INVEST: A Single Arm, Feasibility Study of Minimally Invasive Endoscopic Surgical Treatment With Apollo for Supratentorial Intracerebral Hemorrhage (ICH)
Phase: NA
Conditions: Intracranial Hemorrhage
Sponsor: J. Mocco

INVEST: A Single Arm, Feasibility Study of Minimally Invasive Endoscopic Surgical 
Treatment with Apollo / Artemis for Supratentorial Intracerebral Hemorrhage (ICH)
PI: J. Mocco, MD, MS
NCT02654015
Document Date: 10-24-2017

 
 
 
 
INVEST: A Single Arm, Feasibility Study of Minimally Invasive Endoscopic Surgical Treatment with 
Apollo / Artemis for Supratentorial Intracerebral Hemorrhage (ICH) 
 
 
J Mocco 
Mount Sinai School of Medicine 
 
David Fiorella 
Stony Brook Medical Center 
 
Adam Arthur 
Semmes-Murphy Clinic 
 
 
 
 
 
 
Version 2.0 
12-6-2016 
Version 3.0 
 4-14-2017 
Version 4.0 
10-24-2017 

2 
 
 
 
 
 
 
 
 
Study Title: INVEST: A Single Arm, Feasibility Study of Minimally Invasive Endoscopic Surgical  
Treatment with Apollo / Artemis for Supratentorial Intracerebral Hemorrhage (ICH) 
 
 
 
 
Version Number: 
4 
 
Version Date: 
10/24/2017 
 
Study Center: 
  
 
 
 
I, the undersigned, have read and understand the protocol specified above and agree on its content. I agree to 
perform and conduct the study as described in the protocol and in accordance with the relevant parts of the 
appropriate regulatory requirements and the pertinent individual country laws/regulations. 
 
Site Investigator Name: 
  
 
 
Signature/Date: 
 

3 
 
 
 
 
 
 
 
 
Primary Contacts 
 
 
 
 
Clinical Study Management and 
Physician Sponsor-Investigator 
J Mocco, MD 
Mount Sinai School of Medicine 
New York, NY 10029 
Monitoring 
Statistical and Data Management Center 
Mount Sinai School of Medicine 
New York, NY 10029 
Data Management 
Statistical and Data Management Center 
Mount Sinai School of Medicine 
New York, NY 10029 
Core Laboratory 
Keith Woodward MD 
Oculus Imaging LLC 
2450 EJ Chapman Drive 
Suite 104A 
Knoxville, TN 37996 

4 
 
 
Study Synopsis: 
Title: INVEST: A Single Arm Feasibility Study of Minimally Invasive Endoscopic Surgical Treatment with Apollo 
/ Artemis for Supratentorial Intracerebral Hemorrhage (ICH) 
 
Objective: The primary objective of this multicenter single arm feasibility study is to provide an assessment of 
enrollment and follow up feasibility for this patient population being treated with the Apollo or Artemis Minimally 
Invasive Surgical Treatment (MIES). Patients who do not qualify for the INVEST Feasibility Study will be referred 
to the INVEST Registry study. 
 
Study Design: This study will be a prospective, multi-centered trial that will enroll 50 patients at up to 10 United 
States (US) centers 
 
Patient Population: Patients with moderate-large volume (30-80 cc) supratentorial intracerebral hemorrhage (ICH) 
who present within 24 hours of symptom onset for which the treating physician feels that, in the course of best 
medical care, they will use the Apollo system or Artemis Device. Once enrolled, patients will receive minimally 
invasive endoscopic evacuation with the Apollo system or Artemis Device. 
 
Indication: 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. The Apollo system has been 
cleared for the controlled aspiration of soft tissue and/or fluid during endoscopically guided neurosurgery of the 
ventricular system or cerebrum. In the present study, we propose to investigate the feasibility of studying this 
patient population for eventual implementation of efficacy trials.  
 
Inclusion Criteria: 
1. Patient age ≥ 22 and ≤ 80, or age < 85 with baseline mRS=0 
2. Supratentorial ICH of volume ≥ 30 mL < 80 ml (measured using A x B X C/2 method) 
3. CT/MR demonstrates ICH stability (< 5 cc growth) at least 6 hours after admission scan. If the initial 
stability scan shows growth, a second stability scan can be performed q12h until stability is demonstrated 
or until eligibility for the study has lapsed. 
4. NIHSS ≥ 6 
5. Presenting GCS 5-15 
6. Historical mRS 0 - 2 
7. Symptom onset < 24 h prior initial CT 
8. Apollo / Artemis MIES (minimally invasive endoscopic surgical treatment) can be initiated within 72h of 
ictus/bleed 
9. SBP can be controlled < 180 mmHg and sustained at this level for at least 6 hours 
 
Exclusion Criteria: 
1. Imaging 
a. Expanding hemorrhage on stability CT/MR scan; 
b. “Spot sign” identified on CTA (may perform a second CTA at 12 hours to demonstrate resolution); 
c. Hemorrhagic lesion such as a vascular malformation (cavernous malformation, AVM etc.), 
aneurysm, neoplasm; 
d. Hemorrhagic conversion of an underlying ischemic stroke; 
e. Infratentorial hemorrhage; 
f. Large associated intra-ventricular hemorrhage requiring treatment for IVH-related mass effect or 
shift due to trapped ventricle (EVD (extraventricular drain) for ICP (intracranial pressure) 
management is allowed); 
g. Midbrain extension/involvement. 

