MIND: A Prospective, Multicenter Study of Artemis a Minimally Invasive Neuro Evacuation Device, in the Removal of Intracerebral Hemorrhage
Phase: NA
Conditions: Cerebral Hemorrhage, Brain Hemorrhage, Cerebral Parenchymal Hemorrhage, Intracerebral Hemorrhage
Sponsor: Penumbra Inc.

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MIND: A Prospective, Multicenter Study of Artemis, a 
Minimally Invasive Neuro Evacuation Device, in the Removal 
of Intracerebral Hemorrhage  
Protocol  
CLP 11899.B 
Date of Protocol 
14 Jan 2020 
Device Name 
Artemis Neuro Evacuation Device 
Sponsor 
Penumbra, Inc. 
One Penumbra Place 
Alameda, CA 94502 
USA 

 
 
 
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TABLE OF CONTENTS 
CONTENTS 
1. 
Introduction and Rationale .................................................................................................. 8 
1.1 Randomized Trials of Medical Management of Intracranial Hemorrhage.............................. 8 
1.2 Randomized Trials of Conventional Open Surgical Management of Intracranial 
Hemorrhage ............................................................................................................................................ 9 
1.3 Rationale for Study ........................................................................................................................ 9 
1.4 Conclusions ................................................................................................................................... 15 
2. 
The Artemis Neuro Evacuation Device ............................................................................. 16 
3. 
Risk Analysis ....................................................................................................................... 17 
4. 
Study Overview ................................................................................................................... 20 
4.1 Study Design ................................................................................................................................. 20 
4.2 Study Objectives/Endpoints ........................................................................................................ 21 
4.3 Method of Randomization ........................................................................................................... 21 
4.4 Blinding ......................................................................................................................................... 22 
5. 
Study Population ................................................................................................................. 22 
5.1 Inclusion Criteria ......................................................................................................................... 22 
5.2 Exclusion Criteria ........................................................................................................................ 22 
6. 
Study Procedures ................................................................................................................ 23 
6.1 Overview of Study Flow .............................................................................................................. 23 
6.2 Study Visits ................................................................................................................................... 24 
6.3 Recruitment .................................................................................................................................. 25 
6.4 Screening and Baseline Evaluation ............................................................................................ 25 
6.5 Informed Consent ........................................................................................................................ 26 
6.6 Randomization ............................................................................................................................. 27 
6.7 Treatment Procedure ................................................................................................................... 27 
6.8 24 hours post MIS or 72 hours post randomization (MM subjects) ........................................ 30 
6.9 Day 7/Discharge ........................................................................................................................... 31 
6.10 Post Discharge Follow-Up ........................................................................................................... 31 
7. 
Investigator Responsibilities .............................................................................................. 34 
7.1 Institutional Review Board/Ethics Committee Approval ......................................................... 34 
7.2 Informed Consent ........................................................................................................................ 34 
7.3 Adherence to Protocol/Amendments and Applicable Law ...................................................... 34 
7.4 Case Report Form Completion ................................................................................................... 34 
7.5 Image Upload ............................................................................................................................... 35 
7.6 Reporting ...................................................................................................................................... 35 
7.7 Administration of Neurological Exams and Stroke Scales ....................................................... 39 
7.8 Device Disposition ........................................................................................................................ 39 
7.9 Records Retention ........................................................................................................................ 40 
8. 
Sponsor Responsibilities ..................................................................................................... 40 
8.1 Training ........................................................................................................................................ 40 
8.2 Investigator List ........................................................................................................................... 41 
8.3 Adverse Event Reporting ............................................................................................................ 41 
8.4 Data Monitoring ........................................................................................................................... 41 
8.5 Data Management ........................................................................................................................ 42 
9. 
Ethical Considerations........................................................................................................ 43 

 
 
 
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9.1 Declaration of Helsinki ................................................................................................................ 43 
9.2 Informed Consent ........................................................................................................................ 43 
9.3 Subject Data Protection ............................................................................................................... 43 
10. Statistical Procedures ......................................................................................................... 44 
10.1 Sample Size Estimation for the Primary Outcome ................................................................... 44 
10.2 Control of Systematic Error and Bias ........................................................................................ 45 
10.3 Missing Data and Imputation Methods ..................................................................................... 45 
10.4 Definition of Populations ............................................................................................................. 45 
10.5 Definition of Analysis Populations ............................................................................................. 46 
10.6 Interim Analysis ........................................................................................................................... 46 
10.7 Statistical Evaluation of Primary Endpoint .............................................................................. 47 
10.8 Statistical Analysis of Primary Safety Outcome ....................................................................... 47 
10.9 Secondary Statistical Analysis .................................................................................................... 47 
10.10 
Baseline Characteristics .......................................................................................................... 48 
10.11 
Pooling Across Centers ........................................................................................................... 48 
10.12 
Health Economics Information .............................................................................................. 48 
10.13 
Final Report ............................................................................................................................. 48 
11. Study Committees and Core Labs ..................................................................................... 49 
11.1 Steering Committee/Scientific Advisory Board ........................................................................ 49 
11.2 Safety Monitoring Committees ................................................................................................... 49 
11.3 Imaging Core Lab ........................................................................................................................ 50 
12. Study Administration ......................................................................................................... 50 
12.1 Clinical Trial Termination/Withdrawal .................................................................................... 50 
12.2 Stopping the Trial Based on Interim Safety Data ..................................................................... 51 
12.3 Missing Visits ................................................................................................................................ 51 
12.4 Protocol Adherence and Amendments ....................................................................................... 52 
12.5 Trial Registration ......................................................................................................................... 52 
13. Publication of Information ................................................................................................. 52 
14. Contact Information ........................................................................................................... 52 
15. References ............................................................................................................................ 53 
16. Appendix .............................................................................................................................. 58 
16.1 Abbreviations ............................................................................................................................... 58 
16.2 Modified Rankin Scale66    ........................................................................................................... 60 
16.3 National Institute of Health Stroke Scale67   .............................................................................. 61 
16.4 Barthel Index68  ............................................................................................................................ 70 
16.5 Glasgow Coma Scale69  ................................................................................................................ 71 
16.6 Stroke Impact Scale63  .................................................................................................................. 72 
 
 
 

 
 
 
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CLP 11899.B  
Protocol Synopsis  
Study Title: 
MIND: A Prospective, Multicenter Study of Artemis, a Minimally Invasive 
Neuro Evacuation Device, in the Removal of Intracerebral Hemorrhage 
Study Objective: The primary objective of this multicenter randomized controlled study is to 
compare the safety and efficacy of minimally invasive hematoma evacuation 
with the Artemis Neuro Evacuation Device to best medical management for the 
treatment of intracerebral hemorrhage (ICH). 
Study Design: 
This study will be a prospective, randomized, multi-center study that will enroll 
up to 500 patients at up to 50 sites globally. 
Indication: 
US/Canada: The Artemis Neuro Evacuation Device is used for the controlled 
aspiration of tissue and/or fluid during surgery of the Ventricular System or 
Cerebrum in conjunction with a Penumbra Aspiration Pump.  
 
The Penumbra Aspiration Pump is indicated as a vacuum source for the 
Penumbra Aspiration Systems. 
 
EU/ROW: The Artemis Neuro Evacuation Device is used for the controlled 
aspiration of tissue and/or fluid during surgery of the Ventricular System or 
Cerebrum for patients age 18 or older in conjunction with a Penumbra 
Aspiration Pump.  
 
The Penumbra Aspiration Pump is indicated as a vacuum source for the 
Penumbra Aspiration Systems. 
Patient 
Population: 
Patients with moderate-large volume supratentorial ICH who present within 24 
hours of symptom onset. 
Study Device: 
Artemis Neuro Evacuation Device 
Study Duration: 
It is anticipated enrollment will take approximately 4 years. Subjects will be in 
the study for approximately one year from enrollment to last follow-up.  
Follow-up: 
Subjects will undergo follow-up at 24 or 72 hours, 7 days, 30 days, 90 days, 
180 days, and 365 days.  
Inclusion 
Criteria: 
1. Patient age ≥ 18 and ≤ 80  
2. Supratentorial ICH of volume ≥ 20 and ≤ 80 cc (measured using A x B x 
C/2 method) 
3. Hemostasis as confirmed by no arterial spot sign (may perform additional 
scan(s) every 6 hours to demonstrate hemostasis)  
4. NIHSS ≥ 6 
5. GCS ≥ 5 and ≤ 15 
6. Historical mRS 0 or 1 
7. Symptom onset < 24 hours prior to initial CT/MR 
8. MIS must be initiated within 72 hours of ictus/bleed 

 
 
 
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CLP 11899.B  
Protocol Synopsis  
Study Title: 
MIND: A Prospective, Multicenter Study of Artemis, a Minimally Invasive 
Neuro Evacuation Device, in the Removal of Intracerebral Hemorrhage 
9. SBP must be < 180 mmHg and controlled at this level for at least 6 hours 
Exclusion 
Criteria: 
1. Imaging 
a. “Arterial Spot Sign” identified on final CTA indicating expanding 
hemorrhage  
b. Hemorrhagic lesion such as a vascular malformation (cavernous 
malformation, AVM etc.), aneurysm, and/or neoplasm 
c. Hemorrhagic conversion of an underlying ischemic stroke 
d. Infratentorial hemorrhage 
e. Primary thalamic ICH (where the center of the hemorrhage emulates 
from the thalamus) 
f. Associated intra-ventricular hemorrhage requiring treatment for IVH-
related mass effect or shift due to trapped ventricle (EVD for ICP 
management is allowed) 
g. Midbrain extension/involvement 
h. Absolute contraindication to CTA, conventional angiography, and MRA 
2. Coagulation Issues 
a. Absolute requirement for long-term anti-coagulation (e.g., mechanical 
valve replacement (bio-prostatic valve is permitted), high risk atrial 
fibrillation) 
b. Known hereditary or acquired hemorrhagic diathesis, coagulation factor 
deficiency 
c. Platelet count < 100 x 103 cells/mm3 or known platelet dysfunction 
d. INR > 1.4, elevated prothrombin time or activated partial 
thromboplastin time (aPTT), which cannot be corrected or otherwise 
accounted for (i.e., lupus anti-coagulant)  
e. Use of direct factor Xa inhibitors (e.g. apixaban, rivaroxaban, 
fondaparinux) within last 48 hours 
3. Patient Factors 
a. Traumatic ICH 
b. High risk atrial fibrillation (e.g., mitral stenosis with atrial fibrillation) 
and/or symptomatic carotid stenosis 
c. Requirement for emergent surgical decompression or uncontrolled ICP 
after EVD 
d. Unable to obtain consent per Institution Review Board/Ethics 
Committee policy 
e. Pregnancy or positive pregnancy test (either serum or urine). Women of 
child-bearing potential must have a negative pregnancy test prior to 
enrollment 
f. Severe active infection requiring treatment (e.g. sepsis or purulent 
wound) at the time of enrollment  
g. Renal failure indicated by creatinine > 2 mg/dL or undergoing dialysis 

 
 
 
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CLP 11899.B  
Protocol Synopsis  
Study Title: 
MIND: A Prospective, Multicenter Study of Artemis, a Minimally Invasive 
Neuro Evacuation Device, in the Removal of Intracerebral Hemorrhage 
h. Any comorbid disease or condition expected to compromise survival or 
ability to complete follow-up assessments through 365 days 
i. Based on investigator’s judgement, patient is unwilling or unable to 
comply with protocol follow up appointment schedule 
j. Active drug or alcohol use or dependence that, in the opinion of the site 
investigator would interfere with adherence to study requirements 
k. Currently participating in another interventional (drug, device, etc.) 
clinical trial. Patients in observational, natural history, and/or 
epidemiological studies not involving intervention are eligible 
Randomization 
Subjects will be randomized to either minimally invasive hematoma evacuation 
with the Artemis Neuro Evacuation Device with medical management (MIS 
group) or best medical management alone (2:1) (MM group). After a subject is 
randomized to a study arm they will be considered enrolled. Randomization 
will be balanced based upon presenting condition (Hemphill Score) and 
hemorrhage location (primarily lobar vs. primarily deep).  
Primary 
Endpoints: 
• Efficacy Endpoint: 180 day global disability assessed via the ordinal 
modified Rankin score (mRS) 
• Safety Endpoint: Rate of mortality at 30 days 
Secondary 
Efficacy 
Endpoints: 
• Weighted mRS at 180 days 
• mRS of ≤ 3 at 180 days 
• mRS of ≤ 2 at 180 days  
• mRS at 365 days 
• Stroke Impact Scale – Mobility at 180 days 
• Stroke Impact Scale – ADLs at 180 days 
• Stroke Impact Scale – Mobility at 365 days 
• Stroke Impact Scale – ADLs at 365 days 
• EQ-5D-5L at 180 days 
• EQ-5D-5L at 365 days 
• Length of hospital stay 
• Length of ICU stay 
• Length of procedure 
Primary 
Statistical 
Hypothesis 
The null hypothesis is that the cumulative odds ratio for mRS at 180 days in the 
MIS group compared to MM group is less than or equal to 1.  
The alternative hypothesis is that the cumulative odds ratio for mRS at 180 
days is greater than 1. 
Primary 
Statistical Test 
The final analysis is a logistic regression analysis of the ordinal 180 day mRS 
scores with scores of 5 and 6 treated as a single category. The primary efficacy 

 
 
 
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CLP 11899.B  
Protocol Synopsis  
Study Title: 
MIND: A Prospective, Multicenter Study of Artemis, a Minimally Invasive 
Neuro Evacuation Device, in the Removal of Intracerebral Hemorrhage 
endpoint is met if the overall treatment effect is positive at a one-sided alpha of 
0.02.    
Sample Size 
Based on simulations, a sample size of 500 has 81% power for a cumulative 
odds ratio of 1.7 with a one-sided alpha of 0.025. The minimum sample size is 
200 patients (133 MIS and 67 MM). 
 

 
 
 
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1. Introduction and Rationale 
Intracerebral hemorrhage (ICH) is the most common subtype of hemorrhagic stroke, 
accounting for 10 – 15% of all strokes and affecting between 10 and 30 people per 
100,000.1-3 The incidence of ICH is increasing, likely secondary to the increasing mean 
age of the population.4,5   
ICH is a devastating disease with the poorest prognosis of all stroke subtypes.6 The 
estimated mortality rate is 40% at 1 month, 50% at 1 year and more than 70% at 5 
years.3,7,8 The majority of survivors are dependent at follow-up.9  If there is a concomitant 
component of intraventricular hemorrhage and hydrocephalus, outcomes are even 
worse.10-13  
Due to the high intensity and the long duration of care required for patients, ICH is ranked 
amongst the most costly of all neurological diagnoses.14  Russell et al. reported that the 
average cost for patients experiencing mortality from their initial hemorrhage was greater 
than 16,500 US dollars (patients admitted between 1999 and 2002). These costs were 
much greater in survivors, increasing to more than 28,000 for the initial hospitalization, 
with an additional 16,000 incurred during the first year after discharge.14{Russell, 2006 
#3026}  A recent RCT of an Australian population provides additional forecasts for long-
term associated costs, with an annual estimate between 3 to 5 years at approximately 
$5,807, increasing to $7,607 at 10 years, and an overall lifetime cost of $54,956.15  
Despite extensive study, benefits from medical or surgical intervention are not well 
established and have not been consistently demonstrated to reduce mortality or improve 
outcomes in patients with ICH.  This is further compounded by the lack of evidence from 
efforts of neuroprotection.16{Lyden, 2007 #1604} This lack of progress is reflected by the 
mortality rate of ICH, which has been relatively stable for the past several decades.3,17   
Medical management consists of admission to an intensive care unit (ICU) or monitored 
stroke unit, airway assessment and management, control of hypertension, and assessment 
for, and reversal/correction of, any inherent or pharmacologically induced coagulopathy.  
The presence of hydrocephalus or elevated intracranial pressures, secondary to mass effect 
or concomitant intraventricular hemorrhage (IVH), may require emergent placement of a 
ventricular drainage catheter.  More pronounced mass effect or herniation may require a 
craniectomy/craniotomy for emergent evacuation of the hemorrhage and/or 
decompression.18,19    
Multiple randomized controlled trials of more aggressive medical management strategies 
as well as conventional surgical evacuation have failed to demonstrate an improvement in 
clinical outcomes or survival.13,18,20-25  
1.1 Randomized Trials of Medical Management of Intracranial Hemorrhage  
In the FAST Trial, 841 patients with ICH were randomized to receive placebo or 
one of two doses, 20 µg or 80 µg per kilogram of bodyweight, of recombinant 
factor VIIa (rFVIIa) within 4 hours of symptom onset.  Although the higher dose of 

 
 
 
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rFVIIa was associated with a significantly lower rate of hematoma expansion, this 
effect did not translate to an improvement in clinical outcomes or mortality.26  
Moreover, the increased incidence of thrombotic complications in the rFVIIa group 
did not account for the failure of the trial to demonstrate a clinical benefit.  
Similarly, two pilot trials of aggressive medical management of blood pressure, 
INTERACT and ATACH, did not demonstrate any benefit for survival or favorable 
clinical outcome when compared to more conservative medical management.20,27     
INTERACT did show a reduction in hematoma growth with aggressive BP 
management.20 A larger trial of aggressive blood pressure control, INTERACT II, 
failed to demonstrate a reduced rate of death or major disability with aggressive 
management, but did show a modest, but statistically significant,  improvement in 
the ordinal analysis of modified Rankin scores (mRS) for the intensive management 
group.28  
Trials of aggressive management of cerebral edema with mannitol have also 
failed.21,22,24    
1.2 Randomized Trials of Conventional Open Surgical Management of 
Intracranial Hemorrhage 
Two large randomized controlled trials of conventional open surgery for 
intracranial hemorrhage (Surgical Trial in Intracerebral Hemorrhage (STICH I and 
STICH II) have both demonstrated no beneficial effect from hematoma 
evacuation.13,23 In STICH I, early surgical management was compared to standard 
medical management in a series of 1033 patients with supratentorial ICH.  Three-
quarters of subjects in both arms of STICH I demonstrated poor clinical outcomes 
or died.  Subgroup analyses of the STICH I cohort indicated a potential benefit for 
those subjects with superficial ICH (within 1 cm of the cortical surface) without 
intra-ventricular extension.  On the basis of this observation, the STICH II trial was 
designed specifically to assess the effects of conventional surgical management in 
this group of subjects.  In STICH II, 601 patients with superficial hemorrhages were 
randomized between early surgery and conservative management with 59% of 
subjects in the surgical group and 61% of the subjects in the medical management 
groups had unfavorable outcomes.  A trend toward improved mortality at 6 months 
(18% in the early surgery group and 24% in the medical management group) failed 
to reach significance (p = 0.095).  
Taken together, this data provides strong evidence that the conventional open 
surgical management of intracerebral hemorrhage is not beneficial in patients with 
ICH who are not in need of emergent, life-saving decompression. 
1.3 Rationale for Study 
ICH is thought to induce neurological injury in a biphasic manner.29 The primary 
neurological injury is caused by the direct mechanical destruction of neurons by the 
original bleed.2 This form of injury is not treatable per se, with the exception 

 
 
