluntary and the patient 
may discontinue participation (refuse all subsequent testing and follow-up) or withdraw 
their consent from the study at any time without affecting their future medical treatment or 
benefits. 
• 
Investigator Termination:  The Investigator may terminate the patient’s participation 
without regard to the patient’s consent if the Investigator believes it is medically 
necessary. 
• 
Lost to Follow-up:  A patient will be considered lost to follow-up after three 
unsuccessful, documented attempts have been made to contact the patient.  
• 
Death of Patient: Upon notification of the death of the patient, the study site will be 
responsible for notifying Sponsor within 24 hours (refer to Section 12.2):   
10 
Study Procedures 
10.1 
Informed Consent 
Prior to patient participation in this study, the Investigator will obtain written Institutional Review 
Board (IRB) approval for the protocol and the informed consent form (ICF).  The approved 
consent form should clearly reflect the IRB approval date and protocol version.  
 
Written informed consent must be obtained for all patients who are screened and meet the 
general inclusion/exclusion criteria prior to enrollment.  The patient or the patient’s Legally 
Authorized Representative (as defined by the local IRB) will be asked to sign the informed 
consent form before any study-specific tests or procedures are performed. A copy of the signed 
and dated informed consent will be provided to the study patient and/or the Legally Authorized 
Representative (LAR). 
 
The nature and scope of the study, potential risks and benefits of participation, any questions the 
patient and/or the LAR may have, are to be addressed by the Investigator or person designated 
by the Investigator who has been trained to the study protocol.  The study will be explained to the 
study patient and/or the LAR in lay terms and native language. Study patients will be assured that 
they may withdraw from the study at any time and for any reason. Trained study staff should 
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explain that even if a patient agrees to participate in the study and signs an Informed Consent 
Form, noninvasive baseline imaging or cerebral angiography may demonstrate that the patient is 
not a suitable candidate for the study treatment.  
 
A Screening and Enrollment Log will be maintained by the site to document basic information 
such as date screened and reason for screen failures for patients who fail to meet the study 
eligibility criteria. Screen failed subjects will not be entered into the electronic database or 
followed beyond the screening visit, and no further data will be collected/recorded. 
10.2 
Pre-Procedure  
All patients will undergo imaging assessments, neurological evaluation, and review of his/her 
medical history to determine eligibility. If any of these tests do not fall within the Investigator’s 
standard clinical practice, they should still be conducted for patients to be enrolled in the study. 
The neurological assessment will include a pre-stroke mRS and a baseline NIH Stroke Scale 
(NIHSS). 
10.2.1 Pre-Procedure Imaging 
The suitability of the common carotid artery for direct access (as part of standard of care) must be 
measured by computerized axial tomography (CT) angiography of both head and neck in 
accordance with the product labeling. 
A CT-Perfusion study (CTP) will also be completed to ensure imaging requirements for inclusion 
criteria are met (Section 8.3). The CTP imaging and report will be submitted by the sites for core 
lab and DSMB review.  
 
10.3 
Transcarotid Endovascular Therapy Procedure 
10.3.1 Intra-Procedural Medications 
All medications will be administered per institution standard of care for endovascular therapy 
procedures.  All medications administered should be recorded on the patient’s medical record.  
Pertinent medication given to the patient will be recorded on the Concomitant Medication Form, 
with clear indication to the procedural step at which the medication was administered, as 
applicable. 
10.3.2  Failed Transfemoral Therapy 
For the purposes of this study, failed transfemoral therapy is defined as either a unsuccessful 
transfemoral mechanical thrombectomy attempt made for at least 15 minutes having elapsed 
from groin puncture or inadequate or prohibitive anatomy deems a transfemoral approach not 
possible, as determined by the operator (see Appendix 4 for definition). 
 
Reasons for failed transfemoral therapy should be documented both on the patient’s medical 
record and study CRFs. 
10.3.3 Establishment of Transcarotid Flow Reversal 
The type of anesthesia used during the procedure is left to the discretion of the Investigator and 
will be documented on the CRFs. Should the investigator choose to start with moderate sedation 
conversion to general anesthetic should only occur if the Investigator deems it necessary. The 
type of anesthesia used will be documented in the CRFs.    
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After completing confirmatory duplex ultrasound, access to the common carotid artery cephalad 
to the clavicle will be gained using surgical techniques. 
Investigators are to follow the NOVIS Transcarotid Neuroprotection System (NPS) Instructions for 
Use (IFU) for setting up and establishing the reverse flow circuit. Upon placement of the NOVIS 
system and prior to clamping the CCA, the differential in pressure causes some blood to flow 
between the CCA and femoral vein. At this point, there is still some antegrade flow in the CCA 
and therefore the carotid and cerebral vasculature is not “protected”.  Once the CCA is clamped 
below the arterial sheath of the system on the Low flow setting, the NPS should remain on Low 
flow setting and switch to High flow upon the introduction of interventional tools through the 
completion of the procedure. Upon initial set-up of the device a pressurized, heparinized saline 
drip is connected to the 3-way stopcock on the side arm of the rotating hemostasis valve.   
Any adverse events that are observed after establishing reverse flow will be followed through 
study exit.  
10.3.4 Endovascular Therapy 
Patients will be treated with endovascular therapy system(s) (stentrievers and/or aspiration 
catheters) currently cleared by the FDA, under their cleared indications for use, for thrombus 
removal in patients experiencing an acute ischemic stroke in the anterior circulation due to large 
vessel occlusion. Investigators will be trained to follow the published instructions for use for the 
endovascular therapy system used in the procedure. Deviations from the cleared time of usage 
must be documented as a protocol deviation.  Ensure the neurointerventional devices are labeled 
with an outer diameter that is compatible with the inner diameter of the NOVIS NPS Arterial 
Sheath and attached rotating hemostasis valve. 
These devices will be introduced into the vasculature via the NOVIS NPS Arterial Sheath, during 
this interventional step the NOVIS NPS will be set to High Flow and remain on this setting until 
the neurothrombectomy has been completed. 
Once the endovascular therapy systems are introduced into the NOVIS NPS Arterial Sheath 
continuous reverse flow will be maintained throughout the interventional steps, until all other 
devices are removed and the thrombectomy attempt is complete.  
The transcarotid intervention may be abandoned at the discretion of the treating operator. The 
operator will document reason for failure in patient records and study case report forms. 
10.3.5 Procedural Angiography 
Angiographic evaluations will be performed pre-procedure, after recanalization, and post 
procedure to determine level of revascularization. Angiography must be performed in the involved 
territory.  
 
Prior to the start of the procedure, the mTICI scores within the vascular territory being treated 
should be assessed. Angiographic films of the occlusion being treated must allow clear 
visualization of the target artery. The same orientation should be used before and after 
endovascular therapy in order to allow a valid analysis of the reperfusion status of the vessel(s). 
These angiographic evaluations will be submitted by the sites for core lab review.  
 
In the event of a procedural complication or adverse event, detailed angiographic images should 
be obtained and submitted. All adverse events that occur during the procedure must be 
documented and recorded on the applicable CRFs. 
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10.4 
Post-Procedure Medications 
Post-procedural medication should be administered per the institution’s standard of care for 
endovascular therapy and should be documented on the Concomitant Medication Form. 
10.5 Post-Procedure Surgical Wound Management 
Surgical wound closure and management should be done per the institutional standard of care.  
Any significant post-procedural adverse event should be assessed and documented on the 
Adverse Event CRF. 
11 
Post-Procedure Evaluations  
All enrolled patients will undergo MRI post-procedurally per the institutional standard of care. 
Post-procedural MRI imaging and reports will be submitted to Sponsor.  
11.1 
24 Hours Post-op 
The NIHSS must be obtained within 24 hours (+/- 6 hours) from the end of the index procedure.  
This test must be performed whether or not it is considered part of the Investigator’s standard of 
care and must be performed by neurologist or NIHSS-certified personnel.  Every attempt should 
be made to have the same person conduct the exam at each follow-up visit. This assessor should 
be independent of the treating operator and patient’s mechanical neurothrombectomy 
procedures. The primary operator of the treated patient may not perform the neurological exam. 
 
Additionally, patients will undergo CT/CTA and CTP, per the Institution’s standard of care at 24 
hours to assess infarct volume, recanalization, hemorrhage, and reperfusion. The CTP imaging 
and report will be submitted by the sites for core lab and DSMB review.  
 
For the 24 hours post-op time period, any changes to the patient’s study medications are to be 
recorded from end of the index procedure up to 24 hours post-op.  All Adverse Events occurring 
from the end of the index procedure to 24 hours post-op are to be reported.  In the case of a 
suspected neurological event, NIHSS should be repeated as close to and prior to the 24th hour of 
symptom onset. 
 