5 
 
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). 
 
3. Patient Factors 
a. Presenting GCS of 3 or 4; 
b. High risk condition for ischemic stroke (high risk Afib (e.g., mitral stenosis with Afib), 
symptomatic carotid stenosis); 
c. Requirement for emergent surgical decompression or uncontrolled ICP after EVD 
d. Unable to obtain consent from patient or appropriate surrogate (for patients without 
competence); 
e. Pregnancy, breast-feeding, or positive pregnancy test (either serum or urine). Woman of child- 
bearing potential must have a negative pregnancy test prior to the study procedure; 
f. Evidence of active infection indicated by fever at or over 100.7 °F, and/or open draining wound at 
the time of enrollment; 
g. Any comorbid disease or condition expected to compromise survival or ability to complete follow- 
up assessments through 180 days; 
h. Based on investigator’s judgment, patient does not have the necessary mental capacity to 
participate or is unwilling or unable to comply with protocol follow up appointment schedule; 
i. Active drug or alcohol use or dependence that, in the opinion of the site investigator would 
interfere with adherence to study requirements; 
j. Currently participating in another interventional (drug, device, etc) research project. 
 
 
Primary Endpoints: 
The primary objective is to provide an assessment of enrollment and follow up feasibility for this patient 
population being treated with the Apollo / Artemis MIES, with endpoints defined as: 
 
• Rate of recruitment over a two-year time span following first patient enrollment 
• Rate of successful 180 day follow up obtainment. Statistical details can be found in section 7. 
Secondary Endpoints: 
• Stroke Impact Scale – Mobility at 180 days 
• Stroke Impact Scale – ADLs at 180 days 
• EQ-5D-5L at 180 days 
• Length of hospital stay 
• Clinical Efficacy Endpoint: 180-day global disability assessed via the modified Rankin score (mRS), 
categorized as either mRS < 3 or mRS > 3 
• Technical Efficacy Endpoint: Rate of surgical success 
o Predominantly or Only ICH: Reduction to < 15 cc total volume AND >60% reduction in hemorrhage 
volume on immediate post-treatment CT scan 
o Predominantly or Only IVH: mGraeb score of < 5 on day 7 CT scan 
• Safety Endpoint: Rate of mortality at 90 days

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Table of Contents 
Contents 
INVEST: A Single Arm, Feasibility Study of Minimally Invasive Endoscopic Surgical Treatment with 
Apollo / Artemis for Supratentorial Intracerebral Hemorrhage (ICH) ............................................................... 1 
Version Number: 4 ........................................................................................................................................................ 2 
Study Synopsis: ................................................................................................................................................................. 4 
Inclusion Criteria: .......................................................................................................................................................... 4 
Exclusion Criteria: ......................................................................................................................................................... 4 
Primary Endpoints: ........................................................................................................................................................ 5 
Secondary Endpoints: .................................................................................................................................................... 5 
1. 
Introduction: ........................................................................................................................................................... 0 
1.1 
Rationale for study ................................................................................................................................................. 1 
2. 
Purpose and Hypothesis ......................................................................................................................................... 6 
3. 
Objectives ................................................................................................................................................................ 7 
3.1 Primary Objective .................................................................................................................................................. 7 
3.2 Secondary Endpoints: ............................................................................................................................................ 7 
4. 
Trial design .............................................................................................................................................................. 7 
4.1 Inclusion criteria ..................................................................................................................................................... 7 
4.2 Exclusion criteria .................................................................................................................................................... 8 
4.3 Overview of Study Flow ......................................................................................................................................... 8 
4.4 Study Visits .............................................................................................................................................................. 9 
4.5 Recruitment............................................................................................................................................................. 9 
4.6 Screening and Baseline Evaluation ....................................................................................................................... 9 
4.7 Informed Consent ................................................................................................................................................. 10 
5. 
Study Screening and Treatment Procedure ....................................................................................................... 10 
5.1 Imaging Assessment for Eligibility for Trial Participation ............................................................................... 10 
5.2 Preparation for Treatment .................................................................................................................................. 11 
5.3 Medication during Intervention .......................................................................................................................... 11 
5.4 Devices and Equipment ........................................................................................................................................ 11 
5.5 Procedural Protocol .............................................................................................................................................. 12 
5.6 Post-Procedure Care ............................................................................................................................................ 12 