 
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perhaps of medical interventions designed to reduce or eliminate hematoma early 
expansion from re-bleeding.  As discussed above, several medical interventions 
have been demonstrated to successfully limit hematoma growth, but none have been 
associated with a compelling clinical benefit.  
Secondary injury to the brain surrounding the hematoma has been theorized to be 
the sequelae of locally increased pressure resulting in reduced regional perfusion as 
well as a direct cytotoxic effect of blood breakdown products on adjacent brain 
tissue (hemotoxicity). 29 It is believed that this secondary injury is manifested as 
peri-hematomal edema (PHE) on imaging studies.30-33   
In patients with ICH undergoing serial CT studies over the course of several weeks, 
Zazulia et al. observed the progression of mass effect at two distinct time periods.  
Early exacerbation of mass effect (within 48 hours) was related to acute hematoma 
expansion.33  Later progression was the result of peri-hematomal cerebral edema, 
which occurred between 9 and 21 days after the original bleed.33  This delayed 
progression of edema and mass effect from days to weeks after ICH provides strong 
supportive clinical evidence of a secondary injury.  Other investigators have also 
observed that mass effect and cerebral edema persists longer after ICH than 
ischemic stroke, with mass effect lasting for up to one month in some cases.34-37   
Studies of regional perfusion in humans have largely failed to demonstrate 
significant regions of ischemia in the brain surrounding ICH.38,39  On the contrary, a 
wealth of pre-clinical evidence has shown that thrombin, hemoglobin, iron and 
other hemoglobin breakdown products have a significant potential for direct toxic 
effects upon brain tissue.40-42 
Theoretically, the early evacuation of blood products could alleviate local mass 
effect and improve regional perfusion, and, in addition, reduce the volume of blood 
products and substrate contributing to hemotoxicity, thus reducing or eliminating 
these potential mechanisms of secondary injury.  At the same time, the procedure 
would be best done in the least invasive manner possible as to avoid inducing 
additional injury to the brain.  
1.3.1 The Case for Minimally Invasive Hematoma Evacuation 
The failure of conventional surgical evacuation to improve outcomes in ICH has 
been attributed to the morbidity associated with the craniotomy and surgical 
approach.  Specifically, it has been proposed that the surgical approach to the 
hematoma may cause enough damage to surrounding brain to offset any potential 
benefits of surgery.42  Correspondingly, it is possible that the potential benefits of 
hematoma evacuation could be realized if the procedure could be performed 
through minimally invasive access.  
A large meta-analysis of surgical treatment strategies for ICH concluded that 
surgery could be beneficial in patients undergoing early surgery (within 8 hours), 
with moderately sized hemorrhages (20 – 50 cc), of moderate age (50 – 69 years) 

 
 
 
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and with moderate to severe clinical deficits (GCS 9 – 12).43  Incidentally, an 
evaluation of the contributing data sets indicates that a single study by Wang et 
al44 largely drove the clinical benefit in each of the cohorts.   
In the study by Wang et al44, 465 patients with moderate volume intracranial 
hemorrhage (ranging between 25 and 40 cc).  Patients were randomized to either 
medical management or minimally invasive craniopuncture therapy.  The 
craniopuncture procedure consisted of the CT-guided placement of a puncture 
needle into the hematoma.  Following the aspiration of hematoma fluid, a lysis 
fluid (containing urokinase) was injected under pressure into the hematoma.  The 
drainage needle was secured into position and allowed to drain for 3 – 5 days after 
placement.  Using this technique, the authors reported a significant improvement 
in clinical outcomes with 41% of the craniopuncture group and 63% of the 
medical management group being dependent (mRS > 2) at 90 days.44  
Kim et al45 performed a similar randomized trial in Korea, randomizing 387 
patients with small to moderate sized hemorrhages (average volume 23 cc, range 
10.4 – 30.0 cc) between MIS and medical management.  MIS was performed 
using an Archimedes screw placed under stereotactic guidance through a burr 
hole access.  They reported significant improvements in clinical outcomes as 
measured by both Barthel Index (90.9 vs. 62.4, p < 0.05) and modified Rankin 
Scale (1.2 vs. 3.0, p < 0.05) at 6 months.45  
This minimally invasive CT-guided craniopuncture technique is routinely 
practiced in China with over 150,000 patients undergoing this procedure 
yearly.44,46  Zhou et al46 reported a meta-analysis of 12 studies including 1955 
patients randomized between medical management and minimally invasive 
surgery.  These investigators reported robust reductions in both death (46% 
relative risk reduction) and death or dependence (47% relative risk reduction) at 
the end of follow-up in subjects undergoing MIS.46  Additionally, a meta-analysis 
by Yang et al. corroborates this finding, reporting a significant reduction in 
mortality or dependence for subjects treated with MIS versus medical 
management (OR 0.52, 95% CI 0.33 – 0.80, p = 0.003).  Conversely, craniotomy 
failed to demonstrate significant clinical outcome compared to conventional 
management (OR 0.72, 95% CI 0.42 – 1.22, p = 0.22).47   
Recently, two small pilot randomized controlled trials of MIS for ICH have been 
completed in the United States – The Minimally Invasive Surgery plus tPA for 
ICH Evacuation (MISTIE) and the Clot Lysis: Evaluating Accelerated Resolution 
of Intraventricular Hemorrhage (CLEAR IVH).48,49   
In MISTIE, 96 patients were randomized between conventional medical 
management (n = 42) and minimally invasive surgery (n = 54).  The minimally 
invasive surgical procedure consisted of the initial stereotactic placement of a 
sheath with manual aspiration of the hematoma followed by the placement of a 
flexible drainage catheter that was irrigated with tPA for up to four days.48 These 
investigators reported a significant reduction in perihematomal edema as well as 

 
 
 
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trends toward better clinical outcomes at 180 and 365 days.48,50  They also 
observed an improvement in mobility and independence in Activities of Daily 
Living (ADL) at follow-up, as well as a reduction in length of stay and healthcare 
expenditures.  Moreover, the degree of improvement in clinical outcome appeared 
to be directly related to the volume of hemorrhage remaining at the end of the 
treatment, with those subjects with < 10 cc’s of residual hemorrhage having the 
best outcomes.  Unfortunately, only a minority of subjects in the MISTIE study 
achieved this level of residual hematoma volume.  Moreover, it often took several 
days of treatment before this level of hematoma reduction was reached.  
In the CLEAR IVH trial, patients with small supratentorial hemorrhages and large 
associated intraventricular hemorrhages requiring ventricular drainage were 
randomized between saline infusion and intrathecal tPA (IT-tPA) through a 
ventricular drain.49  These investigators observed that IT-tPA infusion increased 
the rate at which the IVH cleared.  Moreover, subjects with more rapid and 
complete clearance of IVH demonstrated a more rapid and complete improvement 
in neurological status.  Although a robust signal for a beneficial effect was 
observed in the IT-tPA group overall, 6 of 26 subjects (23%) in this cohort 
experienced symptomatic re-hemorrhage, with three requiring a craniotomy for 
management.  This symptomatic re-hemorrhage rate was considerably higher than 
that observed for irrigation of parenchymal drainage catheters in MISTIE II.  
Moreover, it required an average of 10 days to achieve adequate clearance of IVH 
in the IT-tPA group.  
Recently, data regarding the safety and efficacy of intrathecal tPA in the setting of 
IVH became available for the CLEAR III trial.51  In this pivotal trial, patients with 
small or no ICH (≤ 30 cm3) with associated IVH requiring an EVD were 
randomized to either placebo (normal saline) or r-tPA (1.0 mg) q8 hours (for ≤ 12 
doses) infused through the EVD.  The primary outcome measure was mRS ≤ 3 at 
180 days.  The trial demonstrated that although intraventricular tPA had no effect 
on clinical outcomes in the entire cohort, there was a significant (11%, p = 0.006) 
reduction in mortality at 180 days.  Moreover, safety parameters regarding serious 
adverse events were more favorable for the tPA cohort (46% vs. 60%, p = 0.002).  
In the subset of subjects with IVH volumes > 20 cm3, intraventricular-tPA 
significantly improved rates of good functional outcome (mRS score 0 – 3).  More 
efficient and more complete (> 80%) removal of IVH were directly correlated 
with patient outcomes.  However, most subjects (≈ 70%) did not achieve a 
substantial (> 80%) reduction in IVH with the CLEAR III tPA infusion 
technique.51,52  
Thus, the existing clinical evidence provides support to the pre-clinical data 
suggesting that the evacuation of blood products after ICH could prevent 
secondary injury and improve outcomes.  However, the current techniques are 
relatively rudimentary and have several potentially important shortcomings. 
First, it requires days to achieve an adequate evacuation of blood products using 
the craniopuncture and catheter drainage techniques.  Optimally, the removal of 

 
 
 
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blood products should be accomplished as efficiently as is feasible and safe to 
limit or eliminate the potential for secondary injury related to local hypoperfusion 
and/or hemotoxicity.  Second, the requirement for an indwelling drainage catheter 
with periodic access for irrigation presents the potential for infection and also is 
labor and resource intensive.  This irrigation is typically performed within an 
intensive care unit setting.  In addition, patients undergoing tPA infusions require 
multiple serial scans to assess the reduction in hematoma volume and to survey 
for re-bleeding.  Finally, there is some risk of inducing re-bleeding with the 
infusion of tPA after surgery.  
1.3.2 The Case for Minimally Invasive Hematoma Evacuation using a 
Mechanical Device 
Several mechanical techniques have been devised for the minimally invasive 
evacuation of intracranial hemorrhage.  A primarily mechanical approach offers 
several potential advantages.  First, an effective mechanical approach provides a 
means by which to achieve an immediate, efficient, and predictable reduction in 
hemorrhage volume.  This is particularly true if the technique is performed with 
direct visualization and/or periodic active monitoring with cross-sectional CT 
imaging and/or ultrasound.  It stands to reason that an immediate and substantial 
reduction in blood product volume may better reduce the cumulative secondary 
injury than would a gradual reduction over several days.  Second, with some 
purely mechanical approaches, no post-procedural drainage catheter is required, 
eliminating the resources required for the maintenance of the catheter as well as 
the potential for infection or additional hemorrhage associated with catheter 
manipulation.  Third, the avoidance of catheter irrigation with tPA reduces the 
potential for re-hemorrhage secondary to the local thrombolytic effect.  
1.3.2.1 Intra-operative CT-guided Endoscopic Surgery for ICH (ICES) 
The ICES technique involves the stereotactic placement of an endoscopic 
sheath into the hematoma.  The hematoma is then evacuated using suction 
and irrigation from two pre-specified depths.  The endoscope is then used to 
make an assessment of the volume of residual hemorrhage as well as to 
assess, and potentially control, any active intracranial hemorrhage using 
cautery.53  In a small, single-center series of six patients, the operators were 
able to achieve an 80% reduction in hemorrhage volume and a 60% 
reduction in midline shift.  In a second small, single-center trial, ten patients 
were randomized between the ICES technique and medical management.  In 
the ICES group (n = 6), the operators achieved an 80% reduction in 
hematoma volume, while the medical management group demonstrated an 
80% enlargement, both over a 24-hour period after treatment allocation.54   
The trial was ultimately halted due to slow enrollment and the recognition 
from the operators that the technique required optimization within the 
context of a single-arm study prior to the performance of a randomized trial. 
Recently, a larger trial by Vespa et al55 randomized 14 patients to receive 
ICES and 4 to receive medical management.  The control arm of the 

 
 
 
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MISTIE trial was also used to analyze the trial outcome.  Results 
demonstrated a 71.2% reduction in ICH immediately post treatment; at 72 
hours, the reduction in ICH volume was significant (21.1 cm3, p = 0.0002) 
in the ICES group as compared to the medical group.  Despite being 
underpowered to yield significant clinical outcome, there was a trend 
towards good neurological outcome (mRS ≤ 3) for the ICES cohort (42.9% 
vs. 23.7%, p = 0.19).  Notably, the trial demonstrated the feasibility of ICES 
as a safe and effective modality with a potential to yield good clinical 
outcome.55   
The MISTIE II trial evaluated safety and efficacy of hematoma evacuation 
after ICH using minimally invasive surgery and rt-PA in ICH evacuation in 
2 stages (dose finding occurred in 2005-2009 and safety analysis during 
2009-2012).72  There were seventy-nine surgical subjects and 39 medical 
subjects with minimally invasive surgery and rt-PA in ICH evacuation for 
mean hematoma volume; 69 subjects in the surgery cohort underwent 
surgical aspiration and rt-PA and 10 subjects underwent surgical aspiration 
alone.  The reduction in edema was 5.6 in the surgical arm and -11.4 in the 
medical arm (P<0.001) and the authors concluded that the finding was 
consistent with the hypothesis that hematoma evacuation would lead to a 
significant reduction in edema volume. 
The MISTIE III Trial was a randomized, blinded endpoint, open label, phase 
III study that was conducted in the U.S., Canada, Europe, Asia, and 
Australia (Hanley, 2019)70.  There were 78 hospitals that enrolled and 
treated 499 patients with an intracerebral hemorrhage (n=250 MISTIE arm 
and n=249 standard medical arm).  The MISTIE arm subjects were treated 
with image-guided minimally invasive catheter evacuation followed by 
thrombolysis.  
The main objective was to asses if minimally invasive surgery (MIS) 
followed by thrombolytic irrigation of the catheterized intracerebral 
hemorrhagic clot was safe and could improve functional outcomes at 365 
days after a stroke.  The primary efficacy outcome was good functional 
outcome (mRs score 0-3) at 365 days after a stroke and the safety outcomes 
were all-cause mortality at 30 days, procedure related mortality at 7 days, 
bacterial brain infection at 30 days, and symptomatic bleeding within 72 
hours from last dose.  The trial used an imaging core lab and a Data Safety 
Monitoring Board (DSMB) reviewed clinical safety data. 
 
The trial arms were well matched, but there was a higher number of subjects 
actively taking anticoagulants at the time of enrollment in the MISTIE arm 
(10%) compared to the SOC arm (4%).  For the primary outcome of the 
mITT set after adjusting for baseline variables, 45% of subjects (n=249) in 
the MISTIE arm achieved an mRS score of 0-3 at 365 days compared to 
41% in the SOC arm (n=240).  The MISTIE arm had fewer subjects that 

 
 
 
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died within 7 days compared to the SOC arm (1% vs 4%, P=0.018, 
respectively) and also at 30 days (9% vs 15%, P=0.066), respectively.  
There were 2 bacterial brain infections with 30 days in the MISTIE arm and 
none in the SOC arm.  The MISTIE arm and SOC arm had comparable 
symptomatic brain bleeds with 72 hours from the last thrombolytic dose (2% 
vs 1%, P=0.325).  However, asymptomatic brain bleeds within 72 hours 
from the last thrombolytic dose was significantly higher in the MISTIE arm.  
There were fewer serious adverse events reported in the MISTIE arm 
compared to the SOC arm (126 events vs 142, P=0.012), which was 
statistically significant.  The authors reported that an exploratory analysis of 
clot removal did show an association between extent of removal and a lower 
mRS score (0-3), possibly due to the benefit of the procedure or due to 
unmeasured confounding effects.  Furthermore, the authors concluded that 
there were few negative consequences to MISTIE, and it was safe with 
regards to serious bleeding and infection. The procedural risks were also 
reported as comparable between the two arms. 
 
Another analysis of the MISTIE III data was published (Awad et al.2019) to 
examine results of a multivariate and univariate model to assess hematoma 
evacuation efficacy in relation to mRS scores of 0-3.71  Using a linear spline 
model, the authors determined that a reduction of ICH hematoma volume of 
< 15 mL correlated with a good functional outcome of mRS 0-3 (OR 0.90, 
95% CI 0.85-0.96, p= 0.002).  The results indicated that a reduction beyond 
the 15 mL threshold increased the chance of having a good outcome by 10% 
per mL of hematoma removed.  The reduction of hematoma volume by 
>70% increased the likelihood to achieve an mRS 0-3 score; each additional 
mL removed beyond 70% translated to a 6% improvement to achieve a good 
outcome for mRS 0-3 (OR 1.06, 95% CI 1.02-1.10, p=0.002).  End of 
treatment ICH volume < 30 mL also had a significant better survival 
outcome (OR 5.545, CI 2.362-13.019, p<0.001).  At ≤ 30 mL end of 
treatment ICH volume, or >53% volume reduction, a mortality benefit was 
observed.  Initial hematoma volume, history of hypertension, irregular-
shaped hematoma, number of alteplase doses given, surgical protocol 
deviations, and catheter manipulation problems were significant 
factors in failing to achieve ≤15mL goal evacuation.  The analysis was 
significant, as it was the first report of thresholds for reduction of ICH 
volume correlated with mortality and functional outcomes. 
1.4 Conclusions 
Intracranial hemorrhage is a devastating disease associated with poor clinical 
outcomes.  To date, no surgical or medical therapy has been demonstrated to 
improve outcomes in these patients.  Of all the strategies tested, the most 
encouraging data exist for minimally invasive strategies employed to achieve a 
reduction in hemorrhage volume.  Initial data derived from preliminary studies of 
thrombolytic-assisted catheter drainage have been encouraging, but there are 

 
 
 
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significant potential shortcomings of this technique compared to the purely 
mechanical approach with the Artemis Neuro Evacuation Device (Artemis Device).  
Early experience with the Apollo/Artemis in regards to its application to remove 
parenchymal hemorrhages has evolved.  As such, now that the technical approach 
has matured, it is necessary to proceed with a pivotal randomized controlled trial to 
assess the potential for clinical benefit and safety of MIS with the Artemis Device 
in patients with supratentorial ICH. 
2. The Artemis Neuro Evacuation Device 
A successor to the Apollo System, the Artemis Device is a surgical instrument designed to 
aid a physician in the removal of tissue and/or fluid during image-guided neurosurgery.  
The Artemis Device has two functions.  These functions are control and transfer of 
aspiration and generation of rotational energy.  Aspiration is generated by a Penumbra 
Aspiration Pump, which the Artemis Device connects to through flexible tubing.  The 
Artemis Device has a rigid cannula containing a wire to facilitate removing tissue and/or 
fluid with the assistance of rotational energy and aspiration.  The Artemis cannula fits 
through the working channels of commercially available neuroendoscopes (e.g. Lotta, 
Karl Storz, Tuttlington, Germany) such that clot evacuation can be performed under direct 
visualization.56  The technique is very similar to the ICES technique in that a sheath is 
placed within the hematoma and evacuation is typically performed under direct 
endoscopic visualization.  In some settings, periodic evaluation of the remaining 
hematoma is performed using intra-procedural CT or ultrasound.56  The method of action 
of removal is first vacuum aspiration, which draws the tissue and/or fluid into the lumen 
of the Artemis cannula.  Next, the wire inside the lumen of the Artemis cannula is rotated, 
facilitating movement of any tissue and/or fluid that may otherwise clog the cannula 
lumen. 
The conceptual principles of operation remain the same for the Artemis Neuro Evacuation 
Device and the Apollo System, both of which are used for the controlled aspiration of 
tissue and/or fluid removal. 
The Artemis Device utilizes rotational energy, rather than vibrational energy used for the 
Apollo System, to prevent clogging of tissue and/or fluid aspirated into the Artemis 
cannula.  The helical wire prevents the Artemis cannula from clogging by interacting with 
the aspirated tissue and/or fluid throughout the entire length of the cannula.  The electrical 
power to rotate the wire in the Artemis cannula is provided by a battery which drives a 
motor, both of which are contained in the disposable handle. 
In an initial multi-center, retrospective series of 29 ICH patients undergoing treatment 
with the Apollo System, an average reduction in hemorrhage volume of 54% was 
achieved, with a reduction of the hemorrhage volume to < 10 cm3 in 48% of subjects 
treated.  As opposed to the ICES technique, in most cases, no drainage catheters were 
placed following the initial evacuation.56 
Thus, the Artemis Device potentially provides a means by which to efficiently and reliably 
achieve a minimally invasive, mechanical evacuation of intracranial hemorrhage under 

 
 