In the event of patient death prior to the 24-hour assessment, all available information regarding 
the primary cause of death and date/time of death will be reported. Additionally, site will report if 
the patient had “do not resuscitate” (DNR) or “comfort care only” status prior to expiration.  All 
deaths must be reported to Sponsor within 24 hours of becoming aware (as per section 12).  
11.2 
Day 5-7 or Discharge 
The patient may be discharged from the hospital when clinically stable, at the Investigator’s 
discretion. The following neurological assessments must be obtained between Day 5-7 (if patient 
remains in hospital) or prior to discharge, whichever is earlier:  
 
 
NIH Stroke Scale 
 
Modified Rankin Scale 
 
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The neurological assessment must be performed whether or not it is considered part of the 
Investigator’s standard of care and must be performed by neurologist or NIHSS-certified 
personnel.  Every attempt should be made to have the same person conduct the exam at each 
follow-up visit. This assessor should be independent of the treating operator and patient’s 
mechanical neurothrombectomy procedures. The primary operator of the treated patient may not 
perform the neurological exam.  
 
Records of any changes to the patient’s study medications are to be recorded from the 24-hour 
post-op visit up to discharge.  All Adverse Events occurring from the 24-hour post-op visit to 
patient discharge are to be reported.  In the case of a suspected neurological event, NIHSS 
should be repeated as close to and prior to the 24th hour of symptom onset. 
 
In the event of patient death prior to the 5-7 day or discharge assessment, all available 
information regarding the primary cause of death and date/time of death will be reported. 
Additionally, site will report if the patient had “do not resuscitate” (DNR) or “comfort care only” 
status prior to expiration.  All deaths must be reported to Sponsor within 24 hours of becoming 
aware (as per section 12).  
11.3 
Clinical Follow-up  
Trained study staff at each site will review the study requirements with the patient to maximize 
compliance with the follow-up schedule. The trained study staff will instruct patient to return for 
follow-up assessments according to the study schedule of events listed in Appendix 1.   
11.3.1 30 Days 
The following neurological assessments must be obtained 30 days (+/- 7 days) from the index 
procedure: 
 
NIH Stroke Scale (required only for in office visits) 
 
Modified Rankin Scale 
 
This visit may be completed via phone or in office visit. If a phone visit is administered, then the 
NIHSS will not be completed. If an in-office visit is completed both the NIHSS and mRS 
assessments should be completed. This visit and associated neurological assessments must be 
performed whether or not they are considered part of the Investigator’s standard of care and must 
be performed by neurologist or NIHSS-certified personnel.  Every attempt should be made to 
have the same person conduct the exam at each follow-up visit. This assessor should be 
independent of the treating operator and patient’s mechanical neurothrombectomy procedures.  
The primary operator of the treated patient may not perform the neurological exam.  
 
Records of any changes to the patient’s study medications are to be recorded from discharge up 
to the 30-day follow-up visit.  All Adverse Events occurring from discharge to the 30-day follow-up 
visit are to be reported.  In the case of a suspected neurological event, NIHSS should be 
repeated as close to and prior to 24th hour of symptom onset. 
 
In the event of patient death prior to the 30-day assessment, all available information regarding 
the primary cause of death and date/time of death will be reported. Additionally, site will report if 
the patient had “do not resuscitate” (DNR) or “comfort care only” status prior to expiration.  All 
deaths must be reported to Sponsor within 24 hours of becoming aware (as per section 12).  
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11.3.2 90 Days 
The following neurological assessments must be obtained 90 days (+/- 14 days) from the index 
procedure: 
 
NIH Stroke Scale 
 
Modified Rankin Scale 
 
This visit is expected to be completed as an in-office visit. The neurological assessment must be 
performed whether or not it is considered part of the Investigator’s standard of care and must be 
performed by neurologist or NIHSS-certified personnel.  Every attempt should be made to have 
the same person conduct the exam at each follow-up visit.  This assessor should be independent 
of the treating operator and the patient’s mechanical neurothrombectomy procedures. The 
primary operator of the treated patient may not perform the neurological exam. 
 
Records of any changes to the patient’s study medications are to be recorded from the 30-day 
follow-up call/visit up to the 90-day follow-up visit.  All Adverse Events occurring from the 30-day 
follow-up call/visit to the 90-day follow-up visit are to be reported.  In the case of a suspected 
neurological event, NIHSS should be repeated as close to and prior to 24th hour of symptom 
onset. 
 
In the event of patient death prior to the 90-day assessment, all available information regarding 
the primary cause of death and date/time of death will be reported. Additionally, site will report if 
the patient had “do not resuscitate” (DNR) or “comfort care only” status prior to expiration.  All 
deaths must be reported to Sponsor within 24 hours of becoming aware (as per section 12).  
 
If the COVID-19 Pandemic impacts the ability of the patient or site to complete this visit on-site, a 
remote phone visit may be done. If a phone visit is administered, then the NIHSS will not be 
completed.  
 
 
 
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11.4 
Patient Flow Diagram 
 
Obtain consent 
from patient or LAR
• Patient is ≥ 18 years of age
• NIHSS ≥ 6
• ASPECTS ≥ 6 
• Pre-stroke mRS  0-1
• LKW < 24 hours
• Confirm exclusions # 3 and 5-
19  have not been met 
• SOC Imaging Assessments Completed (CT/CTA and CTP)  
• Occlusion of the intracranial ICA,  MCA M1, proximal MCA 
M2, single-vessel MCA M2, dominant MCA M2 or co-
dominant MCA M2 segment
• <1/3 MCA territory involvement
• For patients treated within 6 to 24 hours LKW, Clinical Imaging 
Mismatch defined as one of the following on CTP: 
• 0-20 cc core infarct and NIHSS ≥ 10 (and age ≥ 80 years old)
• 0-30 cc core infarct and NIHSS ≥ 10 (and age < 80 years old)
• 31 cc to ≤ 50 cc core infarct and NIHSS ≥ 20 (and age <80 
years old)  
• Confirm exclusion #1-2 and 4 have not been met
Transfemoral 
Procedure 
Attempted
Patient does not require 
additional MT intervention: 
SCREEN FAILURE
Patient deemed 
ELIGIBLE for 
NOVIS NPS 
Pt Enrolled/ 
ITT cohort
NOVIS 
NPS 
Procedure
24 Hour 
Follow-up
(+/- 6 hrs.)
Day 5-7/
Discharge 
Follow-up
30 Day 
Follow-up
(+/- 7 days)
90 Day 
Follow-up
(+/- 14 days)
STUDY EXIT
TF failure per 
protocol 
definition
Screening Procedures (Standard of Care Procedures) 
 
Image also provided in Appendix 5.  
12 
Adverse Events  
Adverse event (AE) data will be collected and recorded from index procedure through 90-day 
follow-up period (or until patient discontinuation) for all enrolled patients on the Adverse Event 
CRF.  At each evaluation, the Investigator or coordinator will determine whether an adverse event 
has occurred based on, but not limited to reports from the study patient, observed by the 
investigator or coordinator or documented in the medical record.  For the purpose of this protocol, 
an adverse event is any untoward medical occurrence in a study patient, which may or may not 
have a causal relationship with the study device. It includes any pre-existing condition that 
increases in severity or frequency or any new events that occur after the index procedure. An 
elective procedure for a pre-existing condition (that has not worsened) is not considered an AE.   
 