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5.7 Recovery ................................................................................................................................................................ 13 
5.7.1 
Discharge............................................................................................................................................................ 13 
5.8 Hospital Costs ....................................................................................................................................................... 13 
5.9 Follow-Up Examination ....................................................................................................................................... 13 
5.9.1 
Clinical....................................................................................................................................................... 13 
5.9.2 
Cross-Sectional Imaging .......................................................................................................................... 14 
5.9.3 
Serious Adverse Events ............................................................................................................................ 16 
6. 
Study Primary Endpoints .................................................................................................................................... 16 
6.1 Analysis of Primary Endpoint ............................................................................................................................. 17 
6.1.1 
Definition of Analysis Samples ......................................................................................................................... 17 
7. 
General Statistical Considerations General Design ........................................................................................... 17 
7.1 Sample Size Estimation for the Primary Outcome ............................................................................................ 17 
7.2 Statistical Evaluation ............................................................................................................................................ 17 
7.3 Missing Data and Imputation Methods .............................................................................................................. 18 
7.4 Secondary Statistical Analysis ............................................................................................................................. 18 
7.5 Safety Analysis ...................................................................................................................................................... 18 
7.5.2 
Interim Safety Monitoring................................................................................................................................ 18 
7.6 Blinding ................................................................................................................................................................. 19 
8. 
Study Withdrawal................................................................................................................................................. 19 
8.1 Unattended Visits .................................................................................................................................................. 19 
9. 
Data Safety Monitoring Board (DSMB) ............................................................................................................. 19 
10. 
Trial Operating Committee (TOC) ..................................................................................................................... 20 
11. 
Steering Committee (SC) ..................................................................................................................................... 20 
12. 
Study Management ............................................................................................................................................... 20 
13. 
Investigator Responsibilities ................................................................................................................................ 20 
14. 
Required Documents from the Investigator ....................................................................................................... 21 
15. 
Investigator Records ............................................................................................................................................. 21 
15.1 Data Collection ...................................................................................................................................................... 22 
15.1.2 
Data Acquisition and Central Study Database ...................................................................................... 22 
15.2 Reporting Module ................................................................................................................................................. 23 
15.3 Security, Privacy, and Confidentiality ................................................................................................................ 23 
16. 
Adverse Events ...................................................................................................................................................... 23 

8 
 
16.1 Serious Adverse Events ........................................................................................................................................ 24 
16.2 Reporting and Review of Adverse Events .......................................................................................................... 24 
17. 
Ethical Considerations ......................................................................................................................................... 25 
18. 
Protection of Patient Confidentiality .................................................................................................................. 25 
19. 
Ethics Committee/Institutional Review Board Approval.................................................................................. 26 
20. 
Informed consent .................................................................................................................................................. 26 
21. 
Quality Assurance ................................................................................................................................................. 26 
22. 
Protocol Deviations ............................................................................................................................................... 27 
23. 
Final Report .......................................................................................................................................................... 28 
24. 
Information Confidentiality ................................................................................................................................. 28 
25. 
Trial Registration.................................................................................................................................................. 28 
26. 
Risk Analysis ......................................................................................................................................................... 28 
27. 
Publication Policy ................................................................................................................................................. 28 
28. 
References ............................................................................................................................................................. 29 
 

 
 
1. 
Introduction: 
 
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 100,0001, 2. The incidence of ICH is increasing, likely secondary 
to the increasing mean age of the population3, 4. 
 
ICH is a devastating disease with the poorest prognosis of all stroke subtypes5. The estimated mortality rate is 50% at 
1 year and more than 70% at 5 years6. The majority of survivors are dependent at follow-up7. If there is a 
concomitant component of intraventricular hemorrhage and hydrocephalus, outcomes are even worse8-11. 
 
The high level of intensity and the duration of care required for these patients is manifest in astronomical costs, with 
ICH being ranked amongst the most costly of all neurological diagnoses12. 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 discharge12. 
 
Despite extensive study, no medical or surgical intervention has ever been demonstrated to reduce mortality or 
improve outcomes in patients with ICH. This lack of progress is reflected by the mortality rate of ICH, which has 
been relatively stable for the past several decades13. 
 
Medical management consists of admission to an 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 decompression14. 
 
In those patients lacking an unambiguous indication for life-saving surgical decompression, 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 8, 15-21. 
 
Randomized Trials of Medical Management of Intracranial Hemorrhage: 
 
In the Factor VII for Acute Intracerebral Hemorrhage Trial, 841 patients with ICH were randomized to receive 
placebo or one of two doses of recombinant factor VIIa (rFVIIa) within 4 hours of the onset of symptoms. 
Although the higher dose of rFVIIa was associated with a significantly lower rate of hematoma expansion, this 
effect did not translate to an improvement in clinical outcomes or mortality10. Moreover, it did not appear that an 
increased incidence of thrombotic complications in the rFVIIa group accounted for the failure of the trial 
demonstrate a clinical benefit. 
 
Similarly, two small pilot trials of aggressive medical management of blood pressure INTERACT and ATACH, 
failed to demonstrate any benefit for survival or favorable clinical outcome when compared to more conservative 
medical management15, 16. INTERACT I did show a reduction in hematoma growth with aggressive BP 
management16. 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 significant, but modest, improvement 
with an ordinal analysis of modified Rankin scores (mRS) for the intensive management group. 
 
Trials of aggressive management of cerebral edema with mannitol have also failed17-19. 

 
 
 
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 for hematoma 
evacuation8, 20. In STICH I, early surgical management was compared to standard medical 
management in a series of 1033 patients with supratentorial ICH. Three-quarters of patients 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 patients 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 patients. In STICH II, 601 patients with superficial hemorrhages were 
randomized between early surgery and conservative management. 59% of patients in the surgical group and 61% of 
the patients 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, these data provide 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. 
 
1.1 
Rationale for study 
 
Why would the minimally invasive evacuation of ICH be beneficial? 
 
ICH is thought to induce neurological injury in a biphasic manner. The primary neurological injury is caused by the 
direct mechanical destruction of neurons by the original bleed1. This form of injury is not treatable per se, with the 
exception 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 has 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)22. It is believed that this secondary injury is manifest as peri-hematomal edema 
(PHE) on imaging studies23-25. 
 
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. Later progression was the result of peri-hematomal cerebral edema, which 
occurred between 9 and 21 days after the original bleed23. This delayed progression of edema and mass effect 
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 cases26-29. 
 