 
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direct visualization and control using a neuroendoscope without the requirement for 
subsequent catheter placement and thrombolytic irrigation. 
The Apollo System received FDA clearance for the controlled aspiration of tissue and/or 
fluid during surgery of the ventricular system or cerebrum in March 17, 2016 and CE 
marking in May 10, 2016 and is commercially available in the United States and 
throughout Europe.  The Artemis Neuro Evacuation Device received FDA clearance 
(K171332) on August 14, 2017. 
Figure 1:  Image of the Artemis Neuro Evacuation Device cannula at Site of Bleed 
 
3. Risk Analysis 
The overall risks associated with the procedure depend on a number of factors including, 
but not limited to, the device, anesthesia, disease condition and medical management.  The 
primary risks to subjects in this study are associated with the minimally invasive surgical 
(MIS) procedure and the associated general anesthetic.  Imaging performed throughout the 
course of the study, while specified in the protocol, falls within the standard of care for the 
initial evaluation and follow-up of patients with intracranial hemorrhage.  The MIS 
procedure is performed in a manner which is similar to that of other neuroendoscopic 
procedures and the associated risks are similar.  In brief (see Section 6.7 for a detailed 
description of the procedure), the MIS procedure involves the creation of a burr hole/1 – 2 
cm craniectomy and dural incision.  An endoscopic sheath is then placed through the 
access site into the hematoma under imaging control using neuronavigation.  Under 
endoscopic guidance, the hemorrhage is evacuated using the Artemis Device.  Following 
the evacuation, the endoscope and Artemis Device are removed.  Intraoperative CT 
imaging is performed to assess the remaining hemorrhage volume and to assess for 
immediate procedural complications.  Ultrasound may also be used during the procedure 
to evaluate removal of the hematoma.  Based on the intra-operative CT imaging, either an 
additional pass(es) is made or the procedure is terminated.  Following the procedure, all 
equipment is removed and the cranial access is closed in a standard manner.  
The potential clinical risks that may be associated with the use of Artemis Device or with 
the procedure include, but may not be limited to:  
 

 
 
 
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Hematoma expansion 
Increased blood pressure  
Fever 
Infections 
Headaches 
Seizures  
Vomiting 
Intraventricular hemorrhage  
Hyperglycemia  
Hydrocephalus 
Edema  
Thromboembolic events  
Re-bleeding  
Decreased consciousness  
Death 
Craniotomy  
Bleeding 
Unintended Removal of Tissue leading to 
Neurological and/or sensory deficit 
The complications particularly related to the procedure include bleeding, infection, or 
damage to surrounding structures during the creation of the cranial access or placement of 
the sheath.  During evacuation of the hemorrhage with the Artemis Device, there is the 
possibility of inducing or encountering an additional hemorrhage in the operative bed.  In 
a retrospective multicenter study of the Apollo procedure for the treatment of ICH, re-
bleeding was encountered in 2 of 29 subjects (6.9%).56  There may be residual fluid or 
blood requiring additional surgery in the future. 
The risk related to the general anesthetic in this patient population is estimated to be 
approximately 1 – 5% for major morbidity and mortality (e.g. airway management issues, 
aspiration, hypotension or drug reaction), given that their American Stroke Association 
score would typically be 4 or 4e in this category of patients.57,58  A thorough risk analysis 
was performed as part of design control recommendations of the Quality System 
Regulation (21 CFR 820). 
Best medical management (MM) will be provided as specified in the AHA/ESO 
guidelines.18,59  As such, for subjects randomized to the MM arm of the study, there is no 
additional risk.  With the natural history of ICH/IVH and standard of care, there are 
expected medical events, or expected adverse experiences, that are listed below.  Since 
these medical events are expected in the disease process or after MM, the events are thus 
expected to occur in any patients with the disease irrespective of the treatment arm. Best 
medical management (MM) will be provided as specified in the AHA/ESO guidelines.19,60 
As such, for subjects randomized the MM only arm of the study, there is no additional 
risk.  
EXPECTED EVENTS  
Nervous System 
Other Systems 
Cerebral Edema and Mass Effect 
Acute Kidney Injury  
Brain Stem Compression 
Acute Respiratory Distress Syndrome 
Brain Herniation 
Aspiration 
Brain Re-bleeding near Initial Hemorrhage Site 
Catheter-related vascular infections 
Catheter Tract Bleeding/Hemorrhage Enlargement 
Deep Vein Thrombosis 
Cerebral Infarction 
Dysphagia 
Cerebritis 
Fever/Hyperthermia 

 
 
 
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Coma 
Hyponatremia 
Death 
Hypoxia 
Decreased Level of Consciousness 
Hypercapnia 
Delirium 
Hyperglycemia/Hypoglycemia 
Diaschisis 
Hypertension (Induced or Not Induced) 
Elevated ICP 
Hypotension (Induced or Not Induced) 
Headache 
Impaired Nutritional Status 
Hydrocephalus 
Infectious Complications 
Intracranial Abscess 
Nausea 
Meningitis (Bacterial or Non-Bacterial) 
Vomiting 
Perihematomal Ischemia 
Pericarditis 
Seizures 
Pulmonary Edema 
Ventriculitis (Bacterial or Non-Bacterial) 
Pneumonia (including Ventilator-Associated) 
 
Pulmonary Embolus 
 
Sepsis/Bacteremia 
 
Spontaneous Bleeding from Non-Cerebral Sites 
 
Thromboembolic Complications 
 
Urinary Tract Infections 
  
Vascular Injury/Puncture Site Bleeding 
Medical Management of ICH should include18: 
 
• Hemostasis and Coagulopathy, Antiplatelet Agents, and Thromboembolic 
Prophylaxis:  Patients with ICH should have intermittent pneumatic compression for 
prevention of venous thromboembolism beginning the day of hospital admission. 
• Blood Pressure Management:  Early BP reduction with an SBP target of 140 mmHg 
for patients with ICH presenting with an SBP between 150 and 220 mmHg and without 
any contraindication to acute BP treatment.  For patients with ICH presenting with an 
SBP > 220 mmHg, aggressive BP reduction with continuous intravenous infusion and 
frequent BP monitoring may be reasonable.  
• General Monitoring and Nursing Care:  Initial monitoring and management of 
patients with ICH should take place in an intensive care unit or dedicated stroke unit 
with physician and nursing neuroscience acute care expertise. 
• Glucose Management:  Glucose should be monitored.  Both hyperglycemia and 
hypoglycemia should be avoided. 
• Seizures and Antiseizure Drugs:  Clinical seizures should be treated with antiseizure 
drugs.  Patients with a change in mental status who are found to have electrographic 
seizures on electroencephalography should be treated with antiseizure drugs. 
• Management of Medical Complications:  A formal screening procedure for 
dysphagia should be performed in all patients before the initiation of oral intake to 
reduce the risk for pneumonia. 

 
 
 
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• Prevention of Recurrent ICH:  BP should be controlled in all patients with ICH.  
Measures to control BP should begin immediately after ICH onset. 
• Rehabilitation and Recovery:  Given the potentially serious nature and complex 
pattern of evolving disability and the increasing evidence for efficacy, it is 
recommended that all patients with ICH have access to multidisciplinary rehabilitation. 
In order to minimize risks to subjects enrolled into the clinical study, Investigators will be 
qualified in accordance with FDA requirements and Good Clinical Practice.  Investigators 
using the devices will be trained on proper use of the Artemis Device in accordance with 
Section 8.1 herein prior to initiation of treatment at each facility.  Patients will be carefully 
evaluated before treatment to ensure that the treatment with the Artemis Device is 
appropriate.  During treatment, the procedure should be performed in an operating room 
(OR) or a procedure room with appropriate resources for emergent intervention should 
complications arise.  All treating facilities should conform to national guidelines, and the 
treating physician should be experienced in treating patients presenting with this 
condition. 
Subjects will be carefully monitored during the procedure and the follow-up period.  
Clinical study participants will be routinely questioned to confirm whether adverse 
events/effects have occurred at study visits.  The physician should examine and perform 
various diagnostic tests before, during, and after the procedure with appropriate long-term 
follow-up. 
The anticipated risks will be monitored during the study for changes in event rates.  On-
going monitoring of adverse events, serious adverse events, and device malfunctions will 
be conducted during the study.  A Clinical Events Committee (CEC) will adjudicate pre-
defined AE/SAEs for causality and attribution.  A Data Safety Monitoring Board (DSMB) 
will monitor the overall safety during the clinical study.  Penumbra, Inc. or its 
representatives will continue to monitor the complaints and report them as mandated by 
FDA or other national agencies. 
4. Study Overview 
The primary aim of minimally invasive surgery (MIS) for supratentorial intracranial 
hemorrhage is to achieve an atraumatic evacuation of blood products from the brain to 
prevent the secondary injury that occurs after the initial bleed.  To date, several pilot 
studies and a small Phase II feasibility trial have suggested that MIS with catheter 
mediated thrombolytic irrigation may be associated with an improvement in clinical 
outcomes in ICH.44,48,50,54,60-62  Currently no prospective study exists to evaluate the 
efficacy of MIS with the Artemis Device for this purpose.  The purpose of this pivotal 
randomized study is to demonstrate the efficacy of MIS with the Artemis Device to 
improve outcomes in patients with small to moderate volume supratentorial ICH. 
4.1 Study Design 
This is a prospective, multicenter randomized study comparing MIS with MM (MIS 
group) with MM alone in patients with supratentorial intracerebral hemorrhages.  

 
 
 
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MM will be determined by practice standards utilized in the operator’s region of 
practice and following the existing AHA/ESO guidelines (as above).  Patients will 
be enrolled who meet the inclusion and exclusion criteria, with consent to 
participate, and are randomized to either MIS or MM.  Subjects will be randomly 
assigned by a central web-based system in a 2:1 manner to treatment with MIS or 
MM.  Data for each subject will be collected at the time of enrollment and 
treatment, and at subsequent follow-up visits. 
4.2 Study Objectives/Endpoints 
4.2.1 Primary Endpoints 
The primary objective is to demonstrate the efficacy of MIS in patients with 
supratentorial intracranial hemorrhage to improve clinical outcomes when 
compared with best medical therapy with respect to the endpoints defined as: 
• Efficacy Endpoint: 180 day global disability assessed via the ordinal modified 
Rankin score (mRS) 
• Safety Endpoint:  Rate of mortality at 30 days 
4.2.2 Secondary Endpoints 
• Weighted mRS at 180 days 
• mRS of ≤ 3 at 180 days 
• mRS of ≤ 2 at 180 days 
• mRS at 365 days 
• Stroke Impact Scale – Mobility at 180 days 
• Stroke Impact Scale – ADLs at 180 days 
• Stroke Impact Scale – Mobility at 365 days 
• Stroke Impact Scale – ADLs at 365 days 
• EQ-5D-5L at 180 days 
• EQ-5D-5L at 365 days 
• Length of hospital stay 
• Length of ICU stay 
• Length of procedure 
4.3 Method of Randomization 
Randomization takes place centrally through a commercially available Interactive 
Web Response System (IWRS).  Randomization will occur in a 2:1 ratio to either 
MIS or MM.  The treatment allocation will be balanced by Hemphill Score (0 – 2, 3 
– 4) and hemorrhage location (primarily lobar, primarily deep).  Once a patient is 
determined to meet all study eligibility criteria, the Investigator (or authorized team 
member) obtains the treatment assignment for that subject.  Crossover is not 
permitted after randomization.  Once a subject is randomized, the subject is 

 
 
 
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considered enrolled in the study and that subject must be followed through to the 
end of study or to subject’s termination of consent. 
4.4 Blinding 
The protocol is designed to have open label treatment assignment.  The Penumbra, 
Inc. clinical team, the Investigator, site study personnel, and the subject will not be 
blinded to each subject's randomized treatment group throughout the course of the 
study.  Each site will designate one or more individual(s) to perform the blinded 
mRS assessment at 180 days.  The blinded evaluator(s) will be identified on the 
Delegation of Authority Log and shall not perform data entry or any other tasks that 
would reveal the study arm assignment of subjects.  Due to the nature of the 
procedure, subjects will be provided with a hat at the 180 day mRS assessment to 
prevent the blinded assessor from seeing a scar.  If the blind is broken for any 
reason, this will be documented on the case report forms.  The blinded evaluator 
who performs the mRS assessment will be instructed to follow a scripted interview 
to control for potential bias. 
5. Study Population 
5.1 Inclusion Criteria 
1. Patient age ≥ 18 and ≤ 80 
2. Supratentorial ICH of volume ≥ 20 and < 80 cc (measured using A x B x C/2 
method) 
3. Hemostasis as confirmed by no arterial spot sign (may perform additional 
scan(s) every 6 hours to demonstrate hemostasis) 
4. NIHSS ≥ 6  
5. GCS ≥ 5 and ≤ 15 
6. Historical mRS 0 or 1 
7. Symptom onset < 24 hours prior to initial CT/MR 
8. MIS must be initiated within 72 hours of ictus/bleed 
9. SBP must be < 180 mmHg and controlled at this level for at least 6 hours 
5.2 Exclusion Criteria 
1. Imaging 
a. “Arterial Spot Sign” identified on final CTA indicating expanding 
hemorrhage  
b. Hemorrhagic lesion such as a vascular malformation (cavernous 
malformation, AVM etc), aneurysm, and/or neoplasm 
c. Hemorrhagic conversion of an underlying ischemic stroke 
d. Infratentorial hemorrhage 
e. Primary thalamic ICH (where the center of the hemorrhage emulates from 
the thalamus) 

 
 
 
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f. Associated intra-ventricular hemorrhage requiring treatment for IVH-related 
mass effect or shift due to trapped ventricle (EVD for ICP management is 
allowed) 
g. Midbrain extension/involvement 
h. Absolute contraindication to CTA, conventional angiography, and MRA 
2. Coagulation Issues 
a. Absolute requirement for long-term anti-coagulation (e.g., mechanical valve 
replacement (bio-prostatic valve is permitted), high risk atrial fibrillation) 
b. Known hereditary or acquired hemorrhagic diathesis, coagulation factor 
deficiency 
c. Platelet count < 100 x 103 cells/mm3 or known platelet dysfunction 
d. INR > 1.4, elevated prothrombin time or activated partial thromboplastin 
time (aPTT), which cannot be corrected or otherwise accounted for (i.e., 
lupus anti-coagulant) 
e. Use of direct factor Xa inhibitors (e.g. apixaban, rivaroxaban, fondaparinux) 
within last 48 hours 
3. Patient Factors 
a. Traumatic ICH 
b. High risk atrial fibrillation (e.g., mitral stenosis with atrial fibrillation) 
and/or symptomatic carotid stenosis 
c. Requirement for emergent surgical decompression or uncontrolled ICP after 
EVD 
d. Unable to obtain consent per Institution Review Board/Ethics Committee 
policy 
e. Pregnancy, or positive pregnancy test (either serum or urine).  Women of 
child-bearing potential must have a negative pregnancy test prior to 
enrollment 
f. Severe active infection requiring treatment (e.g. sepsis, purulent wound) at 
the time of enrollment 
g. Renal failure indicated by creatinine > 2 mg/dL or undergoing dialysis 
h. Any comorbid disease or condition expected to compromise survival or 
ability to complete follow-up assessments through 365 days 
i. Based on Investigator’s judgement, patient is unwilling or unable to comply 
with protocol follow up appointment schedule 
j. Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements 
k. Currently participating in another interventional (drug, device, etc.) clinical 
trial.  Patients in observational, natural history, and/or epidemiological 
studies not involving intervention are eligible 
6. Study Procedures 
6.1 Overview of Study Flow 

 
 
 
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All sites will keep a screen failure log of all ICH patients presenting within 24 hours 
of symptom onset but who are not randomized into the study.  Reason(s) for 
exclusion will be recorded.  Screening information will be reported in an electronic 
data capture system (EDC).  Recruitment rates will be tracked over time for each 
site.  The actual recruitment rates as well as potential recruitment rates will be 
useful for planning further clinical trials and determining the potential impact of the 
therapy. 
Figure 2: Study Flow 
Final Screening to Confirm Elgibility
(e.g. imaging to demonstrate homeostasis, pregnancy test)
Pre-Screening
(e.g. medical chart review)
Informed Consent
Meets Inclusion/Exclusion Criteria
Initial Screening/Baseline
(e.g. imaging, neurological exams)
MIS* + Medical 
Management
24 hr Post 
Procedure FU  
± 12 hrs
Discharge and/or 7 
day FU 
± 1day
30 day FU
 ± 14 days
90 day FU 
± 14 days
365 day FU/ 
Study Exit 
± 35 days
180 day FU 
± 14 days
Primarily Lobar + 
Hemphill 0-2
Primarily Lobar + 
Hemphill 3-4
Primarily Deep + 
Hemphill 0-2
Primarily Deep + 
Hemphill 3-4
Medical 
Management
72 hr Post 
Randomization FU 
 ± 24 hrs
Discharge and/or 7 
day FU 
± 1day
30 day FU
 ± 14 days
90 day FU 
± 14 days
365 day FU/ 
Study Exit 
± 35 days
180 day FU 
± 14 days
*Within 72 hrs Ictus
MIS* + Medical 
Management
24 hr Post 
Procedure FU  
± 12 hrs
Discharge and/or 7 
day FU 
± 1day
30 day FU
 ± 14 days
90 day FU 
± 14 days
365 day FU/ 
Study Exit 
± 35 days
180 day FU 
± 14 days
Medical 
Management
72 hr Post 
Randomization FU 
 ± 24 hrs
Discharge and/or 7 
day FU 
± 1day
30 day FU
 ± 14 days
90 day FU 
± 14 days
365 day FU/ 
Study Exit 
± 35 days
180 day FU 
± 14 days
MIS* + Medical 
Management
24 hr Post 
Procedure FU  
± 12 hrs
Discharge and/or 7 
day FU 
± 1day
30 day FU
 ± 14 days
90 day FU 
± 14 days
365 day FU/ 
Study Exit 
± 35 days
180 day FU 
± 14 days
Medical 
Management
72 hr Post 
Randomization FU 
 ± 24 hrs
Discharge and/or 7 
day FU 
± 1day
30 day FU
 ± 14 days
90 day FU 
± 14 days
365 day FU/ 
Study Exit 
± 35 days
180 day FU 
± 14 days
MIS* + Medical 
Management
24 hr Post 
Procedure FU  
± 12 hrs
Discharge and/or 7 
day FU 
± 1day
30 day FU
 ± 14 days
90 day FU 
± 14 days
365 day FU/ 
Study Exit 
± 35 days
180 day FU 
± 14 days
Medical 
Management
72 hr Post 
Randomization FU 
 ± 24 hrs
Discharge and/or 7 
day FU 
± 1day
30 day FU
 ± 14 days
90 day FU 
± 14 days
365 day FU/ 
Study Exit 
± 35 days
180 day FU 
± 14 days
2:1 Randomization
2:1 Randomization
2:1 Randomization
2:1 Randomization
 
6.2 Study Visits 
Subjects enrolled in this study will follow the visit schedule below and will 
continue to receive standard of care treatment at each follow up visit. 
• Initial Screening/Baseline 
• Final Screening 
• Treatment Procedure (if randomized to MIS) 
• Post procedure (within 24 (± 12) hours, MIS subjects ) or 72 (± 24, MM) hours 
after presentation 
• 7 days post-enrollment or discharge (whichever comes first) 
• Discharge (if beyond 7 days) 
• 1 month (defined as 30 days) follow-up (± 14 days) 
• 3 month (defined as 90 days) follow-up (± 14 days) 

 
 
 
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• 6 month (defined as 180 days) follow-up (± 21 days) 
• 12 month (defined as 365 days) follow-up (± 35 days) 
6.3 Recruitment 
The target population are patients ≥ 18 and ≤ 80 years of age who have a diagnosis 
of spontaneous, non-traumatic, intracerebral hemorrhage (ICH) ranging ≥ 20 and < 
80 cc, with an associated significant neurological deficit (NIHSS ≥ 6) who do not 
require emergent open surgical decompression related to uncontrolled intracranial 
pressure or mass effect. 
Potential study subjects will be identified by the study team at each site to 
determine eligibility and obtain consent.  The study allows for enrollment up to 500 
subjects at up to 50 sites globally. 
6.4 Screening and Baseline Evaluation 
The subject should be clinically evaluated in the same manner as any patient with 
non-traumatic spontaneous intra-parenchymal hemorrhage which includes medical 
history screened, available clinical/neurological exams (focused exam, NIHSS, 
GCS, historical mRS and Barthel Index) obtained, laboratory work, and imaging 
information per institutional standard of care.  Selected concomitant medication and 
standard of care lab values will be recorded. 
Patients will be screened against study eligibility criteria during standard clinical 
practice.  A signed study-specific Institutional Review Board (IRB)/Ethics 
Committee (EC) approved informed consent form (ICF) must be obtained before 
performing any test that goes beyond standard clinical care.  In any case, consent 
must be obtained before randomization/enrollment. 
The neurologic examinations used to confirm eligibility should be performed by a 
study team member trained to administer the exams and able to give unbiased 
neurological and functional assessments (NIHSS, Glasgow Coma Score (GCS), and 
perform a historical mRS determination).  These exams were chosen on the basis of 
their reliability, familiarity to the neurologic community, adaptability for use in 
patients who have had a stroke, and comparability to end points used in other trials 
of intracranial hemorrhage.  All scores will be recorded in source documentation 
and entered into the electronic case report forms (eCRFs).  All of the following are 
found in the Appendix, if permitted per licensing agreements. 
• modified Rankin Scale: mRS is an overall assessment of global handicap.  mRS 
must be done by a certified examiner, if not a physician.  A historical mRS will 
be obtained to assess the patient’s level of function prior to the ICH.  
• Barthel Index:  The Barthel Index is an ordinal scale used to measure 
performance of activities of daily living.  A historical Barthel Index score will 
be obtained to assess the patient’s level of function prior to the ICH.  