Event, date of onset, duration, severity, seriousness, treatment, outcome and relationship to the 
device or procedure will be recorded on the Adverse Event CRF and cross-tabulated according 
to: 
 
• 
Severity (Mild, Moderate, Severe) 
• 
Seriousness (Serious Adverse Event (SAE), Non-serious AE) 
• 
Serious Adverse Device Effect (SADE) 
• 
Unanticipated Adverse Device Effect (UADE) 
• 
Procedure-Relatedness (Not Related, Possibly Related, Probably Related, 
Causal/Related) 
• 
Device-Relatedness (Not Related, Possibly Related, Probably Related, Causal/Related) 
 
Anticipated AEs have been listed in Section 23.1, 23.2, 23.3 & 23.4, and all AEs will be monitored 
until they are adequately resolved or explained at the end of the study follow-up period. Beyond 
the routine annual reports, interim progress report will be provided every three months to FDA. 
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12.1 
Severity  
The term “severe” is used to describe intensity (severity) of a specific event. An event itself, may 
be of relatively minor medical significance (such as a severe headache). This is not the same as 
a “serious”, which is based on an outcome usually associated with events that pose a threat to 
the subject’s life or functioning. (See Section 12.2 for definition of a serious adverse event.) 
12.2 
Serious Adverse Events 
When an adverse event meets the definition for serious adverse event, it should be considered as 
such and reported immediately (within 24 hours) of becoming aware of the event to the Sponsor 
and recorded in the source documentation. The SAE should be further reported to the reviewing 
IRB per hospital IRB requirements.  An adverse event is considered serious if the event: 
 
Leads to death; 
 
Leads to a serious deterioration in the health of the patient that: 
o 
Results in life-threatening illness or injury; 
o 
Results in permanent impairment of a body structure or a body function; 
o 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
o 
Results in medical or surgical intervention to prevent permanent impairment to a 
body structure or a body function.   
An Adverse Event form will be completed promptly and no later than 10 working days after 
becoming aware of the event. Reports relating to the patient’s subsequent medical course must 
be submitted to the Sponsor and the reviewing IRB until the event has subsided or, in case of 
permanent impairment, until the event has stabilized, and the overall clinical outcome has been 
ascertained. 
12.3 
Serious Adverse Device Event 
Serious adverse device events are defined as a device related AEs that has resulted in any of the 
consequences characteristic of a serious adverse event. The Investigator will report these events 
within 24 hours of becoming aware of the event to the Sponsor and to the reviewing IRB per 
hospital IRB requirements.  
Reports relating to the patient’s subsequent medical course must be submitted to the Sponsor 
and the reviewing IRB until the event has subsided or, in case of permanent impairment, until the 
event has stabilized, and the overall clinical outcome has been ascertained. 
12.4 
Unanticipated Adverse Device Effects 
Unanticipated adverse device effects are defined as any serious adverse effect on health, safety 
or any life-threatening problem or death caused by, or associated with the study device; if that 
effect, problem, or death was not previously identified in nature, severity or degree of incidence in 
the study protocol and informed consent.  When an adverse event meets the definition of an 
unanticipated adverse device effect (UADE) or that relationship is unknown, the Investigator will 
report the event to the Sponsor within 24 hours and provide documentation within 10 working 
days after the Investigator first learns of the effect and to the reviewing IRB as required. 
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Follow-up reports relating to the patient’s subsequent medical course must be submitted to the 
Sponsor and the reviewing IRB until the event has subsided or, in case of permanent impairment, 
until the patient’s condition stabilizes, and the likely overall clinical outcome has been 
ascertained. 
12.5 
Relatedness 
The relationship between the use of the medical device (including the medical - surgical 
procedure) and the occurrence of each adverse event shall be assessed and categorized by the 
site Investigator. During causality assessment activity, clinical judgement shall be used, and the 
protocol consulted. The presence of confounding factors, such as concomitant 
medication/treatment, the natural history of the underlying disease, other concurrent illness or risk 
factors shall also be considered by the Investigator. Causality assessment will also be reviewed 
and adjudicated by the Clinical Events Committee.  
Each AE will be classified according to four different levels of causality. The Sponsor and the 
Investigators will use the following definitions to assess the relationship of the adverse event to 
the investigational medical device or procedures: 
• 
Not Related:  The adverse event is determined to be solely caused by the underlying 
disease, disorder or condition of the study patient, or attributable solely to other 
extraneous causes (unrelated to the device, device malfunction or procedure). 
• 
Possible: the relationship with the use of the investigational device is weak but cannot 
be ruled out completely. Alternative causes are also possible (e.g., an underlying or 
concurrent illness/ clinical condition or/and an effect of another device, drug or 
treatment). Cases where relatedness cannot be assessed, or no information has been 
obtained should also be classified as possible. 
• 
Probable: the relationship with the use of the investigational device seems relevant 
and/or the event cannot be reasonably explained by another cause, but additional 
information may be obtained. 
• 
Causal / Related:  The adverse event is clearly caused by the use of the device, device 
malfunction or the procedure, as confirmed by: the event is recognized as a known event 
associated with the device or procedure, the event has a temporal relationship to device 
or procedure, the event involves the body site or organ the device or procedure is applied 
to or has an effect on, or event is related error in use.  
12.6 
Device Failures, Malfunctions and Nonconformities 
All investigational device failures, malfunctions, and product nonconformities will be documented 
on the appropriate CRF and the involved device(s) should be returned to the Sponsor for 
analysis, if possible. Instructions for returning the investigational device(s) will be provided to the 
study sites in their Study binder. Device failures and malfunctions should also be documented in 
the subject’s medical record. All investigational device failures, malfunctions, and product 
nonconformities shall be reported within 24 hours of becoming aware to the Sponsor.  
All device malfunctions and nonconformities related to the interventional mechanical 
thrombectomy devices used in the procedure also should be reported in the CRFs.   
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13 
Safety Monitoring 
13.1 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will review the safety data, including 
reportable adverse events. The DSMB will be empowered to recommend suspension of 
enrollment or termination of the study based on safety concerns. Based on their analysis, the 
DSMB may recommend that the sponsor modify or stop the study. Every effort will be made to 
allow the DSMB to complete an unbiased review of internal and external scientific factors relevant 
to the safety of the patient populations and the conduct of the study. The DSMB will be composed 
of a multi-disciplinary group of physicians and a statistician. The committee members will not be 
participating in the study and will not have an affiliation with the Sponsor, Investigators, 
Investigational sites, or core laboratories. Names of the members will not be announced but will 
be provided by the sponsor to the appropriate regulatory agencies upon request. The DSMB 
chairperson will notify the sponsor of any safety or compliance issues throughout the course of 
the study. The committee will also provide confidential recommendations, when necessary, of 
study termination based on safety stopping rules determined at the study onset, or because a 
clinically significant result or trend was identified in safety analyses of data. All DSMB reports will 
remain strictly confidential but will be made available to the appropriate regulatory agencies upon 
request. 
During the course of the study, the DSMB will review accumulating safety data to monitor the 
incidence of Adverse Events and other trends that would warrant modification or termination of 
the study. The DSMB will meet at pre-specified intervals to assess the data against the 
prespecified safety and efficacy stopping rule as described within the DSMB Charter. In addition 
to the pre-specified meetings, the DSMB will meet for any other safety concerns that might arise 
during the active enrollment phase of the study. In addition, a designated member of the DSMB 
will be sent SAE data at regular time intervals, independent from the pre-planned DSMB meeting 
schedule. Data will be supplied to, and reviewed by, the DSMB as tables and/or listings. After 
review of the aggregate data, the DSMB may request additional information. The DSMB can also 
consider external data when appropriate, (e.g., published articles). Any DSMB recommendations 
for study modification or termination because of concerns over subject safety or issues relating to 
data monitoring or quality control will be submitted in writing to the Sponsor for consideration and 
final decision. However, if the DSMB at any time determines that a potential serious risk exists to 
subjects in this study, the DSMB chairman will immediately notify the Sponsor. The composition, 
guiding policies, operating procedures and stopping rules (if safety concerns arise during the 
review of the study data) will be described in the DSMB Charter. 
13.2 
Clinical Events Committee (CEC) 
An independent Clinical Events Committee will be assembled to review and adjudicate all 
potential endpoint events and their relationship to the device or procedure that occur while a 
patient is enrolled in the trial. The committee will be comprised of a multidisciplinary group of 
physicians including at least one neurointerventionalist and at least one cardiologist. The 
committee members will not be participating in the trial and will not have an affiliation with the 
Sponsor, Investigators or Investigational sites. The composition, guiding policies and operating 
procedures will be described in the CEC Charter.  
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13.3 
Core Lab 
A central imaging core lab will be established to independently review angiographic and CTP 
imaging. Angiographic images will be reviewed to provide an independent assessment of the 
secondary efficacy endpoint of mTICI reperfusion scores at post procedure. CTP images 
obtained at baseline and at 24 (+/- 6) hours will be reviewed to determine volume of infarct and 
mismatch for DSMB assessment.  
 
Instructions for standardized imaging and transfer will be provided to site by Sponsor. An imaging 
core lab charter will ensure that consistent policies and procedures are applied throughout the 
imaging core lab review and determination process, and will include a minimum of two core lab 
members. If an unresolvable disagreement is encountered, then a third member may be included 
or an alternative method may be used as needed. 
 