Studies of regional perfusion in humans have largely failed to demonstrate significant regions of ischemia in the 
brain surrounding ICH30, 31. 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 32-34. 
 

 
 
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. 
 
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. 
Correspondingly, it is possible that the potential benefits of hematoma evacuation could be realized if the procedure 
could be performed through a 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 (20-50cc), of moderate age (50 – 69 
years) and with moderate to severe clinical deficits (GCS 9 – 12). Incidentally, an evaluation of the contributing 
data sets indicates that a single study (Wang et al.) largely drove the clinical benefit in each of the cohorts35. 
 
Wang et al. conducted a randomized trial in 465 patients with intracranial hemorrhage, randomizing patients 
between medical management and 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) 90 days35. 
 
This minimally invasive CT-guided craniopuncture technique is routinely practiced in China with over 150,000 
patients undergoing this procedure yearly35, 36. Zhou 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 patients undergoing MIS (minimally invasive surgery)36. 
 
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)37, 38. 
 
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 t-PA for up to four days. These investigators reported a significant reduction in perihematomal edema as well as 
trends toward better clinical outcomes at 180 and 365 days25, 37. They also observed an improvement in mobility and 
independence in ADLs 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 patients with < 10 cc’s of residual hemorrhage having the best 
outcomes. Unfortunately, only a minority of patients 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 trial38, 48 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. These investigators observed that IT-tPA infusion increased the rate at which the IVH 
cleared. Moreover, patients 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 patients (23%) in this cohort experienced symptomatic re-hemorrhage, with four 
requiring 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. 
 
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 suffer 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 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, re-bleeding with thrombolytic irrigation is not an 
insignificant risk, particularly with respect to intraventricular administration, as demonstrated in CLEAR IVH. 
 
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 t-PA 
reduces the potential for re-hemorrhage secondary to the local thrombolytic effect. 
 
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 cautery39. 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 allocation40. 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. 

 
 
The Apollo System and Artemis Device 
 
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. 
 
The Apollo System is an aspiration-irrigation apparatus, which is coupled to a low-profile wand (2.1 and 2.6 mm 
diameter sizes). The Apollo Wand houses an internal vibrating element that, when actuated with a foot pedal, 
macerates clot material within the wand to maintain patency of the system during aspiration. This design allows a 
targeted evacuation of blood products through a minimally invasive access without clogging. The Apollo Wands fit 
through the working channels of commercially available neuroendoscopes (Lotta, Karl Storz, Tuttlington, 
Germany) such that clot evacuation can be performed under direct visualization41, 42. 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 ultrasound42. 
 
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 visualization41, 42. 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 ultrasound42.  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 
cc in 48% of patients treated. As opposed to the ICES technique, in most cases, no drainage catheters were placed 
following the initial evacuation43. 
 
Thus the Apollo System and the Artemis Device potentially provides a means by which to efficiently and reliably 
achieve a minimally invasive, mechanical evacuation of intracranial hemorrhage under direct visualization and 
control using a neuroendoscope without the requirement for subsequent catheter placement and thrombolytic 

 
 
irrigation. 
 
 
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 significant potential shortcomings of this technique compared to the purely mechanical approach with the 
Apollo system or Artemis Device. Apollo system, has been commercially available for over 3 years and early 
experience with the system in regards to its application to remove parenchymal hemorrhages has evolved. As such, 
now that the technical approach has matured, it is necessary to carry out a feasibility single arm study before 
proceeding to a randomized controlled trial with a larger patient population. 
 
Rationale for the INVEST Feasibility Design 
 
The INVEST feasibility study was designed to include those patients who theoretically hold the highest potential to 
benefit from the Apollo or Artemis MIES procedure and thereby assess our ability to recruit and follow this patient 
population, which has been identified to maximize the odds of potentially observing a treatment effect in subsequent 
RCTs. Specific components of the design are addressed below. 
 
Patients with presenting GCS of < 4 have been excluded from the INVEST feasibility study. Patients with very 
low GCS (3-4) represent a heterogeneous group and many will have severe, unrecoverable injuries potentially 
involving the brain stem. While some in this group may, in fact, benefit from the Apollo or Artemis MIES procedure, 
it is likely that majority will not. Furthermore, this severely injured patient population will likely have substantial 
barriers to follow up and may limit long-term data collection. As such, these patients are excluded from the INVEST 
feasibility study so as not to include a population that might eventually dilute any evidence of a potential treatment 
effect in a subsequent RCT. At the same time, if experienced operators at INVEST centers identify individual patients 
in this group whom they feel will benefit from the Apollo or Artemis MIES procedure and intend to treat the patients 
outside of the INVEST feasibility study, these patients may be eligible for enrollment in the companion INVEST 
single-arm observational registry (see accompanying protocol).  
 