 
 
 
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• The National Institutes of Health Stroke Scale:  A 42-point scale that quantifies 
neurologic deficits in 11 categories.  Normal function without neurologic deficit 
is given a score of zero.  NIHSS must be done by a certified examiner, if not a 
physician, as close to the specified times as possible.  
• Glasgow Coma Scale: A neurological scale which aims to give a reliable and 
objective way of recording the conscious state of a person for initial as well as 
subsequent assessment.  A subject is assessed against the criteria of the scale, 
and the resulting points give a subject score between 3 (indicating deep 
unconsciousness) and either 15 (fully awake person). 
 
The CT or MR imaging performed to provide a diagnosis of ICH will be used to 
determine hemorrhage volume using the A x B x C/2 method.  
A CTA (or MRA) performed, as standard of care to rule out vascular malformations 
or aneurysm as well used to determine the presence of “Arterial Spot Sign” to 
identify an active bleed.  If an active bleed is detected, additional CT/CTA/MRAs 
may be taken every 6 hours if per standard of care at institution and within 72 hours 
of ictus until hemostasis is confirmed.  
An NIHSS and GCS score must be obtained prior to enrollment.  The NIHSS score 
must be ≥ 6 and the GCS score > 5 and ≤ 15 for inclusion in the study.  
The Hemphill Score will be assigned based upon the clinical presentation and 
imaging.   
A pregnancy test must be conducted for applicable subjects (female, < 50 years old 
and of child bearing potential). 
If patient meets all eligibility criteria, they will be randomized 2:1 to either MIS or 
best MM alone.  After a subject is randomized they will be considered enrolled.  
Randomization will be balanced using stratification based upon presenting 
condition (Hemphill Score) and hemorrhage location (primarily lobar vs. primarily 
deep).  If randomized to surgery, MIS must be performed within 72 hours of the 
ictus.  
6.5 Informed Consent 
The Investigator or designee will obtain written informed consent from the subject 
or approved delegate using the current IRB/EC approved consent form per IRB/EC 
policy.  Consent must be obtained prior to enrollment into the study.  
For sites in the United States, informed consent must be obtained by the subject, 
unless the subject is unable to make the decision to participate in a clinical study 
(e.g. unconscious subject) in which case a Legally Authorized Representative 
(LAR) can be utilized.   

 
 
 
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All informed consent documents used under this protocol will be consistent with 
applicable elements of EN ISO14155, Clinical investigation of medical devices for 
human subjects - Good clinical practice and 21 CFR Part 50 and 54, and will be 
approved by the site’s reviewing IRB/EC prior to study initiation. 
6.6 Randomization 
After all inclusion and exclusion criteria is confirmed and written informed consent 
obtained, randomization will occur as described above in section 4.3.  
Randomization is day 0 for determining follow-up visit dates. 
6.7 Treatment Procedure 
The treatment procedure is described briefly below.  The study procedure will take 
place within 72 hours of the ictus – after completion of the clinical baseline 
assessment, the presentation and imaging, and following randomization.  
6.7.1 Preparation for Treatment 
Subjects randomized to the control group will receive best MM for ICH as 
determined by the stroke physician.  All physicians will follow current AHA/ESO 
guidelines for the treatment of ICH.18,59  {Hemphill, 2015 #1049;Steiner, 2014 
#2487}Subjects randomized to MIS will also receive best MM in addition to the 
procedure.  Reversible coagulopathies at presentation will be corrected as 
determined by the physician managing the subject.  Ventricular drains will be 
placed as deemed necessary by the managing interventional team to manage ICPs.  
MIS will be performed under general anesthesia.  The MIS procedure must occur 
within 72 hours of ictus.  The subject should be prepared for the planned 
intervention according to standard hospital procedures.  MIS will be performed as 
described below (6.7.4) 
6.7.2 Medication during Intervention 
 
Medications may be administered during the procedure as determined by the 
attending anesthesiologist and/or interventionist in accordance with standard of 
care at each facility.  For all subjects, tPA is excluded during the procedure. 
6.7.3 Devices and Equipment 
 
In addition to the Artemis Device, other devices needed for the procedure are 
listed in Table 1.  Such devices should be used in accordance with the 
manufacturer’s indication and instructions for use.     
Table 1:  Devices that may be used during the MIS procedure. 
Standard Cranial Access 
Devices and Endoscopy Sheath 
All FDA cleared or CE marked (as applicable) 
cranial access systems and suitably sized 

 
 
 
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endoscopy sheaths (19 F or smaller) will be 
allowed in the study (e.g., Aesculap Inc, Center 
Valley, PA). 
Neuronavigation System  
All FDA cleared or CE marked (as applicable) 
neuronavigation systems will be allowed in the 
study 
Including:  
• Neuronavigation software, (e.g., iPlan Net, 
Brainlab, Feldkerchin Germany)  
• Neuronavigation Localization Mechanism 
(Skull Reference Base with Skull 
Reference Array with Reflective Marker 
Spheres, e.g., Brainlab) 
• Localization Array (Instrument Adapter 
Clamp with Instrument Adapter Array, 
e.g., Brainlab) 
Penumbra Aspiration System 
The Aspiration Pump and canister for all FDA 
cleared or CE marked (as applicable) Penumbra 
Aspiration Systems will be allowed in the study 
Neuroendoscopy System or 
Equivalent  
All FDA cleared or CE marked (as applicable) 
neuroendoscopy systems (e.g., Lotta, Karl Storz, 
Tuttlington, Germany) which incorporate a 
working channel that will accommodate either the 
1.5, 2.1, or 2.8 mm Artemis Device will be 
allowed in the study.  Exoscope use is not 
permitted. 
CT Monitoring (within or 
outside of OR) 
All FDA cleared or CE marked (as applicable) 
computed tomography or cone beam computed 
tomography systems will be allowed in the study 
(e.g., dynaCT, Siemens, Medical Imaging, 
Erlangen, Germany). 
 
All medical therapy decisions should be in accordance with guidelines from the 
AHA/ESO or critical care guidelines. 
6.7.4 Procedural Protocol 
The Artemis Device and Penumbra Aspiration Pump and canister usage shall 
follow the Instructions For Use (IFU). 
Appropriately protocoled (depending on the institution and neuronavigation units) 
MR or CT imaging studies will be uploaded into the neuronavigation software for 
procedural planning and guidance.  A trajectory will be selected that is both 
technically feasible and allows access to the longest possible axis of the 
hematoma and limits damage to adjacent healthy brain tissue. 

 
 
 
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Subjects will be placed supine or prone upon the procedural table, and a sterile 
field prepared.  An external localization array or other neuronavigation 
localization mechanism will be placed for registration.  Following registration, a 
second sterile field will be prepared over the region of the cranial access.  A burr 
hole/1 – 2 cm craniectomy will then be created in a standard manner of a size 
large enough to accommodate the selected endoscopy sheath.  A localization array 
will be attached to the hub of the selected neuroendoscopic sheath and registered 
to the navigation system.  It is advisable that the neuroendoscope is also registered 
to the navigation system whenever possible.  The sheath will then be advanced 
using neuronavigation into the targeted landing zone within the distal aspect of 
the hematoma and once in place the inner obturator removed.  The sheath will 
then be stabilized (e.g., manually stabilized, mechanically stabilized, or peeled 
away and stapled down) into position.  The neuroendoscope will then be inserted 
into the sheath and under direct visualization the Artemis cannula will be placed 
through the working channel of the neuroendoscope.  The sheath will be irrigated 
at the discretion of the operator using one of the irrigation ports of the endoscope 
while keeping the opposite port open at all times to avoid an increase in ICP and 
the irrigant will be intermittently or continually aspirated until a clear working 
view is created within the sheath that allows visualization of the surgical field at 
the sheath tip.  
When organized hematoma is visualized at the tip of the sheath, the Artemis 
cannula will be advanced under direct visualization to, or just beyond the tip of 
the sheath and actuated to evacuate the blood products.  If the working view 
becomes obscured by blood products within the sheath, additional irrigation and 
aspiration will be performed to clear the field.  When all accessible blood 
products are cleared from the working field, the sheath will be retracted serially 
and the procedure repeated.  The position of the sheath and/or endoscope will be 
continually monitored directly using the neuronavigation system.  This technique 
of evacuating the hemorrhage from distal to proximal will be performed until the 
sheath has been withdrawn through the entire long axis of the hematoma as 
documented on the neuronavigation.  Ultrasound can be used as a tool to visualize 
the hematoma.  
At that point, the neuroendoscopic and Artemis Device will be removed.  An 
intra-operative CT will then be performed using cone-beam CT, an intra-operative 
or portable conventional CT unit, or the OR room (or procedure room) will be 
held open for re-operation(s) and the subject may be scanned on a conventional 
departmental CT unit with the option to immediately return to the OR room, if 
necessary.  The control CT will function to confirm adequate hematoma 
evacuation and to assess for any complications (e.g., re-bleeding, hydrocephalus, 
increased mass effect).  Additional evacuation will be performed as specified 
above at the discretion of the operator, based upon the data from the CT.  It is 
recommended to achieve a 65% reduction in hemorrhage volume and a final 
hemorrhage volume of < 15cc.50   

 
 
 
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After the hemorrhage evacuation is completed, the sheath will be removed and the 
cranial access site will be closed in a standard manner.  
6.7.5 Post-Procedure Care 
Subjects randomized to both groups will receive MM for ICH as determined by 
the attending physician.  Standardization of medical management in both arms 
will occur according to the following: 
• 
General medical management according to AHA/ESO guidelines18,59  
• 
Admission to monitored or intensive care unit for at least 24 hours 
• 
Close monitoring of BP with treatment according to AHA/ESO 
guidelines18,59  
• 
Follow-up imaging studies as indicated in any patient with neurologic 
deterioration 
Additional imaging will be obtained at the discretion of the managing service 
based upon clinical data and established institutional standard of care.  Images 
may need to be sent into the Sponsor and/or Core Lab for further review. 
The subject will be recovered from the procedure (if randomized to MIS) and 
discharged from the hospital as per standard practices.  
6.8 24 hours post MIS or 72 hours post randomization (MM subjects) 
MIS Group: 
• A post-procedural CT scan will be obtained within 24 hours (± 12 hours) in all 
subjects undergoing MIS.  
• Neurological and functional exams will be conducted within 24 hours (± 12 
hours) in subjects undergoing MIS, assessment completed according to Table 2. 
MM Group: 
• A CT (preferred) or MR will also be obtained in MM subjects 72 hours (± 24 
hours) after randomization.  
• Neurological and functional exams will be conducted within 72 hours (± 24 
hours) of randomization in subjects undergoing MM, assessment completed 
according to Table 2. 
The volume of hemorrhage on the diagnostic scan will be calculated using a 
standard A x B x C/2 calculation.  On the CT slice with the largest area of ICH, the 
largest diameter (A) is measured in cm.  The dimension of the hemorrhage 
perpendicular to the largest diameter (B), represents the second diameter.  The third 
diameter (C) will be calculated either by multiplying the number of CT slices which 
depict the hematoma by the slide thickness or determined on coronal or sagittal 
reconstructions.  

 
 
 
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6.9 Day 7/Discharge 
The subject may be discharged from the hospital when clinically stable, at the 
Investigator’s discretion.  At day 7, the following will be completed by a qualified 
member of the research or clinical care team: a focused physical exam, a 
neurological exam (including GCS, NIHSS and mRS), a review of any adverse 
events, and a review of selected current medications.  If discharge occurs before 7 
days after randomization, the discharge clinical examinations will also substitute for 
the 7-day clinical evaluation and a standard of care CT (preferred) or MR will be 
obtained at that time.  For subjects who remain in the hospital past Day 7, only 
SAEs and neurological AEs are reportable.  For all subjects who expire prior to the 
Day 7/Discharge assessment, available information regarding the primary cause of 
death will be recorded, as well as whether the subject made “do not resuscitate” 
(DNR) prior to expiration.  
6.10 Post Discharge Follow-Up 
The designated staff at the clinical site will review the study requirements with the 
subject to maximize compliance with the follow-up schedule.  The staff will instruct 
subjects to return for follow-up assessments according to the Schedule of 
Assessments in Table 2.  Study staff should establish a date and time for the follow-
up visits with the subject, if possible, at the time of hospital discharge. 
The study will be considered complete after all subjects have completed 365 day (± 
35 days) follow-up assessment as outlined in Table 2.  Requirements of each 
follow-up evaluation are detailed below.  Post Discharge, all subjects will be 
followed-up after 30 days (± 14 days), 90 days (± 14 days), 180 days (± 21 days), 
and 365 days (± 35 days).  The 90 day visit can be done via a clinical visit or a 
telephone call.  
6.10.1 
Post Discharge Assessments 
• Focused Exam, which includes a review of subject’s vitals. 
• mRS:  As described in section 6.4 above.  It is preferred that mRS 
measurements are done at the study site, but if subject is unable to come into the 
study site for the follow-up visit, a mRS evaluation may be obtained via 
telephone for 30 day, 90 day, and 365 day using the approved telephone 
questionnaire/worksheet. The 180 day evaluation of mRS must be conducted in-
person. 
• Barthel Index:  As described in section 6.4 above.  
• NIHSS:  As described in section 6.4 above. 
• GCS:  As described in section 6.4 above. 

 
 
 
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• EQ-5D-5L is a standardized instrument for use as a measure of health outcome.  
Applicable to a wide range of health conditions and treatments, the 
questionnaire provides a simple descriptive profile and a single index value for 
health status.  The 90 day EQ-5D-5L should be done using the approved 
telephone questionnaire if the visit is conducted via the telephone.  
• Stroke Impact Scale:  Additionally, a quality of life scale outcome measure will 
be utilized in this study.  Quality of life scales are designed to be sensitive to 
changes in outcome from mild and moderate stroke undetected by other 
outcome measures.  Important parameters not fully interrogated by conventional 
outcome scales can be assessed by quality of life scales, including emotion, 
communication, cognition, and social role function.  Standard measures, such as 
the mRS, primarily evaluate physical aspects of stroke outcome, not addressing 
more relevant quality of life measures.  The Stroke Impact Scale is a validated 
assessment of quality of life specifically in patients with stroke.63 
All day 30, day 90, day 180, and day 365 outcome measures will be assessed by a 
qualified member of the research or clinical team.  The schedule of neurological 
assessments is listed in Table 2.  At each visit, the subject medical record will be 
surveyed for any new or interim neurological adverse or serious adverse events and 
selected concomitant medication.  In addition, the subject, LAR, or approved 
delegate will be asked about any interim neurological adverse or serious adverse 
events.  The subject, LAR, or approved delegate will also be specifically asked 
about any interim neurosurgical procedures.  Best medical management should be 
followed throughout the post discharge follow up period.  
6.10.2 
Unscheduled Visits 
If a subject returns to the study site between follow-up visits a focused exam and 
mRS value should be obtained and recorded in the unscheduled visit CRF.  Subject 
should also be screened for reportable adverse events and any medications used to 
treat those events, as well as any changes to medications should be recorded.

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Table 2: Schedule of Assessments* 
ACTIVITY 
INITIAL 
SCREENING
/ BASELINE 
FINAL 
SCREENING  
TREATMENT 
PROCEDURE 
MM ONLY: 
72-HOUR 
POST 
RAND  
(±24 hours) 
MIS ONLY: 
24- HOUR 
POST 
ARTEMIS 
(±12 hours) 
DISCHARGE 
AND /OR 7 
DAYS  
(± 1 day) 
30 DAY      
(± 14 days) 
90 DAY 
PHONE 
CALL 
(± 14 days) 
180 DAY     
(± 21 days) 
365 DAY     
(± 35 days) 
UN 
SCHEDULED 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
Verify I/E Criteria 
X 
  
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
Focused Exam 
X 
  
X 
X 
X 
X 
 
X 
X 
X 
Standard of Care 
Labs 
X 
X2 
  
X 
X 
X 
  
  
  
  
  
Pregnancy Test4 
X 
  
  
 
  
  
  
  
  
CT/MR 
X1 
X1,2,3 
 X 
X1 
X1 
X2 
 
  
  
  
  
CTA or MRA 
X 
X3 
 
  
 
  
  
  
  
  
Barthel Index 
Historic 
  
  
  
  
X 
X 
X 
X 
  
NIHSS 
X2 
X6 
  
X6 
X6 
X6 
X6 
X2, 6 
X6 
X6 
X2 
GCS  
X2 
X 
  
X 
X 
X 
X 
X2 
X 
X 
X2  
mRS6 
Historic 
  
X 
X 
X 
X 
X 
X8 
X 
X 
Randomization 
  
X7 
  
  
  
  
  
  
  
  
  
Artemis 
Procedure5 
  
 
X  
 
 
  
  
  
  
  
  
Stroke Impact 
Scale (QoL) 
  
  
  
  
  
  
X 
 
X 
X 
  
EQ-5D-5L QoL 
  
  
  
  
  
  
X 
X 
X 
X 
  
Con Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
Review 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
 X 
1 Image to be sent to central core lab within 14 days of 72-hr post randomization (MM group) or 24-hr post Artemis (MIS group) visit 
2 If done as standard of care 
3 As necessary to demonstrate hemostasis  
4 For Women of childbearing potential 
 
5 Under general anesthesia within 72 hours of ictus if randomized to MIS group 
6 Performed by certified assessor (or physician) delegated for task  
 
 
 
 
7 After all eligibility criteria confirmed  
 
 
 
 
 
 
8 Performed by blinded certified assessor (or physician) delegated for task 
 
 
 
 
 
 
* Subjects in both MM and MIS group should follow medical management per AHA/ESO guidelines 

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7. Investigator Responsibilities 
7.1 Institutional Review Board/Ethics Committee Approval  
Prior to enrolling patients into the study, the investigator will ensure that proper 
IRB/EC approval is obtained in accordance with applicable local state and federal laws 
and regulations.  The IRB/EC shall approve all study documents as appropriate, 
including but not limited to the final protocol, amendments to the protocol, Instructions 
for Use, and the Informed Consent Form. 
 