For each enrolled subject, all images must be appropriately de-identified and submitted for core 
lab review. It is important that the images be saved in native DICOM format, and that all imaging 
sequences are sent (without pre-selecting specific frames). It is also important that the imaging 
sequences are captured chronologically and are clearly labeled with date and time stamps so that 
they can be correlated to pre-procedure, after recanalization, and post-procedure time points.  
14 
Statistical Methods and Sample Size  
14.1 
Populations for Analysis 
The Intent-to-Treat (ITT) population is defined as patients who are enrolled as discussed in 
Section 9  who have consented (only once prior to screening),  who meet all inclusion and none 
of the exclusion criteria , and in whom transfemoral therapy has been deemed a failure.  
The per protocol (PP) population will be comprised of patients from the ITT population AND for 
whom no major protocol deviations have occurred. 
14.2 
Sample Size 
A minimum of 30 and a maximum of 40 patients will be enrolled into the PP population and 
analyzed in this study. Enrollment in the ITT cohort will cease when 30 PP patients have been 
accrued. Additional patients beyond 30 who are successfully enrolled while waiting for the 30th 
PP patient to complete the 90-day follow-up period, will be analyzed in the cohort for which they 
qualify, whether PP or ITT.  Enrollment will continue till a maximum of 60 patients are enrolled in 
the ITT population or the DSMB stops the study for safety reasons.  
14.3 
Endpoint Analyses and Hypothesis Testing 
No formal statistical hypothesis will be tested because this is a feasibility study with a small 
sample size. Serious Adverse Events will be tabulated and reported accordingly.  
The primary endpoint and all secondary endpoints will be analyzed based on both the ITT and PP 
population.  All available data on the ITT patients who enrolled in the study will be included. 
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15 
Data Collection 
Data will be entered into a validated electronic data management system using standardized 
electronic Case Report Forms (eCRFs).  All efforts should be made by the Investigator and 
trained study staff to complete the eCRFs in their entirety. This includes all data regarding 
adverse events, protocol deviations, patients lost to follow-up, and other relevant data. 
15.1 
Required Data 
For the duration of the study, the Investigator will maintain complete and accurate documentation, 
including but not limited to, medical records, study progress notes, laboratory reports, CRFs, 
signed patient informed consent forms, device accountability logs, correspondence with the 
reviewing IRB, sponsor and Study Monitor, adverse event reports, and information regarding 
patient discontinuation or completion of the study. 
The Investigator/institution will permit direct access to source data and documents for study-
related monitoring, audits, IRB reviews, event adjudication and regulatory inspections to be 
performed.  The Investigator will obtain, as part of the informed consent process, permission for 
authorized sponsor employees, study monitors or regulatory authorities to review, in confidence, 
any medical records that concern patients in this trial, whether or not they contain personally 
identifying information.   
15.2 
Source Documentation 
Regulations require that the Investigator maintain information in the patient’s medical records, 
which corroborate data collected for the study.  In order to comply with these regulatory 
requirements, at minimum, the following is a list of information that should be maintained: 
 
Medical history / general physical condition of the patient before involvement in the study 
of an enough nature to verify the protocol eligibility criteria.  
 
Dated and signed study/progress notes on the date of entry into the study documenting 
the following: 
 
o 
the general health of the patient,  
o 
completion of the informed consent process   
 
Dated and signed notes from each patient visit to support all data recorded on the CRFs. 
 
Adverse events reported and their continuation or resolution at EACH visit, including 
supporting documents such as discharge summaries, catheterization lab reports, lab 
results, CT/MRI reports. 
 
Notes regarding prescribed medications taken during the study (including start and stop 
dates if known). 
 
Patient’s general health and medical condition upon completion of, or withdrawal from, 
the study. 
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15.3 Record Retention 
The Investigator will maintain all essential documents and source documentation (patient medical 
records) that support the data collected on the enrolled patients in compliance with ICH/GCP 
guidelines. Documents must be retained for at least two years after (1) study completion following 
the FDA or other regulatory approval, or (2) the study has been terminated by the Sponsor. 
Documents must be retained until Silk Road Medical (SRM) informs the Investigator that study 
documentation no longer needs to be maintained. The participating physician will take measures 
to ensure that these essential documents are not accidentally damaged or destroyed. If the 
participating physician withdraws responsibility for maintaining these essential documents, 
custody must be transferred to an individual who will assume responsibility, written notification 
sent to Sponsor who will notify FDA. 
15.4 Confidentiality 
All data and information collected during this study will be considered confidential by the Sponsor.  
All data used in the analysis and summary of this study will be presented while protecting 
individual patient health information (PHI).  Access to patient files will be limited to authorized 
personnel of the Sponsor, the Investigator, Clinical site research staff and authorized Regulatory 
Authorities.  Authorized regulatory personnel have the right to inspect and copy all records 
pertinent to this study. 
 
15.5 Release of Data/ ClinicalTrials.gov 
For applicable clinical trials that are subject to 42 CFR 11.42, the standard submission deadline 
for study results on ClinicalTrials.gov is no later than 1 year after the study's Primary Completion 
Date, as described in 42 CFR 11.44(a) of the final rule. 
16 
Site Responsibilities 
16.1 
Investigator Responsibilities 
The Investigator is responsible for ensuring that the clinical study is conducted according to this 
Clinical Protocol, and all conditions of IRB approval and applicable regulations.  Written 
confirmation of IRB approval must be provided to SRM prior to the enrollment of any patient in the 
clinical study.  The Investigator is responsible for ensuring Informed Consent is obtained from all 
patients prior to any diagnostic tests or treatments outside of the standard course of treatment if 
this patient were not considered for enrollment in this clinical study. 
Patients must be informed that their medical records will be subject to review by the Sponsor, its 
authorized designee, or local regulatory representatives.  Patients will be informed that they are 
free to refuse to participate in this clinical study without loss of benefits to which they are 
otherwise entitled, and if they choose to participate, they may withdraw at any time without 
prejudice to future care.  The informed consent approved by the respective clinical sites’ IRB 
must be signed prior to study participation.  The original signed informed consent for each patient 
must be retained by the Investigator and is subject to review by Sponsor and the local regulatory 
authorities.  
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17 
Device Accountability 
The Investigator shall maintain adequate records of the receipt and disposition of the study 
devices.  Device Accountability Logs supplied by the sponsor, must be completed for each study 
device.  The disposition of all devices must be documented, including those that have been 
discarded and those returned to the sponsor.  Devices that are not associated with use for a 
study patient should only be identified with a patient number (for example, devices that are 
inadvertently contaminated during a case).  When the enrollment phase of the study is complete, 
the Investigator will return to the sponsor any unused devices and a copy of the completed 
Device Accountability Logs. 
Use of the device outside of this study protocol is strictly forbidden and will constitute grounds for 
removal of the Investigator and/or institution from the study. 
17.1 Device Returns 
All investigational devices that are required to be returned to the Sponsor will use the sponsor’s 
Return Materials Authorization (RMA) procedures that are outlined in the Study Manual. These 
devices may include the following: 
 
All unused study devices when enrollment is complete 
 
All study devices associated with a device malfunction or failure 
 
All opened but unused study devices that may be contaminated, have a defect in the 
sterile barrier prior to use, or have some other potential defect that was identified   
 
All expired study devices. 
Study devices that were opened in error, prepped incorrectly or contaminated in the lab, for 
instance dropped on the floor, do not need to be returned to the sponsor. 
18 
Sponsor Responsibilities 
Prior to shipping product, the Sponsor is responsible for selecting Investigators and obtaining and 
reviewing copies of appropriate IRB approvals.  It is the sponsor’s responsibility to ensure that the 
study is conducted according to Good Clinical Practice (GCP), applicable regulatory 
requirements, the Study Protocol, and any additional conditions that are indicated or mandated by 
the IRB at each site, or regulatory authorities.  Additionally, the sponsor will ensure proper 
training of the site and sponsor personnel, regular monitoring of the study, and ensure that 
Informed patient consent is obtained for each study patient prior to the completion of the index 
procedures.   
18.1 
Selection of Clinical Investigators and Sites 
The sponsor will select Investigators approved by training and experience in participating in 
clinical trials. Up to 8 US will be recruited and selected based upon a site assessment, 
appropriate facilities, and the qualifications of the Primary Investigator/s.  Individual Investigators 
will be evaluated by the sponsor based on experience with the intended procedure(s), and ability 
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to conduct the study according to the study protocol. Additional selection criteria may be applied 
in site and/or Investigator selection: 
 
Adequate study population to meet the requirements of the study 
 
Adequate time to be personally involved in the conduct of the study 
 
Adequate research staff and resources to support the study 
 
Experience in conducting studies 
 
Appropriate OR (hybrid or otherwise) permitting transfemoral and surgical approaches to 
be performed without moving the patient within the hospital 
 
Investigators must be individual(s) experienced with endovascular therapy AND 
Investigator must be a Neurosurgeon 
 
Investigator must be TCAR trained  
 
Investigator must currently perform or have hospital privileges to perform CEA. 
 
The facility must be certified as a Comprehensive Stroke Center through an accredited 
organization.  
 