Patients with hemorrhages less than 30 cc or greater than 80 cc are excluded from the INVEST feasibility 
study. Our preliminary experience has indicated that hemorrhages ranging between 30 and 80 cc are feasibly treated 
with Apollo/Artemis MIES1. A supratentorial hemorrhage of < 30 cc is not likely to create an injury great enough to 
reach an NIHSS of 6 or higher as required for inclusion. Patients with hemorrhages of < 30 cc also have a higher 
likelihood of making an excellent functional recovery without intervention as was referenced in Broderick, et.al.2. As 
such it is likely that including patients with small hemorrhages could obscure our ability to see a signal for a treatment 
effect. Also at this volume level, the hemorrhage represents a much smaller “target”, which increases the challenge of 
accurately placing the sheath into the hemorrhage. When hemorrhages are larger than 80 cc, patients are more likely 
to require very early open surgical evacuation or decompression due to the initial mass effect (even if they were 
thought to be non-surgical at presentation). To reduce (to the extent possible) the incidence of early open surgical 
“bail-out” (or cross—over to Apollo/Artemis MIES) for patients randomized into the medical management arm of the 
trial, these patients are excluded. Moreover, when lobar hemorrhages are larger than 80 cc, they tend to be irregularly 
shaped and multi-compartmental, with areas that are difficult to access with the Apollo system/Artemis Device -- thus 
reducing the potential to achieve the pre-determined surgical goal (> 60% reduction and volume < 15 cc) without 
requiring multiple access sites or a larger craniotomy with multiple sheath trajectories1. 

 
 
 
Vascular imaging is required in all patients being enrolled in the INVEST feasibility study.  Computed 
tomographic angiography (CTA) (or MRA and conventional angiography) is very informative in patients with 
spontaneous supratentorial ICH – both lobar and deep. Vascular imaging is critical for excluding an underlying 
vascular lesion, and it is also important for identifying patients at-risk for early hematoma expansion (e.g., those with 
a “spot sign”). The new AHA ICH guidelines list CTA as a class IIa treatment effect (benefit >> risk)3.  We feel that 
the requirement for CTA (or MRA in patients with contra-indication to CTA – i.e., history of severe contrast allergy) 
markedly increases patient safety and is critical to the study. High quality vascular imaging is particularly critical in 
patients who will undergo Apollo or Artemis MIES, which could be disastrous if undertaken in the presence of an 
underlying unsecured vascular lesion. MRA may be performed in patients who have absolute contraindications to 
CTA. Also, conventional angiography may be substituted for CTA or performed for further evaluation of selected 
patients at the discretion of the investigator.  
 
2. 
Purpose and Hypothesis 
 
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. Currently no 
prospective study exists evaluating the efficacy of the minimally invasive endoscopic surgery (MIES) with the 
Apollo system or Artemis Device for this purpose. The purpose of this feasibility trial is to provide an initial 
assessment of the enrollment and follow up practicality within the patient population receiving MIES treatment. 
 
2.1 
Risk Analysis 
 
The primary risks to subjects in this study are associated with the minimally invasive surgical procedure and the 
associated general anesthetic. Imaging performed throughout the course of the study, while specified in the protocol, 
falls well within the standard of care for the initial evaluation and follow-up of patients with intracranial hemorrhage. 
The Apollo or Artemis MIES procedure is performed in a manner, which is similar to that of other                      
neuroendoscopic procedures, and the associated risks are likewise similar. In brief (see Section 5 for a detailed 
description of the procedure), the Apollo/Artemis MIES procedure itself involves the creation of a mini- 
craniectomy and dural incision. An endoscopic sheath (19-22F) is then placed through this access site into the 
hematoma under imaging control using neuronavigation. Then, under endoscopic guidance, the hemorrhage is 
evacuated with the Apollo system or Artemis Device. Following the evacuation, the endoscope and Apollo system or 
Artemis Device are removed. 
 
Control intraoperative (as specified in Section 5) CT imaging is performed to assess the remaining hemorrhage 
volume and to assess for immediate procedural complications. Based on the intra-operative control 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. 
 
Risks related to the procedure include bleeding, infection or damage to surrounding structures during the creation of 
the cranial access or placement of the sheath. These risks are all unlikely and are estimated to occur in less than 5% 
of cases. During evacuation of hemorrhagic products with the Apollo system / Artemis Device, there is the 
possibility of inducing or encountering additional hemorrhage in the operative bed. In a retrospective multicenter 
study of the Apollo / Artemis procedure for the treatment of ICH, re-bleeding was encountered in 2 of 29 patients 
(6.9%). 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 Society of Anesthesiologists (ASA) score would typically be 4 or 4e in this category of 
patients. 
 
All information concerning subjects will be kept confidential. Subjects will be assigned study ID #. No personal 
identifying information will be used in presentation or publication of data from this study. 
 
A list of all anticipated adverse events is listed in the Manual of Procedures 
 
3. 
Objectives 
 
3.1 
Primary Objective 
 
• The primary objective is to provide an initial assessment of enrollment and follow up feasibility for the patient 
population being treated with the Apollo / Artemis MIES.  Primary Endpoint: rate of successful obtainment of 
modified Rankin score (mRS) at 180 days 
3.2 
Secondary Endpoints: 
 
Secondary Endpoints: 
• Stroke Impact Scale – Mobility at 180 days 
• Stroke Impact Scale – ADLs at 180 days 
• 5Q-5D-5L at 180 days 
• Length of hospital stay 
• Clinical Efficacy Endpoint: 180-day global disability assessed via the modified Rankin score (mRS), 
categorized as either mRS < 3 or mRS > 3 
• Technical Efficacy Endpoint: Rate of surgical success 
o Predominantly or Only ICH: Reduction to < 15 cc total volume AND >60% reduction in hemorrhage 
volume on immediate post-treatment CT scan 
o Predominantly or Only IVH: mGraeb score of < 5 on day 7 CT scan 
• Safety Endpoint: Rate of mortality at 90 days 
 
4. 
Trial design 
 
This is a prospective, multicenter feasibility trial utilizing Apollo / Artemis MIES in patients with supratentorial 
intracerebral hemorrhages. Patients will be enrolled who meet the inclusion and exclusion criteria and consent to 
participate. Data on each patient will be collected at the time of enrollment and treatment, and at subsequent 
follow-up visits. 
 