The investigator will report to the Sponsor or designee immediately if, for any reason, 
the approval to conduct the investigation is withdrawn by the IRB/EC or Competent 
Authority.  The report will include a complete description of the reason(s) for which 
approval was withdrawn. 
 
7.2 Informed Consent  
The investigator is responsible for ensuring that a signed and dated informed consent is 
obtained in accordance with Section 6.5 of this protocol and according to country and 
local requirements prior to conducting any study-related assessments, prior to 
administration of any pre-procedure medications or sedation, and prior to enrolment 
into the study. 
 
7.3 Adherence to Protocol/Amendments and Applicable Law 
The investigator is responsible for overseeing, ensuring that the study is conducted, and 
completing the study according to this protocol and in accordance with the relevant 
aspects of EN ISO 14155:2011, Declaration of Helsinki, along with any conditions 
imposed by the reviewing IRB or EC and all other applicable regulations.  The 
investigator shall approve and adhere to this protocol and any amendments that arise 
during the course of the study.  
 
It is the investigator's responsibility to ensure that the staff assisting with the study have 
the appropriate qualifications, are fully instructed on the study procedures, and will 
respect the confidentiality statement. 
7.4 Case Report Form Completion 
The investigator and study staff shall complete the case report forms (CRFs) associated 
with this study.  Subject numbers shall be used to identify individual subjects in this 
study.  The CRFs should be a complete and accurate record of subject data collected 
during the study according to relevant aspects of ISO 14155 and Good Clinical 
Practices (GCP) requirements.  It is the investigator's responsibility to ensure the 
quality of the data collected and recorded. 
 
 

 
 
 
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7.5 Image Upload 
Sites will be provided with instructions for how images should be collected and 
submitted within 14 days of the acquisition of the final required imaging at 72-hr post 
randomization (MM group) or 24-hr post Artemis (MIS group) visit.  Additional 
images may be requested for adverse event adjudication. In the case of rebleeding 
immediate post procedure image may be requested for upload.  If the site is unable to 
provide the images within this timeframe, the appropriate Sponsor contact should be 
notified.  Study staff shall ensure that no images contain protected health information or 
personally identifying information as defined per local regulatory requirements. 
7.6 Reporting 
The investigator will be responsible for reporting the following: 
7.6.1 Adverse Events 
Adverse events or adverse device effects must be recorded by the investigator on 
the CRFs and must be carefully monitored during the study.  All adverse events 
will be collected starting at enrollment through discharge and/or 7 day visit.  After 
discharge and/or 7 day visit, all SAEs and neurological AEs are reportable 
through final follow-up visit. 
Minimum requirements of data to be recorded are: type of event, duration of event 
(start through end), seriousness, action taken, outcome, and causality. 
In order to ensure prompt reporting of AEs, we require that all reportable AEs (as 
well as all related study data) be entered timely into the Electronic Data Capturing 
(EDC) web-based database.  All UADE should be reported immediately by 
calling Penumbra Clinical Affairs and all SAEs should be reported in the EDC 
within 72 hours of the study site staff first being made aware of the occurrence of 
the SAE.  If the EDC system is unavailable, a written report can be sent via email 
to Penumbra. 
The investigator must report the SAE or ADE to the IRB/EC according to local 
requirements.  Reporting time frames should comply with local or national 
requirements.  In addition, the investigator should report to the Sponsor and 
IRB/EC any device malfunctions that could have led to a SAE, if required by 
national regulations or by local authorities. 
For the purpose of reporting within this protocol, pre-existing conditions or 
planned procedures for pre-existing conditions are not reported as AEs unless 
there is worsening of the condition with an increase in severity or frequency 
during the course of the investigation.  An event does not need to be reported as a 
SAE if it represents a relapse or an expected change or progression of the 
condition.  This type of event is considered an AE.  All deaths should be reported 
regardless of causality.  When reporting a death, the primary condition or 

 
 
 
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diagnosis that contributed to the fatal outcome should be reported as a SAE with 
an outcome of death.  If the cause of death is unknown, please report “unknown 
cause of death” as an SAE.  
Detailed form and narrative reports of the following specific adverse events will 
be obtained: 
• Death (all cause) within 30 days of enrollment 
• Death within 7 days of enrollment:  Immediate periprocedural death 
• Symptomatic Re-Hemorrhage or New Hemorrhagic Event:  Any new 
intracranial hemorrhage or increase in size of pre-existing hemorrhage (IPH, 
IVH or extra-axial bleed) within 30 days associated with an NIHSS increase 
of ≥ 4 or a GCS decrease > 2 persisting for at least 24 hours, requiring 
emergency surgical decompression or resulting in death. 
• Symptomatic Evolution of Perihematomal Edema:  Edema with increased 
mass effect or uncontrolled ICPs within 30 days requiring emergency surgical 
decompression NOT related to new or increased hemorrhage (i.e. edema 
related) associated with an NIHSS increase of ≥ 4 or a GCS decrease > 2 
persisting for at least 24 hours, requiring emergency surgical decompression 
or resulting in death. 
• Symptomatic Ischemic Stroke:  A new ischemic stroke (ipsilateral, 
contralateral; contiguous with bleed/operative site or remote; cortical, 
subcortical or perforator distribution) within 30 days associated with an 
NIHSS increase of ≥ 4 or a GCS decrease > 2 persisting for at least 24 hours, 
requiring emergency surgical decompression or resulting in death. 
• Surgical complications related to MIS:  Surgical site infection, brain abscess 
or confirmed meningitis, or documented complication(s) deemed specifically 
related to the procedural anesthetic (medication, access or intubation related) 
within 30 days. 
7.6.1.1 Analysis of Adverse Events  
A medical monitor will review these specific categories of events as they are 
reported.  The medical monitor has the authority to alert the DSMB at any 
time if a potential safety issue arises.  If at any point, these reviews raise any 
safety concerns, the DSMB will be empowered to suggest that the study be 
placed on hold and request additional analyses of the study dataset.  At the 
end of each DSMB meeting, the board shall recommend study (i) continuance 
according to protocol, (ii) modification of the protocol, or (iii) early study 
termination.  The DSMB shall base their recommendations on all available 
evidence and their collective expertise and judgement.  Safety stopping rules 
for the primary safety endpoint will be developed and used to help the DSMB 
make its safety assessments.  Additional details regarding the DSMB 
structure, frequency of meetings and stopping rules will be included in the 
DSMB charter. 

 
 
 
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In addition to the reporting requirements noted above, pre-defined AE/SAEs 
will be evaluated by the Clinical Events Committee (CEC) for an independent 
analysis at regularly scheduled meetings according to the CEC Charter. 
Redacted source documents will be collected for events requiring adjudication 
and for other events where the medical monitor deems necessary.  
7.6.1.2 Definitions 
• Adverse Event (AE):  An AE is any undesirable clinical event occurring 
to a patient, during a clinical trial, whether or not it is considered related to 
the device.  This includes a change in a patient's condition or laboratory 
results which has or could have a deleterious effect on the patient's health 
or well-being. 
• Adverse Device Effect (ADE):  An adverse event related to study 
device(s). 
• Serious Adverse Event (SAE):  A SAE is an event that:  
o Led to death 
o Led to a serious deterioration in the health of the patient that: 
− Resulted in life-threatening illness or injury 
− Resulted in permanent impairment of a body structure or a body 
function 
− Required in-patient hospitalization or prolongation of existing 
hospitalization 
− Resulted in medical or surgical intervention to arrest permanent 
impairment to body structure or a body function 
− Led to Chronic Disease 
− Led to fetal distress, fetal death or a congenital abnormality or 
birth defect 
• 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, if that effect, problem, or death was not 
identified in nature, severity or degree of incidence in the protocol or IFU 
or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects. 
7.6.1.3 Event Relationship 
The investigator will categorize the relation of the adverse event as follows:  
• Index ICH:  Event is clearly attributable to underlying disease state with 
no temporal relationship to the device or treatment  

 
 
 
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• Index Procedure:  Event has a strong temporal relationship to the 
procedure with no relationship to the Artemis Device but may have 
relationship to ancillary devices used to perform the procedure.  Adverse 
events occurring more than 7 days after the MIS procedure are not 
expected to be considered related to the procedure 
• Artemis Neuro Evacuation Device:  Event has a strong temporal 
relationship to the device and alternative etiology is less likely 
o The Artemis Device consists of: powered handle, cannula, tubing and 
suction connector  
7.6.1.4 Relationship to Study Device 
An AE is considered to be device-related when it is reasonable to believe that 
the event may have been caused by or is related to the device.  The following 
definitions will be used to assess the relationship of the adverse event to the 
use of study device.  Any grading for relatedness other than ‘unrelated’ will be 
considered device related. 
• Definite:  The temporal sequence is relevant and the event abates upon 
device application completion/removal, or reappearance of the event on 
repeat device application. 
• Probable:  The temporal sequence is relevant or the AE abates upon 
device application completion/removal or the AE cannot be reasonably 
explained by the subject’s condition or comorbidities.  The AE is related 
or most likely associated with the device. 
• Possible:  The temporal sequence between the device and the AE is such 
that the relationship is not unlikely or there is no contradicting evidence 
that can reasonably explain the subject’s condition.  There is a possibility 
of a relationship between the AE and the device. 
• Unrelated:  The AE is not associated with the device.  There is no relation 
between the AE and the device. 
Similar grading will be used for assessing the relationship to index procedure, 
index ICH, and comorbidities. 
7.6.2 Protocol Deviation 
Any deviations from the protocol identified during monitoring or through other 
means should be clearly documented.  These include but are not limited to: 
• 
Subject does not meet inclusion/exclusion criteria 
• 
Incomplete or missing data 

 
 
 
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• 
Failure to obtain signed informed consent 
• 
Improperly signed or incomplete informed consent 
• 
Delayed reporting of serious adverse events or UADEs 
• 
Out of window visits or assessments 
7.6.3 Device Deficiencies  
All device deficiencies related to the identity, quality, durability, reliability, safety 
or performance of the study medical device shall be documented and reported 
throughout the standard commercial process.  Investigators must report all 
possible device malfunctions or near incidents associated with the device, 
observed during the course of the study.  This includes unexpected outcomes or 
device malfunctions that might have led to a serious adverse event if (a) suitable 
action had not been taken or (b) intervention had not been made or (c) if 
circumstances had been less fortunate. 
Device manufacturers are required to report qualifying medical device incidents 
to the relevant national competent authorities.  An incident is defined as “any 
malfunction or deterioration in the characteristics and/or performance of a device, 
as well as any inadequacy in the labeling or the instructions for use which, 
directly or indirectly, might lead to or might have led to the death of a subject or 
to a serious deterioration in their state of health”.  A deterioration in state of 
health is considered unanticipated if the condition leading to the event was not 
considered in a risk analysis. 
Investigators participating in this study will report all events that could qualify for 
a vigilance incident to the Sponsor via the commercial process, who will evaluate 
the incident against the reporting requirements. 
7.7 Administration of Neurological Exams and Stroke Scales 
The Principal Investigator at each investigative site is responsible for the 
administration of the neurological examinations and grading of subjects on the 
stroke scales (i.e., NIHSS, mRS).  In cases where a designee is assigned, the 
investigator must ensure that the designee is trained and has the appropriate 
qualifications to perform these functions.  Assessors of mRS and NIHSS must be 
certified or practicing physicians. 
 
7.8 Device Disposition 
The investigator shall maintain records pertaining to device disposition.  The 
disposition of each device includes: 
• Subject number  
• Device lot number(s) 

 
 
 
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The Principal Investigator will ensure that, for the purpose of this investigation, 
only trained physicians who are sub-investigators in this study will use the Artemis 
Device on subjects enrolled.  
7.9 Records Retention 
The investigator shall maintain the records associated with this study for a period of 
at least two years after either the date on which the investigation is completed or the 
date that the records are no longer required for supporting a premarket 
approval/notification submission, whichever is later.  Veeva (eTMF) will be used as 
the master repository for all site and Sponsor regulatory documents with the 
exception of DICOMs.  Sites do not need to maintain a duplicate file unless 
otherwise mandated by local institution requirements.  These records include, but 
are not limited to the following: 
• Correspondence with the Sponsor or designee, core laboratory, and other 
investigators 
• Subject source records, including but not limited to, ICF, copies of all 
completed CRFs, and supporting documents (laboratory reports and reports of 
diagnostic tests, medical records, etc.) 
• All versions of study protocol with dates and details of reasons for any 
deviations from the protocol that could affect the scientific quality of the study 
or the rights, safety, or welfare of the subjects 
• Instructions for Use 
• Reports of any serious adverse event or serious device effects 
• A copy of all approvals related to the clinical investigation 
• The approved, blank, informed consent forms and blank CRFs 
• All approval/acknowledgment letters from the by the IRB/EC for all versions of 
the study protocol, ICF and other documents 
• Clinical Trial Agreement 
• Signed and dated curriculum vitae for all study personnel 
• Medical licenses for the Principal Investigator and all participating sub-
investigators 
• Financial disclosure for the Principal Investigator and all participating sub-
investigators 
• All required regulatory documents such as Delegation of Authority and training 
logs 
• Signed Protocol Signature Page(s) 
8. Sponsor Responsibilities 
8.1 Training 
The Sponsor is responsible for providing training on the protocol, study device, 
CRF completion, image upload, and randomization as applicable for all study staff 
per the Delegation of Authority.  

 
 
 
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Prior to an Investigator being activated in the study, he/she must complete a 
minimum of 3 qualified cases to be considered a study operator of the Artemis 
Device.*  Cases must be reviewed by an independent physician(s) prior to 
Investigator being authorized as a study operator. 
• If the Investigator has not used the device in > 3 months, training may be 
repeated. 
*An Investigator may be given a waiver for the outlined training if he/she has been a 
regular user of the Apollo System and/or Artemis Device. 
8.2 Investigator List 
The Sponsor shall keep a list of the names, addresses, and professional positions of 
the clinical investigators for the study. 
8.3 Adverse Event Reporting 
The Sponsor shall evaluate adverse event reports received from the investigational 
sites and found during data monitoring and shall report them to the appropriate 
regulatory bodies and other investigational sites as necessary. 
8.4 Data Monitoring 
 
Penumbra is responsible for ensuring that the study is conducted according to the 
appropriate regulations (US Food and Drug Administration 21 CFR §812, ISO 
14155).  A Penumbra employee or designee will conduct the following site visits: 
8.4.1 Site Qualification Visit 
Conducted to ensure the investigational site has the appropriate staff, facilities, and 
expertise to participate in the study.   
8.4.2 Site Initiation Visit 
Conducted to train the investigational staff on use of the device, study requirements, 
and other relevant training. 
8.4.3 Interim Monitoring Visit 
Conducted as needed to ensure the investigational site is operating in compliance 
with this protocol, continues to have the appropriate staff and facilities, and is 
correctly completing the CRFs.  
To ensure that investigators and their staff understand and accept their defined 
responsibilities, the Sponsor will maintain regular correspondence and perform 
periodic site visits during the course of the study to verify the continued 
acceptability of the facilities, compliance with the investigational plan, and 

 
 
 
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maintenance of complete records.  Clinical monitoring will include review and 
resolution of missing or inconsistent data and source document checks to ensure the 
accuracy of the reported data.  Informed consent, CRFs and medical records for all 
enrolled and screen failed subjects will be made available to the Sponsor for review 
and collection as agreed with the investigator.  The Sponsor will evaluate and 
summarize the results of each site visit in written reports, identifying repeated data 
problems with any investigator and specifying recommendations for resolution of 
noted deficiencies. 
8.4.4 Study Close-Out Site Visit 
 
Conducted at the termination of the study or site closure to resolve any outstanding 
data queries, ensure all regulatory documents are present, and to ensure that any 
remaining study materials are returned to the Sponsor or properly discarded. 
8.5 Data Management 
Electronic Case Report Forms (eCRFs) will be used at all investigational sites.  All 
study data will be entered into a commercially available web-based electronic data 
capture (EDC) system.  Data entry will be performed by the study site personnel.  
Investigators are responsible for completion and timely submission of the data to 
the Sponsor.  Every reasonable effort should be made to complete data entry within 
7 days of data collection.  This EDC system requires no on-site software installation 
or specific hardware to operate.  Investigators, clinical coordinators, data managers, 
and Penumbra clinical personnel access project information and study data centrally 
via a web browser. 
Automated data quality checks will display warnings for invalid data.  Additionally, 
manual review of data listings may be used to identify data discrepancies or 
inconsistencies.  The study site may be queried for clarification concerning eCRF 
discrepancies or inconsistencies identified.  If eCRF corrections are necessary, they 
will be made by the Investigator or an authorized member of the Investigator's staff 
that is delegated to CRF/EDC.  Questions or problems with submitted data will be 
addressed with the Principal Investigator via an electronic querying system, or 
through direct contact.  The Investigator will review the eCRFs for completeness 
and accuracy and provide his/her electronic signature and date to eCRFs as 
evidence thereof.  Any data items that have been changed will require reapplication 
of the electronic signature. 
Study personnel will have individual login and password to access the clinical study 
information based upon each individual’s roles and responsibilities.  The 
application provides hierarchical user permission data entry, viewing, and reporting 
options.  All data entry and data update information, including the date and person 
performing the action, will be available via the audit trail, which is part of the EDC 
system.  

 
 
 
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All eCRFs and other data files will be secured to ensure confidentiality.  
Investigators are required to maintain source documents required by the protocol, 
including laboratory results, patient reports, supporting medical records, and 
informed consent forms.  The source documents will be used during the regular 
monitoring visits to verify information entered on the eCRFs.  
For each enrolled subject, required CT/MRs will be appropriately de-identified, and 
sent to the imaging core lab for evaluation.  The core lab and CEC reviews will also 
be entered into an electronic system.  Each reviewer will provide his/her electronic 
signature and date to reviews as evidence thereof.  Queries may be issued in the 
system or via email to the core lab or CEC for clarification concerning possible 
EDC discrepancies or inconsistencies. 
9. Ethical Considerations 
9.1 Declaration of Helsinki 
The study will be performed in accordance with the applicable aspects of ISO 
14155, recommendations guiding physicians in biomedical research involving 
human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland 
(1964 and later revisions), ICH and US FDA GCP guidelines. 
It is the responsibility of the investigator to obtain approval of the study protocol 
from the IRB/EC and to keep the IRB/EC informed of any serious adverse event, 
serious adverse device effects, and amendments to the protocol.  All 
correspondence with the IRB/EC should be filed by the investigator and copies sent 
to the Sponsor or its designee. 
9.2 Informed Consent 
It is the responsibility of the investigator or his/her designee to give each patient full 
and adequate verbal and written information regarding the objective and procedure 
of the study and the possible risks involved and to obtain signed informed consent 
from all patients prior to inclusion in the study unless the patient's health condition 
does not allow informed consent, in which case the local hospital, state, country, 
and regulatory procedures will be applied.  The original, signed consent is filed 
with the patient study records, and a copy is provided to the patient. 
9.3 Subject Data Protection 
Each subject will be assigned a unique subject identification number at the time of 
enrollment.  This subject identification number will be retained throughout the 
study.  Study sites will keep a log that notes the subject’s name and corresponding 
subject identification number.  All case report forms (CRFs) will be tracked, 
evaluated, and stored using only the subject ID number.  No personally identifying 
information will be included on the case report forms. 