Willingness to observe confidentiality at all times  
 
Compliance to protocol procedures and willingness provide Sponsor with accurate 
performance data in a timely fashion 
 
The facility must be associated with an Institutional Review Board (IRB) that satisfies all 
applicable regulatory requirements and conducts meetings on a regular basis.   
Prior to enrolling patients, each potential Investigator must submit a current, signed and dated 
curriculum vitae, a completed financial disclosure form, a completed Investigator agreement and 
has completed Sponsor approved protocol training.   
18.2 
Training of Investigators and Site Personnel 
The training of appropriate clinical site personnel will be the responsibility of the sponsor. 
Investigators and Site Personnel will be trained on the following aspects of the clinical study: 
 
Protocol 
 
Case Report Forms 
 
Risks and Benefits 
 
Reporting Responsibilities 
 
Informed Consent 
 
Device Usage 
 
Device Instructions for Use 
 
Confidentiality 
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19 
Study Monitoring 
The Sponsor or designee will regularly monitor the study throughout its duration.  Study Monitors 
will visit each site at appropriate intervals to review clinical data for accuracy and completeness 
and to ensure compliance with the protocol.  The Study Monitor may inspect all documents and 
records maintained by the Investigator, including medical records (office, clinic or hospital) for the 
enrolled patients in this study.  The Investigator will facilitate access to these records by 
authorized representatives of the Sponsor, and appropriate regulatory agencies. 
A study termination (close-out) monitoring visit will be conducted at the completion of the study to 
ensure that all clinical study materials and patient data are properly documented and stored until 
SRM informs the Investigator that data collection has been completed.  The sponsor will notify 
each site during the closeout visit of the current data storage requirements. 
If the Study Monitor becomes aware that an Investigator is not complying with the signed 
Investigator Agreement, the Study Protocol or any conditions of approval imposed by the 
reviewing IRB or regulatory authorities, the Sponsor will immediately either secure compliance, 
suspend enrollment at the site, or discontinue shipments of the device to the Investigator until 
compliance is achieved and guaranteed.  The Sponsor may also terminate the Investigator’s 
participation in the study.  The Investigator will be required to return all unused devices to the 
Sponsor unless this action would jeopardize the rights, safety or welfare of a patient. 
19.1 On-Site Audits 
In accordance with FDA and Competent Authority regulations and the Sponsor’s operating 
procedures, the Sponsor or designee may request access to all study records, including source 
documents, for inspection and duplication.  In the event that an Investigator is contacted by a 
regulatory agency in relation to this study, the Investigator will notify the Sponsor immediately. 
The Investigator and/or designee must be available to respond to reasonable requests and audit 
queries made by an authorized regulatory representative during the audit process.  The 
Investigator must provide the Sponsor with copies of all correspondence that may affect the 
review of the current study (e.g., Form FDA 483, Inspection Observations) or their qualification as 
an Investigator in clinical studies conducted by the Sponsor.  Sponsor will provide any needed 
assistance to regulatory audits or correspondence. 
20 
COVID-19 
The mitigation and impact assessments listed in this section are meant as contingencies for 
occurrences of pandemic or endemic-like situations, as seen during the pandemic of 2020 due to 
COVID-19. Sponsor and investigative sites are not limited to the actions or mitigations listed in 
this section and may take additional steps to ensure patient safety and well-being.   
20.1 
ICF Process or Patient Impact 
The study is designed to exclude patients who are known to be positive for COVID-19 at 
enrollment. The consenting guidelines laid out in section 10.1 should be maintained.  
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If an enrolled patient tests positive for COVID-19 during the study follow-up period (post-
procedure and thereafter), the patient will be followed through study exit. 
20.2 
Visits/Procedures 
A site’s ability to conduct follow-up visits on-site may be impacted due to the pandemic.  In these 
circumstances the site should make efforts to conduct e-visits (phone/ video based) within study 
visit windows. If e-visits are implemented, the site will ensure: 
• 
Trained study staff conducting e-visits have been trained on how to conduct e-visits 
(e.g., training on the use of telemedicine applications).  
• 
Procedures to maintain patient’s privacy are in place, as would be done for an on-site 
clinical visit.  
• 
Both the investigator and the trial participant should confirm their respective identities 
with one another before engaging in a real-time video conference visit according to 
an identity verification plan developed by the sponsor.  
It is understood that the use of e-visits will limit the ability of trained study staff to complete all 
protocol required neurological assessments. The NIHSS will not be collected at these e-visits. 
20.3 
Protocol Deviations 
Deviations from study visits and procedures caused by COVID-19 will be reported and collected 
in study case report forms under specified “COVID-19” categorizations. 
20.4 
AE Collection and Reporting 
All reported events will be collected and reported in association to COVID-19 in the study case 
report forms.   
20.5 
On-site Monitoring 
If the sponsor or sponsor representatives are unable to complete on-site monitoring visits due to 
COVID-19, the sponsor will attempt to utilize remote monitoring practices, where possible. The 
Sponsor will focus on trial activities that are essential to the safety of trial participants and/or data 
reliability. The details of these contingencies are laid out in the Monitoring Plan.  
20.6 
Study Personnel Turnover  
In the case of Site Personnel change or turnover, all new personnel will be trained via 
teleconferencing by Sponsor. The extent of this training will be determined based on the role and 
delegated tasks new site personnel will be required to undertake.  
21 
Protocol Amendments 
FDA approved protocol amendments will be provided to the Investigators by the Sponsor prior to 
implementing the amendment.  The Investigator will be responsible for notifying the reviewing IRB 
of the protocol amendment (administrative changes) or obtaining IRB approval of the protocol 
amendment (changes in patient care or safety), according to the instructions provided with the 
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protocol amendment.  The IRB acknowledgement/approval of the protocol amendment must be 
documented in writing prior to implementation and copies provided to the Sponsor. 
22 
Protocol Deviations 
A protocol deviation is defined as an event in which the clinical Investigator or Trained Study Staff 
deviate from the study protocol or study procedures. A major protocol deviation is a deviation 
from the study protocol that affects the patient’s rights, safety, or well-being. If the deviation 
meets any of the following criteria, it is considered a major protocol deviation: 
• 
changing the protocol without prior IRB approval, 
• 
failure to obtain informed consent, or 
• 
falsifying research or medical records.  
It is the Investigator’s responsibility to ensure there are no deviations from the protocol and study 
conduct is in full compliance with all established procedures and conditions of the reviewing IRB. 
The Investigator will inform the sponsor of all deviations, and the reviewing IRB/EC of all protocol 
deviations as per the IRB/EC requirements for this study and confirm notification to the sponsor in 
writing.  The occurrence of protocol deviations will be monitored by the Sponsor for evaluation of 
Investigator compliance to the protocol, Good Clinical Practice, and regulatory requirements. 
Failure to obtain a signed informed consent form prior to the index procedure constitutes a major 
protocol deviation and non-compliance with internationally recognized good clinical practices per 
ISO 14155, the Declaration of Helsinki and the Code of Federal Regulations (21 CFR 50.20 
General requirements for informed consent). 
 
In the event that an Investigator does not comply with the Clinical study/Investigator agreement, 
and/or the protocol, the Investigator will be notified of their non-compliance, and the 
circumstances will be reviewed by the sponsor.  Continued non-compliance may result in 
discontinued shipment of study devices and patient enrollment or termination of the Investigator’s 
and/or investigational site’s participation in the study.   
23 
Risk Benefit Analysis 
23.1 
CT Imaging 
CT/CTA/CTP scans of the brain obtained at baseline and 24 hours post procedure are 
considered standard medical care. The risk associated with performing a CT/CTA/CTP scan is 
the ionizing radiation exposure. The radiation dose that is received is the same dose that would 
be received from standard clinical care to assess and treat the underlying medical condition. 
There is no additional risk of increased ionizing radiation exposure as a result of participation in 
this study. 
A small amount of radiation is used to obtain a CT Angiogram (CTA). The radiation dose from this 
study is below the levels that are thought to result in a significant risk of harmful effect. There is 
some chance of an allergic reaction to the x-ray contrast (dye) used during the CTA.  
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Due to differences in standards of care between sites, it is possible that some patients may 
receive additional follow-up imaging or neurologic examinations other than those required by the 
protocol. The risks of these neurologic examinations are negligible, and the subject would likely 
benefit from enhanced care due to these additional tests. 
23.2 
Diagnostic Angiograms or Fluoroscopy 
The risks associated with angiography are well documented and understood by the medical 
community. The arteriogram itself can cause problems with brain function and it can potentially 
make the subject’s condition worse. Other risks related to the diagnostic angiographic procedure 
are relatively low but may include: 
 