4.1 
Inclusion criteria 
1. Patient age ≥ 22 and ≤ 80, or age < 85 with baseline mRS=0 
2. Supratentorial ICH of volume ≥ 30 mL < 80 ml (measured using A x B x C/2 method) 
3. CT/MR demonstrates ICH stability (< 5 cc growth) at least 6 hours after admission scan 
a. If the initial stability scan shows growth, a second stability scan can be performed q12h 
until stability is demonstrated or until eligibility for the study has lapsed. 
4. NIHSS ≥ 6 
5. Presenting GCS 5 - 15 
6. Historical mRS 0 - 2 
7. Symptom onset < 24 h prior initial CT 

 
 
8. Apollo / Artemis MIES can be initiated within 72h of ictus/bleed 
9. SBP can be controlled < 180 mmHg and sustained at this level for at least 6 hours 
 
4.2 
Exclusion criteria 
1. Imaging 
a. Expanding hemorrhage on stability CT/MR scan  
b. “Spot sign” identified on CTA, MRI/MRA or conventional angiography 
i. May perform a second CTA (or MRI/MRA or angiography) at 12 hours to demonstrate 
resolution 
c. Hemorrhagic lesion such as a vascular malformation (cavernous malformation, AVM etc), aneurysm, 
neoplasm 
d. Hemorrhagic conversion of an underlying ischemic stroke 
e. Infratentorial hemorrhage 
f. Large 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 
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 
 
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) 
3. Patient Factors 
a. Presenting GCS 3 or 4 
b. High risk condition for ischemic stroke (high risk Afib (e.g., mitral stenosis with Afib), symptomatic 
carotid stenosis) 
c. Requirement for emergent surgical decompression or uncontrolled ICP after EVD 
d. Unable to obtain consent from patient or appropriate surrogate (for patients without competence) 
e. Pregnancy, breast-feeding, or positive pregnancy test [either serum or urine] (Woman of child- bearing 
potential must have a negative pregnancy test prior to the study procedure.) 
f. Evidence of active infection [indicated by fever (at or over 100.7 °F) and/or open draining wound] at 
the time of enrollment 
g. Any comorbid disease or condition expected to compromise survival or ability to complete follow- up 
assessments through 180 days. 
h. Based on investigator’s judgment, patient does not have the necessary mental capacity to participate or 
is unwilling or unable to comply with protocol follow up appointment schedule. i Active drug or 
alcohol use or dependence that, in the opinion of the site investigator would interfere with adherence to 
study requirements. 
i. Currently participating in another interventional (drug, device, etc) research project. 
 
4.3 
Overview of Study Flow 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
All sites will keep a screen failure log of all ICH presenting within 24 hours of symptom onset but who are not 
enrolled into the study. Reason(s) for exclusion will be recorded. Logs will be entered by the clinical sites and 
reviewed on a consistent basis. Recruitment rates will be tracked over time for each hospital. The actual recruitment 
rates as well as potential recruitment rates will be useful for planning further clinical trials and determining the 
widespread impact of the therapy. 
 
Patients with ICH or IVH who are not enrolled into the trial, but who undergo Apollo or Artemis MIES at the 
participating sites, will be eligible for a concurrent prospective, observational, registry for 180 days (see the 
Manual of Procedures). 
 
4.4 
Study Visits 
Subjects enrolled to this study will follow the below visits schedule according to their institutional standard of care 
for stroke patient follow-up. 
 
• Pre-Treatment 
• Procedure 
• Post procedure (within 24 hours, Apollo / Artemis MIES patients)  
• 7 days post-enrollment or Discharge (whichever comes first) 
• Discharge (if beyond 7 days) 
• 3 month follow-up (+/- 14 days) 
• 6 month follow-up (+/- 21 days) 
• 12 month follow-up (+/- 35 days) 
•  
4.5 
Recruitment 
The target population for the Apollo / Artemis MIES feasibility study are patients 22-84 years of age who have a 
diagnosis of spontaneous, non-traumatic, intracerebral hemorrhage (ICH) ranging in volume between 30 and 
80cc, 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 participants and/or their legal authorized representative will be identified by the study team at each 
site to obtain consent and determine eligibility. Up to 10 United States sites centers will be included in this study to 
enroll 50 patients. 
 