 
 
 
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The informed consent form will notify subjects that study monitors, auditors, and 
representatives of government agencies will have access to personally identifying 
information to ensure that data reported on the CRFs corresponds to the person who 
signed the consent form and the information contained in the source documentation.  
The patient must be informed that the data will be stored and analyzed by computer, 
that national regulations for handling of computerized data will be followed.  
Furthermore, the patients should be informed about the possibility of inspection of 
relevant parts of the hospital records by the Sponsor or other Health Authorities 
including the FDA. 
 
10. Statistical Procedures 
The primary objective of this multicenter, randomized, clinical study is to investigate the 
potential efficacy of MIS to improve clinical outcomes in patients with spontaneous, non-
traumatic, ICH presenting within 24 hours in comparison to best MM.  The primary 
hypothesis to be tested is that treatment with MIS will improve outcomes at 180 days as 
compared to the best MM group.  Each eligible subject will be randomized in a 2:1 ratio to 
either the MIS or best MM with a balanced randomization based upon the hemorrhage 
location (primarily lobar, primarily deep) and Hemphill Score (0 – 2, 3 – 4).  The 
hemorrhage location and Hemphill Score have been shown to be associated with 
functional outcome.6,10,19,25  An adaptive design approach will be utilized to allow for 
interim analyses and decisions on early stopping for either predicted success or failure. 
10.1 Sample Size Estimation for the Primary Outcome 
The proposed study is a randomized controlled study designed to demonstrate the 
efficacy of MIS to improve clinical outcomes across the entire population of 
patients with supratentorial ICH, as well as to evaluate effect sizes within major 
anatomical sub-groups (e.g., deep vs. lobar hemorrhage) and cohorts (e.g. age, 
presenting GCS).  In addition, the treatment arm will provide, for the first time, a 
prospective, independently adjudicated, characterization of the technical outcomes 
and complication rates associated with the Artemis MIS procedure.  
This design provides 81% power for a cumulative odds ratio of 1.7 for the Day 180 
mRS.  The design’s overall one-sided Type I error rate is 2.5%. 
The maximum study sample size is 500 subjects and the minimum sample size is 
200 subjects.  The final study sample size is estimated to be low if the treatment 
effect is small and the study could be stopped for futility or if the treatment effect is 
large and the study could be stopped for expected success.  The final study sample 
size will be high if the evidence for the treatment effect is inconclusive. 
The Day 180 mRS distribution used for sample size estimation was based on 
control arm data from the following published studies:  MISTIE48, STICH13, and 
SICHPA64.  The distribution of mRS functional outcomes utilized in the sample 
size estimation is provided in Table 3. 

 
 
 
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Table 3. Distribution of mRS Functional Outcomes  
mRS 
Distribution 
0 
1 
2 
3 
4 
5/6 
MM 
3% 
10% 
7% 
7% 
14% 
59% 
MIS 
5% 
15% 
10% 
9% 
16% 
46% 
 
10.2 Control of Systematic Error and Bias 
Randomization takes place centrally through a commercially available Interactive 
Web Response System (IWRS).  The clinical study will be conducted under a 
common protocol for each investigational site with the intention of pooling the data 
for analysis.  Every effort will be made to promote consistency in study execution 
at each investigational site. 
The interim analysis of the primary endpoint will be conducted by an independent 
statistician. 
10.3 Missing Data and Imputation Methods 
Every effort will be made to keep all missing data, particularly the Day 180 
outcomes, to a minimum.  Despite the clinical sites’ best efforts, some missing data 
may be inevitable mainly due to lost-to-follow-up (LTFU).  Subjects not 
completing the 180 day follow-up mRS will be imputed for the primary endpoint 
using the mRS as of the last available follow-up visit (i.e., Day 30, Day 90) by 
estimating the probability distribution of the Day 180 mRS conditional on Day 30 
or Day 90 mRS.  The imputed mRS scores will be utilized in both the interim and 
final primary analyses.  Sensitivity analysis will be performed. 
10.4 Definition of Populations 
10.4.1 
Screened 
All patients considered for participation in the study, whether or not they sign an 
informed consent. 
10.4.2 
Screen Failure 
All patients considered for participation in the study, who failed to meet inclusion 
criteria or met exclusion criteria.  Patients can be screen failed based on general or 
imaging criteria.  These patients may or may not have signed an informed consent. 
10.4.3 
Enrolled (Randomized) 
All subjects who have been randomized based on the result of the baseline imaging 
and other inclusion/exclusion criteria.  Informed consent must be obtained prior to 
randomization. 

 
 
 
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10.4.4 
Completed 
All subjects who were enrolled (randomized) and completed the study follow-up or 
were known to have died prior to the follow-up timepoint.  The completed subject 
metric will be provided for Day 180 and Day 365 follow-up. 
10.4.5 
Early Termination: 
Subjects who were enrolled (randomized) but did not complete follow-up and were 
not known to have died.  The early termination subject metric will be provided for 
Day 180 and Day 365 follow-up. 
10.5 Definition of Analysis Populations 
10.5.1 
Target Population 
The target population is patients 18 – 80 years of age who have a diagnosis of 
spontaneous, non-traumatic, intracerebral hemorrhage (ICH) ranging in volume 
between and including 20 and 80 cc, with an associated significant neurological 
deficit (NIHSS > 6) who do not require emergent open surgical decompression 
related to uncontrolled intracranial pressure or mass effect.  
10.5.2 
Intent to Treat Sample 
As the primary analysis, all efficacy and safety outcome measures will be analyzed 
under the intent-to-treat (ITT) principle.  Under this principle, the evaluable sample 
includes all subjects who are randomized.  Each subject will be analyzed according 
to the treatment group to which they were randomly assigned at the time of 
randomization.  This population is the primary population for all efficacy 
parameters. 
10.5.3 
Per Protocol Sample 
In addition to the defined ITT analysis sample, a per-protocol (PP) sample is 
defined as a subset of the ITT sample.  The per-protocol sample will include all 
randomized subjects that do not have significant protocol deviations (e.g., eligibility 
violation, crossover). 
10.5.4 
Safety Analysis (As Treated) Sample: 
In the case of cross-overs, a safety sample that is the same as the ITT sample will be 
examined in which subjects will be analyzed according to the actual treatment 
received.  Subjects who receive Artemis device-based therapy are included in the 
MIS arm and subjects who receive only medical therapy are included in the MM 
arm. 
10.6 Interim Analysis 

 
 
 
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Interim data analysis of the primary efficacy and safety endpoints is planned after 
200 subjects have been enrolled.  Additional interim analyses will be conduct after 
every 50 subjects are enrolled.  The interim analyses will include imputing the 180 
day mRS score for subjects who do not have a 180 day score.  Based on the 
predictive probability that the study would be a success the study may be stopped 
early for futility or enrollment may be stopped based on expected success.  The 
specific details of the planned analyses are described completely in the adaptive 
design report. 
10.7 Statistical Evaluation of Primary Endpoint 
The primary endpoint is the Day 180 global disability assessed via the ordinal 
modified Rankin score (mRS). 
The null hypothesis is that the cumulative odds ratio for mRS at 180 days in the 
MIS group compared to MM group is less than or equal to 1.  The alternative 
hypothesis is that the cumulative odds ratio for mRS at 180 days is greater than 1.  
Formally, the null and alternative hypotheses to be tested are as follows: 
H0:  OR ≤ 1 
HA:  OR > 1, 
where OR is the cumulative odds ratio for the mRS at the 180 day follow-up visit, 
with higher values indicating better outcomes in the MIS treatment group. 
Statistical analysis of the primary endpoint will be conducted using a logistic 
regression analysis of the 180 day mRS scores.  The primary efficacy endpoint is 
met if the overall treatment effect is positive at a one-sided alpha of 0.02.  The odds 
ratio and corresponding 95% confidence interval will be estimated from the 
proportional odds model.  The primary analysis will be unadjusted.  A secondary 
analysis model will include the minimization variables of Hemphill Score and 
hemorrhage location. 
The mRS scores of 5 and 6 will be combined into a single group for the purposes of 
endpoint evaluation.  Subjects deceased during study follow-up will be scored as 
mRS 6.  
10.8 Statistical Analysis of Primary Safety Outcome  
With the date of randomization set at day 0, any death occurring on or before Day 
30 will be included as a death.  
10.9 Secondary Statistical Analysis 
The secondary endpoints of Day 180 and Day 365 average improvement in global 
disability will be assessed via the weighted modified Rankin score (mRS) and will 
be analyzed using a generalized linear model.  The mRS scores will be weighted as 

 
 
 
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the following:  1.0 for mRS level 0; 0.91 for mRS level 1; 0.76 for mRS level 2; 
0.65 for mRS level 3; 0.33 for mRS level 4; 0 for mRS level 5; and 0 for mRS level 
6.65 Statistical analysis of the dichotomized Rankin outcome scores of 0 to 2 and 0 
to 3 will be conducted with a logistic regression model.  Group differences will be 
analyzed for the following:  SIS-ADL, SIS-mobility, EQ-5D-5L, length of stay, 
length of procedure.  Other pre-specified analyses will be performed as outlined in 
the statistical plan. 
10.10 Baseline Characteristics 
Baseline data will be analyzed to assess the comparability of treatment groups.  
Baseline data including, but not limited to demographics, clinical characteristics, 
and baseline ICH characteristics will be summarized using descriptive statistics.  
Statistical testing will be performed as appropriate. 
10.11 Pooling Across Centers 
Analyses will be presented by treatment group using data pooled across sites.  The 
site analysis will be conducted using an ordinal logistic regression with terms of 
treatment group and treatment-by-site interaction.  This analysis will be performed 
on the intent-to-treat population.  The primary statistical inference is the treatment-
by-site interaction, which is tested at the significance level of 0.15.  When the 
treatment-by-site interaction is statistically significant (p ≤ 0.15), the treatment 
group differences will be evaluated within each site.  Adjusted analysis on the 
primary outcome using key baseline variables will be used for the site analyses for 
consistency with the overall study result.  If the odds ratio of the treatment effect is 
found to vary by site, then a random-effects model analysis will be performed to 
assess whether there was significant variance in the primary endpoint according to 
study site. 
10.12 Health Economics Information 
The study site will complete CRFs containing healthcare utilization information 
(e.g., ICU days).  This information may be used for analyses to compare overall 
healthcare costs and resource utilization between MIS and MM. 
10.13 Final Report 
A final report will be completed, even if the study is prematurely terminated.  At the 
conclusion of the study, a multi-center abstract reporting the results will be prepared 
and may be presented at a major meeting(s).  A multi-center publication may also 
be prepared for publication in a reputable scientific journal.  The publication of 
results from any single center experience within the study is not allowed until the 
aggregate study results have been published, unless there is written consent from 
the Sponsor. 

 
 
 
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11. Study Committees and Core Labs 
11.1 Steering Committee/Scientific Advisory Board 
The Steering Committee (SC) and/or Scientific Advisory Board (SAB) will be 
comprised of physicians with subject matter expertise.  The SC/SAB will be 
advisors to the Sponsor regarding study planning, execution and data presentation, 
progress of enrollment, subject safety and consideration of new information.  Daily 
study management is the responsibility of the Penumbra.  The SC/SAB will oversee 
dissemination of study results through appropriate scientific sessions and 
publications.  The SC/SAB may recommend additional investigators, based on 
enrollment and adherence to the protocol, to participate on a Publication 
Committee.  The Publication Committee will participate in the review and approval 
of all requests for data analysis, abstract and manuscript preparation and 
submission. 
11.2 Safety Monitoring Committees  
11.2.1 
Data Safety Monitoring Board (DSMB) 
A DSMB will be comprised of members not participating in the study and will 
include neurovascular specialist physicians and a statistician.  The DSMB will 
exercise review of the overall safety of the study and make recommendations to 
adjustments in the study protocol, should any be considered necessary for safety or 
other related reasons.  Additional details will be specified in the DSMB charter.  
11.2.2 
Clinical Events Committee (CEC) 
The Clinical Events Committee (CEC) is made up of independent medical doctors 
who are not participants in the study.  The CEC is charged with the development of 
specific criteria used for the categorization of clinical events and clinical endpoints 
in the study which are based on the protocol.  
At the onset of the study, the CEC will establish explicit rules outlining the 
minimum amount of data required, and the algorithm followed in order to classify a 
clinical event.  While the CEC review of adverse events specific to the 
interventional procedure will unblind the members, all members of the CEC will be 
blinded to the overall primary results of the study. 
The CEC will review and adjudicate appropriate clinical events, mainly related to 
the device and to the study endpoints.  The CEC will also review and rule on all 
deaths that occur throughout the study.  The safety process flow and a web-based 
electronic database will be provided to CEC members for case review and 
adjudication.  The designated Penumbra staff who are responsible for reviewing 
safety data on an ongoing basis will coordinate collection of information for the 
event dossier. 

 
 
 
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11.3 Imaging Core Lab 
The independent imaging core lab will review images from the procedure to 
determine, at a minimum, hematoma volume.  An Imaging core lab charter will 
provide procedure for core lab review.  Penumbra, or designee, is responsible for 
tracking images received, basic quality review and forwarding applicable results to 
the CEC. 
12. Study Administration 
12.1 Clinical Trial Termination/Withdrawal  
Subjects may be terminated or withdrawn from the study for the following reasons: 
• Voluntary withdrawal of consent –– Meaning that a subject voluntarily chooses 
not to participate further in the study.  All data collected up to the date of 
withdrawal of consent will be maintained in the study database.  Withdrawn 
subjects will not have any additional follow-up and will not be replaced. 
• Lost to follow-up –– A subject will not be considered lost-to-follow-up until 
contact is not achieved at the 365 day visit.  At a minimum, the effort to obtain 
follow-up information will include three attempts to make contact via telephone 
or e-mail and if unsuccessful, a letter from the Investigator sent via courier or 
other traceable method will be sent to the subject’s last known address.  These 
efforts to obtain follow-up will be recorded in the subject’s study files and the 
case report forms. 
• Subjects may also be withdrawn at the investigator’s discretion if within their 
best interest.  A subject’s participation in the clinical study will be terminated if 
the investigator believes that this is in the subject’s best medical interest or if 
the subject no longer complies with the clinical study requirements. 
The Sponsor may temporarily suspend or prematurely terminate the study at any 
time for the following reasons: 
• Suspicion of risk to subjects 
• If no positive IRB/EC decision is obtained or if the judgement of the IRB/EC is 
revoked 
• If the applicable regulatory body has made an irrevocable objection 
• If it transpires that continuation of study cannot serve any scientific purpose, 
and this is confirmed by the IRB/EC 
• Business reasons (e.g., Sponsor has been declared insolvent, or if a petition has 
been filed for liquidation) 
The Sponsor will document reasons for study suspension or premature termination 
and notify the PIs.  The Sponsor will ensure that the IRB/ECs and regulatory 
authorities (if required) are notified in a timely manner.   

 
 
 
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The Sponsor will continue to provide resources to fulfill the obligations from the 
study protocol and existing agreements for following up the subjects enrolled in the 
study. 
The Principal Investigators will promptly inform the enrolled subjects at his/her 
site, if appropriate. 
If the Sponsor temporarily suspends the study and wishes to resume it, the Sponsor 
will inform the PIs, IRB/ECs and (if appropriate) regulatory authorities.  The 
Sponsor will provide a rationale for resuming the study.  IRB/ECs must provide 
written approval before the study is resumed. 
12.2 Stopping the Trial Based on Interim Safety Data  
The DSMB will receive periodic safety reports of all reported AEs and SAEs.  In 
addition, the following specific endpoints will be assessed by the medical monitor 
and presented: 
• Death (all cause) within 30 days of enrollment 
• Death within 7 days of enrollment:  Immediate periprocedural death 
• Symptomatic Re-Hemorrhage or New Hemorrhagic Event:  Any new 
intracranial hemorrhage or increase in size of pre-existing hemorrhage (IPH, 
IVH or extra-axial bleed) within 30 days associated with an increase of 4 or 
more points on the NIHSS or GCS decrease > 2 persisting for at least 24 hours, 
requiring emergency surgical decompression or resulting in death 
• Symptomatic Evolution of Perihematomal Edema:  Edema with increased mass 
effect or uncontrolled ICPs within 30 days requiring emergency surgical 
decompression NOT related to new or increased hemorrhage (i.e., edema 
related) associated with an increase of 4 or more points on the NIHSS or GCS 
decrease > 2 persisting for at least 24 hours, requiring emergency surgical 
decompression or resulting in death 
• Symptomatic Ischemic Stroke:  A new ischemic stroke (ipsilateral, 
contralateral; contiguous with bleed/operative site or remote; cortical, 
subcortical or perforator distribution) within 30 days associated with an increase 
of 4 or more points on the NIHSS or GCS decrease > 2 persisting for at least 24 
hours, requiring emergency surgical decompression or resulting in death 
• Surgical complications related to MIS:  Surgical site infection, brain abscess or 
confirmed meningitis, or documented complication(s) deemed specifically 
related to the procedural anesthetic (medication, access or intubation related) 
within 30 days 
Additional details regarding the DSMB structure and stopping rules will be 
included in the DSMB charter.   
12.3 Missing Visits 
Any study subject who does not attend a scheduled follow-up visit should be 
contacted by site personnel to determine the reason for the missed appointment(s).  

 
 
 
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If the missed visit was due to a serious adverse event, (e.g., re-hospitalization) an 
AE CRF must be completed and any reporting requirements met.  Every effort 
should be made in order to bring subject in to scheduled follow-up visits.  
12.4 Protocol Adherence and Amendments 
Prior to beginning the study, the Principal Investigator must sign the protocol 
signature page documenting his/her agreement to conduct the study in accordance 
with this protocol.  An Investigator must not make any changes or deviate from this 
protocol, except to protect the life and physical well-being of a subject in an 
emergency.  Each deviation from the protocol must be documented with the date 
and reported to Penumbra as soon as possible, and to the IRB/EC per local 
guidelines and government regulations. 
The protocol must be followed exactly.  It can be altered only by written 
amendments made by Penumbra.  Following appropriate approval by Penumbra the 
amended protocol will be submitted to the required regulatory agencies before 
being distributed to all participating sites.  Each site must obtain IRB/EC approval 
before implementing the revised protocol.  
12.5 Trial Registration 
The study will be registered in a publicly accessible trial database (e.g., 
clinicaltrials.gov) prior to study initiation. 
13. Publication of Information 
All information and data shared by Sponsor and generated by Investigator or Sponsor or 
other study site in association with this study will be held in strict confidence by the 
Investigator and shall remain the sole property of Sponsor.  Such information may include 
all information recorded in the EDC or any unpublished study data.  All information not 
previously published concerning the test device and research, including patent 
applications, manufacturing processes, basic scientific data, etc., is considered confidential 
and should remain the sole property of Penumbra.  The Investigator agrees to use this 
information for the sole purpose of completing this study and for no other purpose without 
written consent from the Sponsor. 
The results of this study may be offered for publication.  The investigators and the 
Sponsor shall collaborate in the writing of the study to ensure accuracy.   
14. Contact Information 
The address of Penumbra, Inc. is: 
Penumbra, Inc. 
One Penumbra Place 
Alameda, CA 94502 
Tel. (510) 748-3200 

 
 
 
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15. References 
1. 
Labovitz DL, Halim A, Boden-Albala B, Hauser WA, Sacco RL. The incidence of deep 
and lobar intracerebral hemorrhage in whites, blacks, and Hispanics. Neurology 
2005;65:518-22. 
2. 
Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous 
Intracerebral Hemorrhage. New England Journal of Medicine 2001;344:1450-60. 
3. 
van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case 
fatality, and functional outcome of intracerebral haemorrhage over time, according to 
age, sex, and ethnic origin: a systematic review and meta-analysis. The Lancet Neurology 
2010;9:167-76. 
4. 
Feigin VL, Lawes CMM, Bennett DA, Anderson CS. Stroke epidemiology: a review of 
population-based studies of incidence, prevalence, and case-fatality in the late 20th 
century. The Lancet Neurology 2003;2:43-53. 
5. 
Qureshi AI, Suri MF, Nasar A, et al. Changes in cost and outcome among US patients 
with stroke hospitalized in 1990 to 1991 and those hospitalized in 2000 to 2001. Stroke 
2007;38:2180-4. 
6. 
Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral 
hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke 
1993;24:987-93. 
7. 
Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke 
incidence and early case fatality reported in 56 population-based studies: a systematic 
review. The Lancet Neurology 2009;8:355-69. 
8. 
Poon MT, Fonville AF, Al-Shahi Salman R. Long-term prognosis after intracerebral 
haemorrhage: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 
2014;85:660-7. 
9. 
Daverat P, Castel JP, Dartigues JF, Orgogozo JM. Death and functional outcome after 
spontaneous intracerebral hemorrhage. A prospective study of 166 cases using 
multivariate analysis. Stroke 1991;22:1-6. 
10. 
Bhattathiri PS, Gregson B, Prasad KS, Mendelow AD, Investigators S. Intraventricular 
hemorrhage and hydrocephalus after spontaneous intracerebral hemorrhage: results from 
the STICH trial. Acta Neurochir Suppl 2006;96:65-8. 
11. 
Hemphill JC, 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: 
a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32:891-7. 
12. 
Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute 
intracerebral hemorrhage. N Engl J Med 2005;352:777-85. 
13. 
Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial 
conservative treatment in patients with spontaneous supratentorial intracerebral 
haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a 
randomised trial. The Lancet 2005;365:387-97. 