• 
Allergy to the contrast material 
• 
Hematoma 
• 
Arteriovenous fistula formation 
• 
Infection 
• 
Hemorrhage 
• 
Neurological injury 
• 
Death 
• 
Pseudoaneurysm 
• 
Dissection 
• 
Thrombosis 
• 
Distal embolization 
• 
Vessel injury 
 
Renal toxicity and idiosyncratic responses to the injected contrast medium including anaphylactic 
reactions have also been reported. Anticoagulation is not required during EVT for LVO in AIS in 
the NITE 1 protocol. It is unlikely that study patients are on DAPT and so the risk of bleeding is 
possible but unlikely. The risk of bleeding may be increased when diagnostic angiography is 
performed in individuals who are receiving anticoagulation and/or antiplatelet therapy. 
Neurological injury associated with these vascular complications may occur.  
23.3 
Risk Analysis for Endovascular Therapy  
Endovascular therapy has known and well-defined risks, but some patients may be at greater risk 
as a result of existing co-morbidities.  The Investigator will evaluate the risk to each patient on an 
individual basis and discuss the risks and benefits of study participation with each patient or 
legally authorized representative.  This treatment may involve some additional risks to the patient, 
the nature of which are unknown.  The following is a list of possible adverse events that may be 
attributable to the endovascular therapy procedure. These include, but are not limited to, the 
following: 
• 
Access site complications 
• 
Inflammation 
• 
Allergic Reaction 
• 
Ischemia 
• 
Aneurysm perforation/rupture 
• 
Neurologic deterioration including stroke 
progression, stroke in new vascular territory, or 
death 
• 
Air embolism 
• 
Pain 
• 
Angina/coronary ischemia 
• 
Persistent neurological deficits 
• 
Arteriovenous Fistula 
• 
Pseudo aneurysm formation 
• 
Brain Edema 
• 
Rupture 
• 
Change in mental status 
• 
Stroke 
• 
Cranial nerve injury 
• 
Thrombosis 
• 
Death 
• 
Transient Ischemic Attack (TIA) 
• 
Device(s) deformation, collapse, 
fracture or malfunction 
• 
Vessel dissection 
• 
Distal embolization including to a 
previously uninvolved territory 
• 
Vessel occlusion 
• 
Embolism 
• 
Vessel perforation 
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• 
Headache 
• 
Vessel rupture 
• 
Hematoma 
• 
Vessel spasm 
• 
Hemorrhage 
 
• 
Infection 
 
 
Risks and complications of endovascular therapy are also associated with the possible adverse 
events from fluoroscopy, which is routinely used in endovascular procedures. The probability of 
these adverse events increases as procedure time and the number of procedures increase. 
These risks include but are not limited to:     
• 
Alopecia 
• 
Burns ranging in severity from skin reddening to ulcers 
• 
Cataracts 
• 
Delayed neoplasia 
23.4 
Risk Analysis for Transcarotid Access with Reverse Flow  
There exists a risk of access site complications associated with the surgical transcarotid access 
in this protocol, which is comparable to the risks associated with other routes of access used in 
mechanical thrombectomy procedures. These complications may include: 
• 
Abrupt vessel closure 
• 
Pain and tenderness 
• 
Airway compromise 
• 
Pseudo aneurysm formation 
• 
Arteriovenous fistula 
• 
Vessel dissection 
• 
Asphyxiation 
• 
Vessel occlusion 
• 
Cranial nerve injuries 
• 
Vessel perforation 
• 
Hematoma  
• 
Vessel rupture 
• 
Hemorrhage 
• 
Vessel spasm 
• 
Infection/ sepsis 
 
• 
Inflammation 
 
 
Risks associated with the use of a proximal embolic protection device may include: 
• 
Allergic reaction 
• 
Hyperperfusion syndrome 
• 
Aneurysm perforation 
• 
Hypertension/ hypotension 
• 
Aneurysm rupture 
• 
Ischemia/ infarction of tissue/ organ 
• 
Angina/coronary ischemia 
• 
Ischemic stroke 
• 
Bacteremia/septicemia 
• 
Myocardial infarction 
• 
Bradycardia/arrhythmia and other 
conductions disturbances 
• 
Neurologic deterioration including stroke 
progression or stroke in new vascular 
territory 
• 
Cerebral edema 
• 
Persistent neurological deficits 
• 
Component Damage 
• 
Pulmonary embolism 
• 
Congestive heart failure 
• 
Reduced blood flow 
• 
Death 
• 
Renal failure/insufficiency  
• 
Deep vein thrombosis 
• 
Seizure 
• 
Deployment and retrieval failure 
• 
Stroke or other neurological complications 
(e.g., paralysis, paraplegia, or aphasia) 
• 
Device(s) deformation, collapse, fracture or 
malfunction 
• 
Stroke in a contralateral hemisphere or 
brainstem (secondary to intracardiac right-to-
left shunt)  
• 
Distal embolization 
• 
Thrombosis 
• 
Distal embolization to a previously 
uninvolved territory 
• 
Thrombophlebitis 
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• 
Drug reactions 
• 
Transient ischemic attack  
• 
Embolism (which includes thrombus, 
plaque, air, device and / or component) 
• 
Ventricular fibrillation 
• 
Fever 
• 
Unstable angina pectoris 
• 
Fluid overload 
 