4.6 
Screening and Baseline Evaluation 
CT Head/ CT Angiogram 
Stability Scan(s) (CT or MR) 
 

 
 
 
During screening and baseline evaluations consent is obtained, medical history screened, available 
clinical/neurological exams obtained, and laboratory work and imaging information per institutional standard of care 
are evaluated to determine patient eligibility. The baseline neurologic examination will be performed by a health care 
provider or study team member, certified to administer the exams and able to give an unbiased neurological and 
functional assessments (NIHSS, Glasgow Coma Score (GCS), and perform a historical mRS determination). CT 
imaging must be performed to provide an initial diagnosis of IPH (intraparenchymal hemorrhage). Hemorrhage 
volume will be determined using the A x B x C/2 method. Subsequent stability imaging (CT (preferred) or MR) must 
be obtained at least 6 hours after the presenting scan to confirm stability in the hemorrhage volume. A CTA (or MRA 
for CTA ineligible patients) must also be performed, as standard of care; either at presentation with the diagnostic 
CT or with the stability scan. Enrollment will occur in consented patients with a stable hemorrhage volume on follow 
up CT or MR (< 5 cc increase in volume). In the case that the stability scan demonstrates hemorrhage volume 
increase > 5 cc, a second stability scan can be obtained q12 hours until either stability is demonstrated or the patient 
is outside of the window for treatment (72 hours from the time of ictus). In  the case of a “spot sign”, follow up CTA 
(or MRA if ineligible for CTA) can be obtained q12 hours to show resolution of the “spot sign” prior to enrollment. 
An NIHSS must be obtained prior to enrollment, and the score must be > 6 for inclusion in the study. A pregnancy 
test will be conducted for applicable subjects (<50 years old and of child bearing potential). Once the patient meets 
all eligibility criteria, has undergone a stability scan, and the patient or LAR (legally authorized representative) has 
provided written informed consent, they will be considered enrolled in the study. Enrolled patients will be treated 
using Apollo / Artemis MEIS  
 
4.7 
Informed Consent 
A member of the research team will explain the study’s objectives to potential candidate patients, including 
describing standard treatment with the study device, the requirements of the clinical investigation, and risks and 
benefits of participating. All informed consent documents used under this study protocol will be consistent with 
applicable elements of ISO14155, Good Clinical Practice Guidelines (E6, E6(R1), E6(R2)), and 21 CFR Part 50, 
and will be approved by the site’s reviewing IRB/EC prior to study initiation.  
 
5. 
Study Screening and Treatment Procedure 
The treatment procedure is described briefly below. The study procedure will take place within 72 hours of the 
clinical presentation of ICH -- after completion of the clinical baseline assessment, the presentation and stability 
imaging. 
 
5.1 
Imaging Assessment for Eligibility for Trial Participation 
 
The subject should be clinically evaluated in the same manner as any patient with non-traumatic spontaneous intra- 
parenchymal hemorrhage. Clinical assessment documenting NIHSS, GCS, baseline mRS and significant past 
medical history should be obtained. Imaging with CT and CTA (MRA is acceptable in CTA ineligible patients) is 
required to confirm the diagnosis of ICH and exclude a vascular etiology. Hemorrhage volume will be measured 
using an A x B x C/2 algorithm. A Hemphill score will be assigned based upon the clinical presentation and 
imaging. Additional anatomic, vascular and physiologic imaging with MRI, MRA or conventional angiography per 
the institutional standard of care should then be performed on patients as part of a standard evaluation for non-
spontaneous hemorrhage etiology. In patients with a CTA “spot sign” on presentation imaging, a follow up CTA 
must be performed at 12 hours to verify resolution of this finding prior to enrollment. 
Increase in hematoma size of <5 cc will be considered “stable” on the stability scan. In the case that the stability scan 
demonstrates hemorrhage volume increase > 5 cc, a second stability scan can be obtained q12 hours until either 
stability is demonstrated or the patient is outside of the window for treatment (72 hours from the time of ictus). 

 
 
Patients meeting all inclusion and no exclusion criteria will be eligible for enrollment after the stability scan. 
 
5.2 
Preparation for Treatment 
 
Patients enrolled in the trial and receiving Apollo / Artemis MIES will also receive best medical management in 
addition to the procedure. Reversible coagulopathies at presentation will be corrected as determined by the attending 
physician managing the patient. 
Ventricular drains will be placed as deemed necessary by the managing interventional team to manage ICPs. 
 
Apollo / Artemis MIES will be performed under general anesthesia. The Apollo / Artemis MIES procedure must 
occur within 72 hours of clinical presentation (ictus). The subject should be prepared for the planned intervention 
according to standard hospital procedures.  Apollo / Artemis MIES will be performed as described below (5.5) 
 
 
5.3 
Medication during Intervention 
 
Medications may be administered during the procedure as determined by the attending anesthesiologist and/or 
interventionist in accord with established standard procedural management. 
 
5.4 
Devices and Equipment 
In addition to the Apollo System and Artemis Device, other devices required for the procedure are 
listed in Table 5. Table 5: Devices that are used during the Apollo / Artemis MIES procedure 
 
Standard Cranial Access Devices and 
Endoscopy Sheath 
All FDA cleared cranial access systems and 
suitably sized endoscopy sheaths (19-22F) 
will be allowed in the study 
Neuronavigation System 
All FDA cleared neuronavigation systems 
will be allowed in the study 
Neuroendoscopy System 
All FDA cleared neuroendoscopy systems 
(e.g. Storz Lotta) which incorporate a 
trocar with a working channel which will 
accommodate either the 1.5, 2.1,  or 2.8 
mm Artemis Device will be allowed in 
the study.  
Penumbra Aspiration Systems 
 
The Aspiration Pump and canister for all 
FDA cleared Penumbra Aspiration 
Systems will be allowed in the study 
CT Monitoring (within or outside of OR) 
All FDA cleared computed tomography or 
cone beam computed tomography systems 
will be allowed in the study. 
 
 
All medical therapy decisions are recommended to be in accordance with guidelines from the AHA or Critical care 
guidelines. 
 