 
 
 
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CONFIDENTIAL 
Page 54 of 74 
14. 
Russell MW, Joshi AV, Neumann PJ, Boulanger L, Menzin J. Predictors of hospital 
length of stay and cost in patients with intracerebral hemorrhage. Neurology 
2006;67:1279-81. 
15. 
Gloede TD, Halbach SM, Thrift AG, Dewey HM, Pfaff H, Cadilhac DA. Long-term costs 
of stroke using 10-year longitudinal data from the North East Melbourne Stroke 
Incidence Study. Stroke 2014;45:3389-94. 
16. 
Lyden PD, Shuaib A, Lees KR, et al. Safety and tolerability of NXY-059 for acute 
intracerebral hemorrhage: the CHANT Trial. Stroke 2007;38:2262-9. 
17. 
Rincon F, Mayer SA. The epidemiology of intracerebral hemorrhage in the United States 
from 1979 to 2008. Neurocrit Care 2013;19:95-102. 
18. 
Hemphill JC, 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the Management of 
Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From 
the American Heart Association/American Stroke Association. Stroke 2015;46:2032-60. 
19. 
Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. The Lancet 
2009;373:1632-44. 
20. 
Anderson CS, Huang Y, Wang JG, et al. Intensive blood pressure reduction in acute 
cerebral haemorrhage trial (INTERACT): a randomised pilot trial. The Lancet Neurology 
2008;7:391-9. 
21. 
Dziedzic T, Szczudlik A, Klimkowicz A, Rog TM, Slowik A. Is mannitol safe for 
patients with intracerebral hemorrhages? Renal considerations. Clinical Neurology and 
Neurosurgery 2003;105:87-9. 
22. 
Kalita J, Misra UK, Ranjan P, Pradhan PK, Das BK. Effect of mannitol on regional 
cerebral blood flow in patients with intracerebral hemorrhage. J Neurol Sci 2004;224:19-
22. 
23. 
Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM. Early 
surgery versus initial conservative treatment in patients with spontaneous supratentorial 
lobar intracerebral haematomas (STICH II): a randomised trial. The Lancet 
2013;382:397-408. 
24. 
Misra UK, Kalita J, Ranjan P, Mandal SK. Mannitol in intracerebral hemorrhage: a 
randomized controlled study. J Neurol Sci 2005;234:41-5. 
25. 
Qureshi AI. Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH): 
rationale and design. Neurocrit Care 2007;6:56-66. 
26. 
Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated 
factor VII for acute intracerebral hemorrhage. N Engl J Med 2008;358:2127-37. 
27. 
Qureshi AI, Palesch YY, Martin R, et al. Effect of systolic blood pressure reduction on 
hematoma expansion, perihematomal edema, and 3-month outcome among patients with 
intracerebral hemorrhage: results from the antihypertensive treatment of acute cerebral 
hemorrhage study. Arch Neurol 2010;67:570-6. 
28. 
Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with 
acute intracerebral hemorrhage. N Engl J Med 2013;368:2355-65. 
29. 
Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. 
The Lancet Neurology 2006;5:53-63. 
30. 
Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic 
targets. The Lancet Neurology 2012;11:720-31. 
31. 
Ropper AH, King RB. Intracranial pressure monitoring in comatose patients with 
cerebral hemorrhage. Arch Neurol 1984;41:725-8. 

 
 
 
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CONFIDENTIAL 
Page 55 of 74 
32. 
Thiex R, Tsirka SE. Brain edema after intracerebral hemorrhage: mechanisms, treatment 
options, management strategies, and operative indications. Neurosurg Focus 2007;22:E6. 
33. 
Zazulia AR, Diringer MN, Derdeyn CP, Powers WJ. Progression of mass effect after 
intracerebral hemorrhage. Stroke 1999;30:1167-73. 
34. 
Dolinskas CA, Bilaniuk LT, Zimmerman RA, Kuhl DE, Alavi A. Computed tomography 
of intracerebral hematomas. II. Radionuclide and transmission CT studies of the 
perihematoma region. AJR Am J Roentgenol 1977;129:689-92. 
35. 
Mayer SA, Sacco RL, Shi T, Mohr JP. Neurologic deterioration in noncomatose patients 
with supratentorial intracerebral hemorrhage. Neurology 1994;44:1379-84. 
36. 
Mendelow AD, Unterberg A. Surgical treatment of intracerebral haemorrhage. Curr Opin 
Crit Care 2007;13:169-74. 
37. 
Mutlu N, Berry RG, Alpers BJ. Massive Cerebral Hemorrhage. Clinical and Pathological 
Correlations. Arch Neurol 1963;8:644-61. 
38. 
Carhuapoma JR, Wang PY, Beauchamp NJ, Keyl PM, Hanley DF, Barker PB. Diffusion-
weighted MRI and proton MR spectroscopic imaging in the study of secondary neuronal 
injury after intracerebral hemorrhage. Stroke 2000;31:726-32. 
39. 
Zazulia AR, Diringer MN, Videen TO, et al. Hypoperfusion without ischemia 
surrounding acute intracerebral hemorrhage. J Cereb Blood Flow Metab 2001;21:804-10. 
40. 
Hua Y, Wu J, Keep RF, Hoff JT, Xi G. Thrombin exacerbates brain edema in focal 
cerebral ischemia. Acta Neurochir Suppl 2003;86:163-6. 
41. 
Huang FP, Xi G, Keep RF, Hua Y, Nemoianu A, Hoff JT. Brain edema after 
experimental intracerebral hemorrhage: role of hemoglobin degradation products. J 
Neurosurg 2002;96:287-93. 
42. 
Zheng H, Chen C, Zhang J, Hu Z. Mechanism and Therapy of Brain Edema after 
Intracerebral Hemorrhage. Cerebrovasc Dis 2016;42:155-69. 
43. 
Gregson BA, Broderick JP, Auer LM, et al. Individual patient data subgroup meta-
analysis of surgery for spontaneous supratentorial intracerebral hemorrhage. Stroke 
2012;43:1496-504. 
44. 
Wang WZ, Jiang B, Liu HM, et al. Minimally invasive craniopuncture therapy vs. 
conservative treatment for spontaneous intracerebral hemorrhage: results from a 
randomized clinical trial in China. Int J Stroke 2009;4:11-6. 
45. 
Kim YZ, Kim KH. Even in patients with a small hemorrhagic volume, stereotactic-
guided evacuation of spontaneous intracerebral hemorrhage improves functional 
outcome. J Korean Neurosurg Soc 2009;46:109-15. 
46. 
Zhou X, Chen J, Li Q, et al. Minimally invasive surgery for spontaneous supratentorial 
intracerebral hemorrhage: a meta-analysis of randomized controlled trials. Stroke 
2012;43:2923-30. 
47. 
Yang C-D, Chen Y-W, Wu H-C. Meta-analysis of randomized studies of surgery for 
supratentorial intracerebral hemorrhage. Formosan Journal of Surgery 2014;47:90-8. 
48. 
Hanley DF, Thompson RE, Muschelli J, et al. Safety and efficacy of minimally invasive 
surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, 
controlled, open-label, phase 2 trial. The Lancet Neurology 2016;15:1228-37. 
49. 
Naff N, Williams MA, Keyl PM, et al. Low-dose recombinant tissue-type plasminogen 
activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage 
thrombolysis trial. Stroke 2011;42:3009-16. 

 
 
 
CLP 11899.B 
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50. 
Mould WA, Carhuapoma JR, Muschelli J, et al. Minimally invasive surgery plus 
recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation 
decreases perihematomal edema. Stroke 2013;44:627-34. 
51. 
Hanley DF, Lane K, McBee N, et al. Thrombolytic removal of intraventricular 
haemorrhage in treatment of severe stroke: results of the randomised, multicentre, 
multiregion, placebo-controlled CLEAR III trial. The Lancet 2017;389:603-11. 
52. 
Awad AJ, Hanley D. Clear III: efficiency of IVH removal determines mRS. International 
Stroke Conference 2016. 
53. 
Dye JA, Dusick JR, Lee DJ, Gonzalez NR, Martin NA. Frontal bur hole through an 
eyebrow incision for image-guided endoscopic evacuation of spontaneous intracerebral 
hemorrhage. J Neurosurg 2012;117:767-73. 
54. 
Miller CM, Vespa P, Saver JL, et al. Image-guided endoscopic evacuation of spontaneous 
intracerebral hemorrhage. Surg Neurol 2008;69:441-6; discussion 6. 
55. 
Vespa P, Hanley D, Betz J, et al. ICES (Intraoperative Stereotactic Computed 
Tomography-Guided Endoscopic Surgery) for Brain Hemorrhage: A Multicenter 
Randomized Controlled Trial. Stroke 2016;47:2749-55. 
56. 
Spiotta AM, Fiorella D, Vargas J, et al. Initial multicenter technical experience with the 
Apollo device for minimally invasive intracerebral hematoma evacuation. Neurosurgery 
2015;11 Suppl 2:243-51; discussion 51. 
57. 
Jenkins K, Baker AB. Consent and anaesthetic risk. Anaesthesia 2003;58:962-84. 
58. 
Nash DM, Mustafa RA, McArthur E, et al. Combined general and neuraxial anesthesia 
versus general anesthesia: a population-based cohort study. Can J Anaesth 2015;62:356-
68. 
59. 
Steiner T, Al-Shahi Salman R, Beer R, et al. European Stroke Organisation (ESO) 
guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke 
2014;9:840-55. 
60. 
Bauer AM, Rasmussen PA, Bain MD. Initial Single-Center Technical Experience With 
the BrainPath System for Acute Intracerebral Hemorrhage Evacuation. Oper Neurosurg 
(Hagerstown) 2017;13:69-76. 
61. 
Feng Y, He J, Liu B, Yang L, Wang Y. Endoscope-Assisted Keyhole Technique for 
Hypertensive Cerebral Hemorrhage in Elderly Patients: A Randomized Controlled Study 
in 184 Patients. Turk Neurosurg 2016;26:84-9. 
62. 
Labib MA, Shah M, Kassam AB, et al. The Safety and Feasibility of Image-Guided 
BrainPath-Mediated Transsulcul Hematoma Evacuation: A Multicenter Study. 
Neurosurgery 2017;80:515-24. 
63. 
Duncan PW, Wallace D, Lai SM, Johnson D, Embretson S, Laster LJ. The stroke impact 
scale version 2.0. Evaluation of reliability, validity, and sensitivity to change. Stroke 
1999;30:2131-40. 
64. 
Teernstra OP, Evers SM, Lodder J, et al. Stereotactic treatment of intracerebral 
hematoma by means of a plasminogen activator: a multicenter randomized controlled 
trial (SICHPA). Stroke 2003;34:968-74. 
65. 
Chaisinanunkul N, Adeoye O, Lewis RJ, et al. Adopting a Patient-Centered Approach to 
Primary Outcome Analysis of Acute Stroke Trials Using a Utility-Weighted Modified 
Rankin Scale. Stroke 2015;46:2238-43. 

 
 
 
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Page 57 of 74 
66. 
Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: 
implications for stroke clinical trials: a literature review and synthesis. Stroke 
2007;38:1091-6. 
67. 
National Institute of Health NIoNDaS. Stroke Scale. 
68. 
Mahoney FI, Barthel DW. Functional Evaluation: The Barthel Index. Md State Med J 
1965;14:61-5. 
69. 
Moore L, Lavoie A, Camden S, et al. Statistical validation of the Glasgow Coma Score. J 
Trauma 2006;60:1238-43; discussion 43-4. 
70.       Hanley, D. et al. Efficiacy and Safety of minimally invasive surgery with thrombolysis in 
intracerebral hemorrhage evacuation (MISTIE III): a randomized, controlled, open-label, 
blinded endpoint phase III trial. S0140-6736(19)30195-3.71.       Awad, I. et al. Surgical 
Performance Determines Functional Outcome Benefit in Minimally Invasive Surgery 
Plue Recombinant Tissue Activator for Intracerebral Hemorrhage Evacuation (MISTIE) 
Procedure. Neurosurgery. 2019;1-12. 
72.       Mould et al. Minimally invasive surgery plus recombinant tissue-type plasminogen 
activator for intracerebral hemorrhage evacuation decreases perihematomal edema. 
Stroke.2013;44:627-634. 
 
 
 

 
 
 
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16. Appendix 
16.1 Abbreviations 
ADE 
Adverse Device Effect 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AHA 
American Heart Association 
aPTT 
Activated Partial Thromboplastin Time 
ASA 
American Society of Anesthesiologists 
AVM 
Arteriovenous Malformations 
BP 
Blood Pressure 
CE Marking 
European Conformity Marking 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTA 
Computed Tomography Angiography 
DNR 
Do Not Resuscitate 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EEG 
Electroencephalogram 
ESO 
European Stroke Organization 
EU 
European Union 
EVD 
External Ventricular Drain 
FDA 
US Food and Drug Administration 
FU 
Follow-Up 
GCP 
Good Clinical Practices 
GCS 
Glasgow Coma Score 
I/E 
Inclusion/Exclusion 
ICES 
Intra-operative CT-guided endoscopic surgery 
ICF 
Informed Consent Form 
ICH 
Intracerebral Hemorrhage 

 
 
 
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ICP 
Intracranial Pressure 
ICU 
Intensive Care Unit 
INR 
International Normalized Ratio 
IPH 
Intraparenchymal Hemorrhage 
IRB 
Institution Review Board 
ISO 
International Organization for Standardization 
ITT 
Intent to Treat 
IT-tPA 
Intrathecal Tissue Plasminogen Activator 
IVH 
Intraventricular Hemorrhage 
IWRS 
Interactive Web Response System 
LAR 
Legally Authorized Representative 
LTFU 
Lost to follow-up 
MIS 
Minimally Invasive Surgery 
MM 
Medical Management 
MR 
Magnetic Resonance 
MRA 
Magnetic Resonance Angiography 
mRS 
modified Rankin Scale/Score 
NIHSS 
National Institute of Health Stroke Scale 
OR 
Operating Room 
PHE 
Peri-Hematomal Edema 
PI 
Primary Investigator 
PP 
Per Protocol 
QOL 
Quality of Life 
rFVIIa 
recombinant factor VIIa 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SC 
Steering Committee 
SIS 
Stroke Impact Scale 
tPA 
Tissue Plasminogen Activator 
UADE 
Unanticipated Adverse Device Effect 
 
 
 

 
 
 
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16.2 Modified Rankin Scale66    
0 
No Symptoms at all 
1 
No significant disability, despite symptoms; able to perform all 
usual duties and activities 
2 
Slight disability; unable to perform all previous activities but able 
to look after own affairs without assistance 
3 
Moderate disability; requires some help, but able to walk without 
assistance 
4 
Moderately severe disability; unable to walk without assistance and 
unable to attend to own bodily needs without assistance  
5 
Severe disability; bedridden; incontinent, and requires constant 
nursing care and attention 
6 
Death 
 
 

 
 
 
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16.3 National Institute of Health Stroke Scale67   
NIH STROKE SCALE 
Instructions 
Scale Definition 
Score 
1a.  Level of Consciousness:  The 
investigator must choose a response, 
even if a full evaluation is prevented by 
such obstacles as an endotracheal tube, 
language barrier, orotracheal 
trauma/bandages.  A 3 is scored only if 
the patient makes no movement (other 
than reflexive posturing) in response to 
noxious stimulation. 
 
0 = Alert: keenly responsive. 
1 = Not alert, but arousable by minor stimulation 
to obey, answer, or respond. 
2 = Not alert, requires repeated stimulation to 
attend, or is obtunded and requires strong or 
painful stimulation to make movements (not 
stereotyped). 
3 = Responds only with reflex motor autonomic 
effects or totally unresponsive, flaccid, and 
flexic. 
____ 
1b.  LOC Questions:  The patient is 
asked the month and his/her age.  The 
answer must be correct – there is no 
partial credit for being close.  Aphasic 
and stuporous patients who do not 
comprehend the questions will score 2.  
Patients unable to speak because of 
endotracheal intubation, orotracheal 
trauma, severe dysarthria from any 
cause, language barrier or any other 
problem not secondary to aphasia are 
given a 1.  It is important that only the 
initial answer be graded and that the 
examiner not “help” the patient with 
verbal or non-verbal cues. 
0 = Answers both questions correctly. 
 
1 = Answers one question correctly. 
 
2 = Answers neither question correctly. 
____ 
1c.  LOC Commands:  The patient is 
asked to open and close the eyes and 
then to grip and release the non-paretic 
hand.  Substitute another one step 
command if the hands cannot be used.  
Credit is given if an unequivocal 
attempt is made but not completed due 
to weakness.  If the patient does not 
respond to command, the task should be 
demonstrated to him/her (pantomime) 
and score the result (i.e., follows none, 
one or two commands).  Patients with 
trauma, amputation, or other physical 
impediments should be given suitable 
one-step commands.  Only the first 
attempt is scored. 
0 = Performs both tasks correctly. 
 
1 = Performs one task correctly. 
 
2 = Performs neither task correctly. 
____ 
2.  Best Gaze:  Only horizontal eye 
movements will be tested.  Voluntary or 
reflexive (oculocephalic) eye 
movements will be scored but caloric 
0 = Normal. 
 
____ 

 
 
 
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NIH STROKE SCALE 
Instructions 
Scale Definition 
Score 
testing is not done.  If the patient has a 
conjugate deviation of the eyes that can 
be overcome by voluntary or reflexive 
activity, the score will be 1.  If  a patient 
has an isolated peripheral nerve paresis 
(CN III, IV or VI) score a 1.  Gaze is 
testable in all aphasic patients.  Patients 
with ocular trauma, bandages, pre-
existing blindness or other disorder of 
visual acuity or fields should be tested 
with reflexive movements and a choice 
made by the investigator.  Establishing 
eye contact and then moving about the 
patient from side to side will 
occasionally clarify the presence of a 
partial gaze palsy. 
1 = Partial gaze palsy; gaze is abnormal in one or 
both eyes, but forced deviation or total gaze 
paresis is not present. 
 