• 
Headache 
 
• 
Hemorrhagic stroke 
 
23.5 Potential Benefits  
Endovascular therapy remains the standard of care in the treatment of acute ischemic stroke 
caused by large vessel occlusions. The transcarotid approach provides a method of providing 
endovascular therapy even when standard transfemoral therapy options are no longer a viable or 
effective option.  
The transcarotid approach will additionally provide a more direct access and visualization of the 
occlusion and may be impactful in reducing the time needed to engage and recanalize the 
occluded vessel.  This approach will provide for a less tortuous environment for the delivery of the 
thrombectomy devices and may in turn yield a higher rate of first pass efficacy and reperfusion 
rates (mTICI 2b/3). In turn, these higher reperfusion rates may translate to better outcomes at 90 
days post-procedure (mRS 0-2).  
The transcarotid approach may also facilitate rapid exchange of endovascular therapy devices. 
This approach combined with the use of NOVIS NPS to establish flow reversal, augments the 
thrombectomy procedure and may potentially lower the rate of distal emboli or emboli in new 
territories. By directing emboli away from the brain, to the NOVIS NPS acts as a protection 
mechanism before initiating EVT.   
23.6 Minimization of Risks 
In order to mitigate the risks to the patient outlined above in Section 23.2 – 23.4, a variety of 
measures have been implemented into the study design to ensure patient safety.  
The Sponsor will ensure that all Investigators will meet pre-specified criteria for Investigator 
selection and will successfully complete the mandatory device and protocol training provided by 
the Sponsor. All Investigators and Sites selected for this study have sufficient expertise and 
resources to manage any adverse events and conduct endovascular procedures. The Sites 
selected for the study are certified Comprehensive Stroke Centers to ensure necessary staff 
knowledge and appropriate equipment and resources. Participating investigators must be 
neurosurgeons who are also “TCAR trained”, which is a training and credentialing status that 
meets the requirements of the Society for Vascular Surgery (SVS) and represents the operator’s 
knowledge of performing the TCAR procedure using the ENROUTE NPS System, which is the 
predecessor to the NOVIS NPS. Additionally, the investigators must currently perform or have 
hospital privileges to perform CEA at the investigational site in the case that emergent surgical 
repair of the carotid artery becomes necessary. 
The sample size of the study has been limited in size and to patients who have a failed 
transfemoral attempt, leaving no other thrombectomy therapy options other than the study 
procedure.  
Sites must obtain IRB approval prior to screening and enrolling patients into the study. Signed 
Informed Consent will be required prior to participation, which will explain their treatment choices 
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and the risks and benefits of being in the study. CTP neurological imaging maps will be used to 
measure the core infarct volume and only those subjects who have small to moderate core infarct 
volumes will be enrolled into the trial. Sites will be provided with Instructions for Use for the 
NOVIS NPS being used. During the procedure the Investigators will pre-place sutures at the 
planned common carotid artery puncture site to provide rapid hemostasis upon arterial sheath 
retrieval, as outlined in the Instructions for Use. The artery and incision will be closed using 
standard surgical techniques and will be monitored post-operatively. 
 The Site will observe standard hospital procedures in the care of patients who undergo 
endovascular procedures. Frequent neurological and hemodynamic checks will be performed per 
standard hospital procedures during and post-procedure. Vital signs, particularly the patient’s 
heart rate and blood pressure during and after the procedure will be monitored as standard of 
care, since rapid intervention must be undertaken to correct sudden changes in the patient’s 
hemodynamic or neurologic status. 
As part of this study protocol, the Investigator ensures all patients meet all enrollment criteria 
listed in Section 8 with particular adherence being made to ensure that the patient population 
consists of those that have undergone a failed transfemoral attempt (see Appendix 4 for 
definition). 
Additional follow-up assessments at 30- and 90-day intervals are predesigned into the study to 
aid in monitoring patient safety and assessing any change in the patient’s outcomes. The 
investigator will ensure the patient remains compliant with follow-up instructions and visits. The 
patients and their families will also receive the research teams contact information in case of an 
emergency or occurrence of an adverse event. 
Safety monitoring of the data, consisting of individual event and aggregate data review, will be 
ongoing and conducted at a rate commensurate with patient enrollment in the trial. The DSMB 
will provide subject safety oversight and make recommendations to Sponsor regarding continuing 
enrollment, modifying, or stopping the study early based upon a review of the comparative rates 
of SAEs. 
As a result of these risk mitigations, this study has been designed to demonstrate the potential 
benefits of the NOVIS Transcarotid NPS in the treatment of acute ischemic stroke caused by 
large vessel occlusions.  
24 
Non-Protocol Research 
The Sponsor has a legal responsibility to the regulatory authorities to fully report all the results of 
sponsored clinical studies. No investigative procedures other than those in this protocol shall be 
undertaken on the enrolled patients without the PRIOR written approval of the reviewing IRB and 
the Sponsor. 
25 
Use of Information and Publication 
All information and data generated in association with this study will be held in strict confidence 
according to local regulation and remains the sole property of Silk Road Medical, Inc.  The 
Investigator agrees to use this information for the sole purpose of completing this study and for no 
other purpose without written consent from the Sponsor. 
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At the conclusion of this study, a multi-center abstract reporting the primary results may be 
prepared and presented in an appropriate scientific forum.  A multi-center peer-reviewed 
manuscript may also be prepared for publication in a reputable scientific journal.  The publication 
of the principal results from any single center experience within the study will be coordinated with 
the Sponsor.  The site shall have the right to publish their individual results but only after 
publication of the multi-center publication is complete, provided, however, that at least sixty (60) 
days prior to the initial submission of a publication or presentation, the site provides Silk Road 
Medical with a copy of the publication or presentation for Silk Road Medical’s review and 
approval, as referenced in the study Clinical Trial Agreement.  Silk Road Medical reserves the 
right to delay approval either to prevent bias in ongoing clinical trials or to prevent adverse impact 
on the completion of the planned clinical program. 
In accordance with 42 CFR Part 11, Sponsor will register this study on ClinicalTrials.gov and 
submit study results no later than 1 year after the primary completion date of the study or early 
termination date.    
26 
Study Termination 
The Sponsor will monitor the progress of the study and the DSMB will monitor subject safety 
according to the DSMB charter.  If warranted and as specified in the DSMB charter, the study 
may be suspended or discontinued early if there is an observation of serious adverse reactions 
presenting an unreasonable risk to the study population or inadequate patient enrollment. The 
sponsor takes responsibility for releasing any available outcomes in a reasonable and appropriate 
time frame on ClinicalTrials.gov.  
Notification of suspension or termination will occur no later than five (5) working days after the 
Sponsor makes the determination.  In the event of study suspension or termination, the Sponsor 
will send a report outlining the circumstances to the reviewing IRB, the appropriate regulatory 
agencies, and to all participating Investigators.  A suspended or terminated study may not be 
reinitiated without PRIOR approval of the reviewing IRB and the study sponsor. 
The Sponsor may terminate Investigator and site participation in the study if there is evidence of 
an Investigator’s failure to maintain adequate clinical standards or evidence of an Investigator or 
trained study staff’s failure to comply with the protocol, as described in Section 21.
 
 
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Appendix 1.  Schedule of Events  
 
Procedure /Test 
Pre-
procedure 
Procedure 
Post-procedure 
Follow-up Visits 
24 hrs.  
(+/- 6 hrs.) 
Day 5-7 / 
Discharge 
(whichever is 
earlier)  
30 Day 
(+/- 7 days) 
90 Day 
 (+/- 14 days) 
Patient Informed Consent 
x 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
Neurological Examinations 
 
 
 
 
 
 
NIH Stroke Scale  
x 
 
x2 
x 
x3 
x 
Modified Rankin Scale 
x1 
 
 
x 
x 
x 
Imaging Assessments 
 
 
 
 
 
 
CT/CTA  
x4 
 
x2 
 
 
 
CTP 
x 
 
x 
 
 
 
Confirmatory DUS 
 
x 
 
 
 
 
Angiography 
 
x 
 
 
 
 
ASPECTS  
x 
 
 
 
 
 
MRI 
 
 
x 
 
 
Other Assessments 
 
 
 
 
 
 
Endovascular Therapy 
 
x 
 
 
 
 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
Concomitant Therapies 
x 
x 
x 
x 
x 
x 
Adverse Events  
 
x 
x 
x 
x 
x 
 
 
1 Modified Rankin will be evaluated for pre-stroke disabilities. 
2 To determine presence of symptomatic cerebral hemorrhage. 
3 NIH Stroke Scale completed if visit is in-office 
4 CT/CTA at pre-procedure must be of head and neck  
 
 
 
 
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Appendix 2.  Neurological Assessments/Scoring 
Alberta stroke program early CT score (ASPECTS) (Pexman et al. 2001) 
The Alberta stroke program early CT score (ASPECTS) is a 10-point quantitative topographic CT 
scan score used in patients with MCA strokes. Segmental assessment of the MCA vascular 
territory is made, and 1 point is deducted from the initial score of 10 for every region involved: 
• 
caudate 
• 
putamen 
• 
internal capsule 
• 
insular cortex 
• 
M1: "anterior MCA cortex," corresponding to frontal operculum 
• 
M2: "MCA cortex lateral to insular ribbon" corresponding to anterior temporal lobe 
• 
M3: "posterior MCA cortex" corresponding to posterior temporal lobe 
• 
M4: "anterior MCA territory immediately superior to M1" 
• 
M5: "lateral MCA territory immediately superior to M2" 
• 
M6: "posterior MCA territory immediately superior to M3" 
 
Modified Rankin Scale (mRS)(Broderick et al. 2017)  
The modified Rankin scale is used to qualify functional outcome in patient who suffer a 
neurological event. The scale comprises six levels, from 0 to 5, of increasingly severe disability 
where 0-2 is generally considered a good outcome with individuals assuming complete functional 
independence. The assessment should be made in a manner free of attribution to the incident 
stroke or the subject’s condition prior to stroke.  
• 
0: no symptoms/normal 
• 
1: no significant disability despite symptoms; able to carry out all usual duties and activities 
• 
2: slight disability; unable to carry out all previous activities, but able to look after own affairs 
without assistance 
• 
3: moderate disability; requiring 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 requiring constant nursing care and attention 
• 
6: dead 
 
 
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Modified TICI Scale (mTICI Scale)(Zaidat et al. 2013)  
The modified thrombolysis in cerebral infarction (mTICI) grading is a tool for determining the 
response of thrombolytic therapy for ischemic stroke. In neurointerventional radiology it is 
commonly used for assessing patients post endovascular revascularization.  
 
0:  
No Perfusion - No antegrade flow beyond the point of occlusion 
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 
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 
 
2a: 
Only partial filling (< 50%) of the entire vascular territory is visualized 
 
2b: 
Filling of > 50% all the expected vascular territory is visualized, but the filling is 
slower than normal 
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. 
 
National Institutes of Health Stroke Scale (NIHSS)(Meyer et al. 2009)  
The NIHSS is a graded neurological examination assessing consciousness, eye movements, 
visual fields, motor and sensory impairments, ataxia, speech, cognition and inattention. Often 
used to assess the severity of strokes based on the 11 components: 
1. level of consciousness (1a: 0-3, 1b: 0-2 and 1c: 0-2) 
2. best gaze (0-2) 
3. visual fields (0-3) 
4. facial palsy (0-3) 
5. arm motor (0-4) 
6. leg motor (0-4) 
7. limb ataxia (0-2) 
8. sensory (0-2) 
9. best language (0-3) 
10. dysarthria (0-2) 
11. extinction and inattention (0-2) 
These 11 components are then summed and the score correlates to stroke severity:  
• 
0 = no stroke symptoms 
• 
1-4 = minor stroke 
• 
5-15 = moderate stroke 
• 
16-20 = moderate to severe stroke 
• 
21-42 = severe stroke  
 