2 = Forced deviation, or total gaze paresis not 
overcome by the oculocephalic maneuver. 
3.  Visual:  Visual fields (upper and 
lower quadrants) are tested by 
confrontation, using finger counting or 
visual threat as appropriate.  Patient 
may be encouraged, but if they look at 
the side of the moving fingers 
appropriately, this can be scored as 
normal.  If there is unilateral blindness 
or enucleation, visual fields in the 
remaining eye are scored.  Score 1 only 
if a clear-cut asymmetry, including 
quadrantanopia is found.  If patient is 
blind from any cause, score 3.  Double 
simultaneous stimulation is performed 
at this point.  If there is extinction, 
patient receives a 1, and the results are 
used to answer item 11. 
0 = No visual loss. 
 
1 = Partial hemianopia. 
 
2 = Complete hemianopia. 
 
3 = Bilateral hemianopia (blind including 
cortical blindness). 
____ 
4.  Facial Palsy:  Ask, or use pantomime 
to encourage the patient to show teeth 
or raise eyebrows and close eyes.  Score 
symmetry of grimace in response to 
noxious stimuli in the poorly responsive 
or non-comprehending patient.  If facial 
trauma/bandages, orotracheal tube, tape 
or other physical barrier obscures the 
face, these should be removed to the 
extent possible. 
0 = Normal symmetrical movement. 
1 = Minor paralysis (flattened nasolabial fold, 
asymmetry on smiling). 
2 = Partial paralysis (total or near total paralysis 
of lower face). 
3 = Complete paralysis of one or both sides   
(absence of facial movement in the upper and 
lower face). 
____ 

 
 
 
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NIH STROKE SCALE 
Instructions 
Scale Definition 
Score 
5.   Motor Arm:  The limb is placed in 
the appropriate position: extend the 
arms (palms down) 90 degrees (if 
sitting) or 45 degrees (if supine).  Drift 
is scored if the arm falls before 10 
seconds.  The aphasic patient is 
encouraged using urgency in the voice 
and pantomime, but not noxious 
stimulation.  Each limb is tested in turn, 
beginning with the non-paretic arm.  
Only in the case of amputation or joint 
fusion at the shoulder, the examiner 
should record the score as untestable 
(UN), and clearly write the explanation 
for this choice. 
0 = No drift; limb holds 90 (or 45) degrees for 
full 10 seconds. 
1 = Drift; Limb holds 90 (or 45) degrees, but 
drifts down before full 10 seconds: does not hit 
bed or other support. 
2 = Some effort against gravity; limb cannot get 
to or maintain (if cued) 90 (or 45) degrees, drifts 
down to bed, but has some effort against gravity. 
3 = No effort against gravity; limb falls. 
4 = No movement. 
UN = Amputation or joint fusion, explain: 
________________ 
____ 
5a.  Left Arm 
5b.  Right Arm 
____ 
6. Motor Leg:  The limb is placed in the 
appropriate position: hold the leg at 30 
degrees (always tested supine).  Drift is 
scored if the leg falls before 5 seconds.  
The aphasic patient is encouraged using 
urgency in the voice and pantomime, 
but not noxious stimulation.  Each limb 
is tested in turn, beginning with the non-
paretic leg.  Only in the case of 
amputation or joint fusion at the hip, the 
examiner should record the score as 
untestable (UN), and clearly write the 
explanation for this choice. 
0 = No drift; leg holds 30 degrees position for 
full 5 seconds 
1 = Drift; leg falls by the end of the 5 second 
period but does not hit bed 
2 = Some effort against gravity; leg falls to bed 
by 5 seconds, but has some effort against gravity 
3 = No effort against gravity; leg falls to bed 
immediately 
4 = No movement 
UN = Amputation or joint fusion, explain: 
________________ 
____ 
6a. Left Leg      
6b. Right Leg 
____ 
7. Limb Ataxia:  This item is aimed at 
finding evidence of a unilateral 
cerebellar lesion.  Test with eyes open.  
In case of visual defect, ensure testing is 
done in intact visual field.  The finger-
nose-finger and heel-shin tests are 
performed on both sides, and ataxia is 
scored only if present out of proportion 
to weakness.  Ataxia is absent in the 
patient who cannot understand or is 
paralyzed.  Only in the case of 
amputation or joint fusion may the item 
be scored “UN” and the examiner must 
clearly write the explanation for not 
scoring.  In case of blindness test by 
touching nose from extended arm 
position.   
0 = Absent. 
 
1 = Present in one limb. 
 
2 = Present in two limbs. 
 
UN = Amputation or joint fusion, explain: 
________________ 
____ 
8.  Sensory:  Sensation or grimace to 
pin prick when tested, or withdrawal 
0 = Normal; no sensory loss. 
 
____ 

 
 
 
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NIH STROKE SCALE 
Instructions 
Scale Definition 
Score 
from noxious stimulus in the obtunded 
or aphasic patient.  Only sensory loss 
attributed to stroke is scored as 
abnormal and the examiner should test 
as many body areas [arms (not hands), 
legs, trunk, face] as needed to 
accurately check for hemisensory loss.  
A score of 2, “severe or total sensory 
loss,” should only be given when a 
severe or total loss of sensation can be 
clearly demonstrated.  Stuporous and 
aphasic patients will therefore probably 
score 1 or 0.  The patient with brainstem 
stroke who has bilateral loss of 
sensation is scored 2.  If the patient does 
not respond and is quadriplegic score 2.  
Patients in coma (item 1a=3) are 
automatically given a 2 on this item. 
1 = Mild to moderate sensory loss; patient feels 
pinprick is less sharp or is dull on the affected 
side; or there is a loss of superficial pain with 
pinprick but patient is aware he/she is being 
touched. 
 
2 = Severe to total sensory loss; patient is not 
aware of being touched in the face, arm, and leg. 
9.  Best Language:  A great deal of 
information about comprehension will 
be obtained during the preceding 
sections of the examination.  The 
patient is asked to describe what is 
happening in the attached picture, to 
name the items on the attached naming 
sheet, and to read from the attached list 
of sentences.  Comprehension is judged 
from responses here as well as to all of 
the commands in the preceding general 
neurological exam.  If visual loss 
interferes with the tests, ask the patient 
to identify objects placed in the hand, 
repeat, and produce speech.  The 
intubated patient should be asked to 
write.  The patient in coma (item 1a=3) 
will automatically score 3 on this item.  
The examiner must choose a score for 
the patient with stupor or limited 
cooperation, but a score of 3 should be 
used only if the patient is mute and 
follows no one-step commands. 
0 = No aphasia, normal. 
1 = Mild to moderate aphasia; some obvious loss 
of fluency or facility of comprehension, without 
significant limitation on ideas expressed or form 
of expression.  Reduction of speech and/or 
comprehension, however, makes conversation 
about provided material difficult or impossible.  
For example, in conversation about provided 
materials, examiner can identify picture or 
naming card content from patient’s response. 
2 = Severe aphasia; all communication is 
through fragmentary expression; great need for 
inference, questioning, and guessing by the 
listener.  Range of information that can be 
exchanged is limited; listener carries burden of 
communication.  Examiner cannot identify 
materials provided from patient response. 
3 = Mute, global aphasia; no usable speech or 
auditory comprehension. 
____ 
10.  Dysarthria:  If patient is thought to 
be normal, an adequate sample of 
speech must be obtained by asking 
patient to read or repeat words from the 
attached list.  If the patient has severe 
aphasia, the clarity of articulation of 
0 = Normal. 
1 = Mild to moderate dysarthria; patient slurs at 
least some words and, at worst, can be 
understood with some difficulty. 
____ 

 
 
 
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NIH STROKE SCALE 
Instructions 
Scale Definition 
Score 
spontaneous speech can be rated.  Only 
if the patient is intubated or has other 
physical barrier to producing speech, 
may the item be scored as untestable 
(UN), and clearly write an explanation 
for this choice.  Do not tell the patient 
why (s)he is being tested.   
2 = Severe; patient’s speech is so slurred as to be 
unintelligible in the absence of or out of 
proportion to any dysphasia, or is mute/anarthric. 
UN = Intubated or other physical barrier, 
explain: _______________________________  
11. Extinction and Inattention (formerly 
Neglect):  Sufficient information to 
identify neglect may be obtained during 
the prior testing.  If the patient has a 
severe visual loss preventing visual 
double simultaneous stimulation, and 
the cutaneous stimuli are normal, the 
score is normal.  If the patient has 
aphasia but does appear to attend to 
both sides, the score is normal.  The 
presence of visual spatial neglect or 
anosagnosia may also be taken as 
evidence of abnormality.  Since the 
abnormality is scored only if present, 
the item is never untestable. 
0 = No abnormality. 
1 = Visual, tactile, auditory, spatial, or personal 
inattention or extinction to bilateral simultaneous 
stimulation in one of the sensory modalities. 
2 = Profound hemi-inattention or extinction to 
more than one modality; does not recognize own 
hand or orients to only one side of space.   
____ 
 

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

 
 
 
CLP 11899.B 
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Page 68 of 74 
 

 
 
 
CLP 11899.B 
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Page 69 of 74 
 
MAMA 
TIP – TOP 
FIFTY – FIFTY 
THANKS 
HUCKLEBERRY 
BASEBALL PLAYER 
 
 

 
 
 
CLP 11899.B 
CONFIDENTIAL 
Page 70 of 74 
16.4 Barthel Index68  
Activity  
 
 
 
 
 
 
 
 
 
Score 
 
FEEDING 
0 = unable 
5 = needs help cutting, spreading butter, etc., or requires modified diet 
10 = independent 
 
BATHING 
0 = dependent 
5 = independent (or in shower) 
 
GROOMING 
0 = needs to help with personal care 
5 = independent face/hair/teeth/shaving (implements provided) 
 
DRESSING 
0 = dependent 
5 = needs help but can do about half unaided 
10 = independent (including buttons, zips, laces, etc.) 
 
BOWELS 
0 = incontinent (or needs to be given enemas) 
5 = occasional accident 
10 = continent 
 
BLADDER 
0 = incontinent, or catheterized and unable to manage alone 
5 = occasional accident 
10 = continent 
 
TOILET USE 
0 = dependent 
5 = needs some help, but can do something alone 
10 = independent (on and off, dressing, wiping) 
 
TRANSFERS (BED TO CHAIR AND BACK) 
0 = unable, no sitting balance 
5 = major help (one or two people, physical), can sit 
10 = minor help (verbal or physical) 
15 = independent 
 
MOBILITY (ON LEVEL SURFACES) 
0 = immobile or < 50 yards 
5 = wheelchair independent, including corners, > 50 yards 
10 = walks with help of one person (verbal or physical) > 50 yards 
15 = independent (but may use any aid; for example, stick) > 50 yards 
 
STAIRS 
0 = unable 
5 = needs help (verbal, physical, carrying aid) 
10 = independent 
 
TOTAL (0–100):     
 

 
 
 
CLP 11899.B 
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16.5 Glasgow Coma Scale69  
Glasgow Coma Score 
Eye Opening (E) 
Verbal Response (V) 
Motor Response (M) 
4= Open before stimulus 
(Rating=Spontaneous) 
3= After spoken or 
shouted request 
(Rating=To sound) 
2= After fingertip 
stimulus (Rating=To 
pressure) 
1= No opening at any 
time, no interfering 
factor (Rating=None) 
5= Correctly gives name, place 
and date (Rating=Orientated) 
4= Not oriented but 
communicates coherently 
(Rating=Confused) 
3= Intelligible single words 
(Rating=Words) 
2= Only moans/groan 
(Rating=Sounds) 
1= No audible response, no 
interfering factor (Rating=None) 
6= Obey 2-part request 
(Rating=Obeys commands) 
5= Brings hand above clavicle to 
stimulus on head/neck 
(Rating=Localizing) 
4= Bends arm at elbow rapidly 
but features not predominantly 
abnormal (Rating=Normal 
flexion) 
3= Bends arm at elbow, features 
clearly predominantly abnormal 
(Rating=Abnormal flexion) 
2= Extends arm at elbow 
(Rating=Extension) 
1= No movement in arms/legs, no 
interfering factor (Rating=None) 
 
 
Total= E+V+M 
 
 

 
 
 
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16.6 Stroke Impact Scale63  
These questions are about the physical problems which may have occurred as a result of 
your stroke. 
1.  In the past week, how would you 
rate the strength of your.... 
A lot of 
strength 
Quite a bit 
of strength 
Some 
strength 
A little 
strength 
No strength 
at all 
a. Arm that was most affected by your 
stroke? 
5 
4 
3 
2 
1 
b. Grip of your hand that was most 
affected by your stroke? 
5 
4 
3 
2 
1 
c. Leg that was most affected by your 
stroke? 
5 
4 
3 
2 
1 
d. Foot/ankle that was most affected by 
your stroke? 
5 
4 
3 
2 
1 
 
These questions are about your memory and thinking. 
2. In the past week, how difficult was it 
for you to... 
Not difficult 
at all 
A little 
difficult 
Somewhat 
difficult 
Very 
difficult 
Extremely 
difficult 
a. Remember things that people just told you? 
5 
4 
3 
2 
1 
b. Remember things that happened the day 
before? 
5 
4 
3 
2 
1 
c. Remember to do things (e.g. keep scheduled 
appointments or take medication)? 
5 
4 
3 
2 
1 
d. Remember the day of the week? 
5 
4 
3 
2 
1 
e. Concentrate? 
5 
4 
3 
2 
1 
f. Think quickly? 
5 
4 
3 
2 
1 
g. Solve everyday problems? 
5 
4 
3 
2 
1 
 
These questions are about how you feel, about changes in your mood and about your ability to 
control your emotions since your stroke. 
3.  In the past week, how often did you... 
None of 
the time 
A little of 
the time 
Some of 
the time 
Most of 
the time 
All of the 
time 
a. Feel sad? 
5 
4 
3 
2 
1 
b. Feel that there is nobody you are close to? 
5 
4 
3 
2 
1 
c. Feel that you are a burden to others? 
5 
4 
3 
2 
1 
d. Feel that you have nothing to look forward 
to? 
5 
4 
3 
2 
1 
e. Blame yourself for mistakes that you made? 
5 
4 
3 
2 
1 
f. Enjoy things as much as ever? 
5 
4 
3 
2 
1 
g. Feel quite nervous? 
5 
4 
3 
2 
1 
h. Feel that life is worth living? 
5 
4 
3 
2 
1 
i. Smile and laugh at least once a day? 
5 
4 
3 
2 
1 
 

 
 
 
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The following questions are about your ability to communicate with other people, as well as your 
ability to understand what you read and what you hear in a conversation. 
4.  In the past week, how difficult was it 
to... 
Not difficult 
at all 
A little 
difficult 
Somewhat 
difficult 
Very 
difficult 
Extremely 
difficult 
a. Say the name of someone who was in front of 
you? 
5 
4 
3 
2 
1 
b. Understand what was being said to you in a 
conversation? 
5 
4 
3 
2 
1 
c. Reply to questions? 
5 
4 
3 
2 
1 
d. Correctly name objects? 
5 
4 
3 
2 
1 
e. Participate in a conversation with a group of 
people? 
5 
4 
3 
2 
1 
f. Have a conversation on the telephone? 
5 
4 
3 
2 
1 
g. Call another person on the telephone, 
including selecting the correct phone number 
and dialing? 
5 
4 
3 
2 
1 
 
The following questions ask about activities you might do during a typical day. 
5.  In the past 2 weeks, how difficult was it 
to... 
Not difficult 
at all 
A little 
difficult 
Somewhat 
difficult 
Very 
difficult 
Could not 
do at all 
a. Cut your food with a knife and fork? 
5 
4 
3 
2 
1 
b. Dress the top part of your body? 
5 
4 
3 
2 
1 
c. Bathe yourself? 
5 
4 
3 
2 
1 
d. Clip your toenails? 
5 
4 
3 
2 
1 
e. Get to the toilet on time? 
5 
4 
3 
2 
1 
f. Control your bladder (not have an accident)? 
5 
4 
3 
2 
1 
g. Control your bowels (not have an accident)? 
5 
4 
3 
2 
1 
h. Do light household tasks/chores 
(e.g. dust, make a bed, take out 
garbage, do the dishes)? 
5 
4 
3 
2 
1 
i. Go shopping? 
5 
4 
3 
2 
1 
j. Do heavy household chores (e.g. vacuum, 
laundry or yard work)? 
5 
4 
3 
2 
1 
 
 
 
The following questions are about your ability to be mobile, at home and in the community. 
6. In the past 2 weeks, how difficult was 
it to... 
Not difficult 
at all 
A little 
difficult 
Somewhat 
difficult 
Very 
difficult 
Could not 
do at all 
a. Stay sitting without losing your balance? 
5 
4 
3 
2 
1 
b. Stay standing without losing your balance? 
5 
4 
3 
2 
1 
c. Walk without losing your balance? 
5 
4 
3 
2 
1 
d. Move from a bed to a chair? 
5 
4 
3 
2 
1 
e. Walk one block? 
5 
4 
3 
2 
1 

 
 
 
CLP 11899.B 
CONFIDENTIAL 
Page 74 of 74 
f. Walk fast? 
5 
4 
3 
2 
1 
g. Climb one flight of stairs? 
5 
4 
3 
2 
1 
h. Climb several flights of stairs? 
5 
4 
3 
2 
1 
i. Get in and out of a car? 
5 
4 
3 
2 
1 
 
The following questions are about your ability to use your hand that was 
MOST AFFECTED by your stroke. 
7.  In the past 2 weeks, how difficult was it 
to use your hand that was most affected 
by your stroke to... 
Not difficult 
at all 
A little 
difficult 
Somewhat 
difficult 
Very 
difficult 
Could not 
do at all 
a. Carry heavy objects (e.g. bag of groceries)? 
5 
4 
3 
2 
1 
b. Turn a doorknob? 
5 
4 
3 
2 
1 
c. Open a can or jar? 
5 
4 
3 
2 
1 
d. Tie a shoe lace? 
5 
4 
3 
2 
1 
e. Pick up a dime? 
5 
4 
3 
2 
1 
 
The following questions are about how stroke has affected your ability to participate in the 
activities that you usually do, things that are meaningful to you and help you to find 
purpose in life. 
8.  During the past 4 weeks, how much 
of the time have you been limited in... 
None of 
the time 
A little of 
the time 
Some of 
the time 
Most of 
the time 
All of the 
time 
a. Your work (paid, voluntary or other) 
5 
4 
3 
2 
1 
b. Your social activities? 
5 
4 
3 
2 
1 
c. Quiet recreation (crafts, reading)? 
5 
4 
3 
2 
1 
d. Active recreation (sports, outings, travel)? 
5 
4 
3 
2 
1 
e. Your role as a family member and/or friend? 
5 
4 
3 
2 
1 
f. Your participation in spiritual or religious 
activities? 
5 
4 
3 
2 
1 
g. Your ability to control your life as you wish? 
5 
4 
3 
2 
1 
h. Your ability to help others? 
5 
4 
3 
2 
1 
 
Stroke Recovery 
 
On a scale of 0 to 100, with 100 representing full recovery and 0 representing no recovery, 
how much have you recovered from your stroke? 
 
Full  
 
 
 
 
 
 
 
 
 
 
 
        No 
Recovery 
 
 
 
 
 
 
 
 
 
             Recovery 
100 
90 
80 
70 
60 
50 
40 
30 
20 
10 
0