 
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Appendix 3. Abbreviations 
Abbreviation 
Term 
ACA 
Anterior Cerebral Artery 
AE 
Adverse Event 
AHA 
American Heart Association 
AIS 
Acute Ischemic Stroke 
ASA 
American Stoke Association 
CCA 
Common Carotid Artery 
CFR 
Code of Federal Regulations 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CT 
Computerized Tomography 
CTA 
Computerized Tomography Angiography 
CTP 
Computerized Tomography Perfusion 
CV 
Curriculum Vitae 
CVA 
Cerebral Vascular Accident 
DE 
Distal Embolization 
DNR 
Do Not Resuscitate 
ECA 
External Carotid Artery 
ECG 
Electrocardiogram 
ENT 
Embolization to New Territory 
EVT 
Endovascular Treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IA 
Intra-Arterial 
ICA 
Internal Carotid Artery 
ICA-T 
Internal Carotid Artery-Terminus 
ICF 
Informed Consent From 
IFU 
Instructions for Use 
ID 
Identification 
IM 
Intramuscular 
Inc. 
Incorporated 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IU 
International Unit 
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Abbreviation 
Term 
IV 
Intravenous 
LAR 
Legally Authorized Representative 
LVO 
Large Vessel Occlusion 
MCA 
Middle Cerebral Artery 
MRA 
Magnetic Resonance Angiography 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
mTICI 
Modified Thrombolysis in Cerebral Infarction 
N/A 
Not Applicable 
NIH 
National Institutes of Health 
NIHSS 
National Institutes of Health Stroke Scale 
NPS 
Neuroprotection System 
PHI 
Patient Health Information 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
SICH 
Symptomatic Intracranial Hemorrhage 
TCAR 
Transcarotid Artery Revascularization 
TIA 
Transient Ischemic Attack 
TIMI 
Thrombolysis in Myocardial Infarction 
tPA 
Tissue Plasminogen Activator (alteplase) 
UADE 
Unanticipated Adverse Device Effect 
 
 
 
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Appendix 4.  Definitions  
Access Site Complication 
Complication related to the vascular access site for the index procedure including but not limited 
to dissection, pseudoaneurysm, hematoma, arteriovenous fistula, thrombus formation, 
embolization and any vascular complication that may be attributed to the device AND that requires 
surgical repair, surgical wound revision, transfusion etc.  
 
Adverse Event (AE) 
Any unintended disease or injury or untoward clinical sign in a research patient.  
 
CEA—Carotid Endarterectomy 
A surgical procedure in which atherosclerotic plaque is removed from the diseased carotid artery.  
 
CVA—Cerebral Vascular Accident (See definition for Stroke)  
 
Death 
Cessation of brain, cardiac, and pulmonary functions 
Neurologic Death    Death due to stroke or other neurologic cause. 
Cardiac Death    Death due to MI or other cardiac cause. 
Other    Death that cannot be attributed to neurologic or cardiac causes. 
 
Device Malfunction 
The failure of a device to meet any of its performance specifications or perform as intended.  
Performance specifications include all claims made in the labeling of the device.  
 
Device Related Adverse Event 
An Adverse Event that was directly caused by the study device (NOVIS NPS).  
 
Distal Embolization (DE) 
Embolization of pieces of the original thrombus “downstream” in the same vascular territory as 
the original thrombus.  
  
Embolization to New Territory (ENT)  
Any new infarct seen in the ipsilateral ACA for MCA occlusions, on CTA or MRI at the 24-hour 
time point compared to baseline CT or MRI.  
 
Failed Transfemoral Therapy 
Either a transfemoral mechanical thrombectomy attempt was made unsuccessfully with at least 
15 minutes having elapsed from groin puncture, or there is inadequate or prohibitive anatomy 
deeming a transfemoral approach not possible, as determined by the operator. 
 
Good Clinical Outcome 
A measure of neurologic functional outcome with a score of 0–2 on the modified Rankin Scale 
(mRS), assessed at the 90-day follow-up visit. 
 
Intracranial Hemorrhage 
A hemorrhage, or bleeding within the skull 
 
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Isolated Hemisphere 
Intracranial circulation that is fed only by the ipsilateral internal carotid artery and may be 
detected on prior CTA/MRA  
 
Neurological Deterioration/Worsening  
A 4 or more-point increase in NIHSS from baseline to discharge. Neurological worsening could be 
new or evolution/progression of the index stroke. 
 
Permanent Cranial Nerve Palsy or Injury 
Injury to cranial nerves in the vicinity of the treated carotid artery that has not resolved by three 
months after the intervention. Symptoms will depend on the specific nerve that is injured, such as 
hoarseness. 
 
Pre-stroke disability 
Obtained at baseline, but representative of the patient’s status before the index stroke, assessed 
by mRS on medical history obtained from patient’s medical chart, or family members. 
 
Procedure Related Adverse Event 
An undesirable event that occurred as a direct cause of the procedure that was not a direct cause 
of the study device. 
 
Serious Adverse Event (SAE) 
An adverse event in a research patient that led to a death, or led to a serious deterioration in the 
health of the patient that resulted in a life-threatening illness or injury, or resulted in a permanent 
impairment of a body structure or a body function, or required in-patient hospitalization or 
prolongation of existing hospitalization, or resulted in medical or surgical intervention to prevent 
permanent impairment to body structure or a body function. SAEs are a subset of AEs. 
 
Stroke 
A neurological deficit lasting 24 hours or more attributed to an acute focal injury of the central 
nervous system (CNS) by a vascular cause, including cerebral infarction, intracerebral 
hemorrhage (ICH), and subarachnoid hemorrhage (SAH). Stroke can be subclassified as 
Hemorrhagic or Ischemic 
 
Symptomatic Intracranial Hemorrhage (SICH) 
New intracranial hemorrhage detected by brain imaging associated with any of the items below 
(Von Kummer et al. 2015): 
• 
≥ 4 points total NIHSS at the time of diagnosis compared to the pre-procedure NIHSS. 
• 
≥ 2 point in one NIHSS category. The rationale for this is to capture new hemorrhages 
that produce new neurological symptoms, making them clearly symptomatic, but not 
causing worsening in the original stroke territory. For example, a new remote hemorrhage 
in the contralateral occipital lobe may cause new hemianopia that is clearly symptomatic, 
but the patient will not have worsening of ≥ 4 points on the NIHSS score. 
• 
Leading to intubation/hemicraniectomy/EVD placement or other major medical/surgical 
intervention. 
• 
Absence of alternative explanation for deterioration 
 
Technical Success  
Successful introduction of endovascular tools through the NOVIS Transcarotid NPS. 
 
 
 
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Transient Ischemic Attack (TIA) 
Temporary focal brain or retinal deficits caused by vascular disease that resolves completely in 
less than 24 hours. 
 
Unanticipated Adverse Device Effect (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused by 
or associated with a device.  The effect must have not been previously identified in nature, 
severity or degree of incidence in the study plan or IFU.  Other unanticipated serious problems 
associated with the device that relates to the rights, safety or welfare of study patients may also 
be considered UADEs. 
 
Vascular Access Site Complications 
These complications are associated with the NITE procedure whether through the arterial or 
venous access and are categorized into dissections, hemorrhage, infections, perforations, 
pseudoaneurysms and ruptures.  
 
 
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Appendix 5. Patient Flow Diagram 
 
Obtain consent 
from patient or LAR
• Patient is ≥ 18 years of age
• NIHSS ≥ 6
• ASPECTS ≥ 6 
• Pre-stroke mRS  0-1
• LKW < 24 hours
• Confirm exclusions # 3 and 5-
19  have not been met 
• SOC Imaging Assessments Completed (CT/CTA and CTP)  
• Occlusion of the intracranial ICA,  MCA M1, proximal MCA 
M2, single-vessel MCA M2, dominant MCA M2 or co-
dominant MCA M2 segment
• <1/3 MCA territory involvement
• For patients treated within 6 to 24 hours LKW, Clinical Imaging 
Mismatch defined as one of the following on CTP: 
• 0-20 cc core infarct and NIHSS ≥ 10 (and age ≥ 80 years old)
• 0-30 cc core infarct and NIHSS ≥ 10 (and age < 80 years old)
• 31 cc to ≤ 50 cc core infarct and NIHSS ≥ 20 (and age <80 
years old)  
• Confirm exclusion #1-2 and 4 have not been met
Transfemoral 
Procedure 
Attempted
Patient does not require 
additional MT intervention: 
SCREEN FAILURE
Patient deemed 
ELIGIBLE for 
NOVIS NPS 
Pt Enrolled/ 
ITT cohort
NOVIS 
NPS 
Procedure
24 Hour 
Follow-up
(+/- 6 hrs.)
Day 5-7/
Discharge 
Follow-up
30 Day 
Follow-up
(+/- 7 days)
90 Day 
Follow-up
(+/- 14 days)
STUDY EXIT
TF failure per 
protocol 
definition
Screening Procedures (Standard of Care Procedures) 
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