 
 
The specific types of devices used in each Apollo / Artemis MIES procedure will be recorded in the appropriate CRF. 
 
 
5.5 
Procedural Protocol 
 
Appropriately protocoled (depending on the institution and neuronavigation units) MR or CT imaging studies will 
be uploaded into the neuronavigation software (e.g., iPlan Net, Brainlab, Feldkerchin Germany) 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. 
 
Patients will be placed supine upon the procedural table, and a sterile field prepared. An external localization array 
or other neuronavigation localization mechanism (e.g. Skull Reference Base with Skull Reference Array with 
Reflective Marker Spheres, Brainlab) will be placed for registration. Following registration, a second sterile field 
will be prepared over the region of the cranial access. A burr hole or minicraniotomy will then be created in a 
standard manner of a size large enough to accommodate the selected endoscopy sheath. A localization array (e.g., 
Instrument Adapter Clamp with Instrument Adapter Array, Brainlab) will be attached to the selected 
neuroendoscopic sheath (e.g., Aesculap Inc, Center Valley, PA) and registered to the navigation system. The sheath 
will then be advanced using neuronavigation into the targeted landing zone within the distal aspect of the hematoma 
and 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 (e.g., Lotta, Karl Storz, Tuttlington, Germany) 
will then be inserted into the sheath and under direct visualization the Apollo Wand or Artemis Device will be 
placed through the working channel of the trocar. The sheath will be irrigated at the discretion of the operator using 
the irrigation port of the endoscope and the irrigant will be intermittently aspirated with the Apollo system or 
Artemis Device 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 Apollo Wand or Artemis 
Device 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 intermittently to clear the field. When all blood products are cleared from the 
working field, the sheath will be retracted serially and the procedure repeated. The position of the sheath 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. At that point, further visualization of the evacuated cavity through 
the endoscopic may be performed to ensure there is no active bleeding or substantial residual hematoma.  Once completed, 
the neuroendoscopic trocar and Apollo Wand or Artemis Device will be removed. An intra_operative CT (e.g. 
dynaCT, Siemens, Medical Imaging, Erlangen, Germany) will then be performed using cone_beam CT, an intra-
operative or portable conventional CT unit, or the OR room will be held open for re_operations and the patient 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. The surgical goal is to achieve a 
60% reduction in hemorrhage volume AND a final hemorrhage volume of < 15cc4. 
 
After the hemorrhage evacuation is completed, the sheath will be removed and the cranial access site will be closed 
in a standard manner. 
 
 
5.6 
Post-Procedure Care 

 
 
 
Standardization of medical management will occur according to the following: 
 
• General medical management according to AHA guidelines44 
• Admission to monitored or intensive care unit for at least 24 hours 
• Close monitoring of BP with treatment according to AHA guidelines44 
• Follow-up imaging studies as indicated in any patient with neurologic deterioration 
 
A post-procedural CT scan will be obtained within 24 hours in all patients undergoing Apollo / Artemis MIES. 
Neurological and functional exams will be conducted within 24 hours (+/- 12 hours) in patients undergoing Apollo / 
Artemis MIES. A CT (preferred) or MR scan will also be obtained 7 days after enrollment. Additional imaging will 
be obtained at the discretion of the managing service based upon clinical data and established institutional standard 
of care. 
 
5.7 
Recovery 
The subject will be recovered from the procedure and discharged from the hospital as per standard practices. 
 
5.7.1 
Discharge 
 
At discharge, 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 enrollment, 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. 
 
5.8 
Hospital Costs 
 
For each subject, overall costs will attempt to be collected for the initial hospitalization during which study 
enrollment took place. These costs will include device costs (the market price for each device), materials used to 
treat the hemorrhage, and number of days spent in the hospital (ICU and non-ICU length of stay). In summary, 
the total amount billed and the total amount reimbursed will be collected and assessed, if possible. 
 
5.9 
Follow-Up Examination 
 
5.9.1 
Clinical 
 
Several clinical outcome measures were selected for this study. These 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 electronic case report forms as well as within the medical record and/or in research source 
documentation as appropriate.  
 
1. Modified Rankin Scale: mRS is an overall assessment of global handicap. In the original 
Rankin Scale, a score of zero indicates the absence of symptoms and a score of 5, severe 
disability. The modified Rankin Scale adds a score of 6 for fatal outcomes. A historical 
mRS will be obtained to assess the patient’s level of function prior to the ICH. The score 
will be repeated as specified in Table 1. 

 
 
2. 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. The score will be repeated as specified in 
Table 1. 
3. The National Institutes of Health Stroke Scale is a 42-point scale that quantifies 
neurologic deficits in 11 categories. Normal function without neurologic deficit is given a 
score of zero. NIHSS should be done by a certified examiner as close to the specified 
times as possible. 
4. 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. 
5. 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 
byquality 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. 45 45 45 
45 45 4547 
 
 
All day 7, discharge, day 90, day 180 and day 360 clinical outcome measures will be assessed by a 
qualified member of the research or clinical team. The schedule of neurological assessments is listed in 
Table 1. At each visit, the patient medical record will be surveyed for any new or interim neurological 
adverse or serious adverse events. In addition, the patient or LAR will be asked about any interim 
neurological adverse or serious adverse events. The subject or LAR will also be specifically asked about 
any interim neurosurgical procedures. 
 
 
5.9.2 
Cross-Sectional Imaging 
 
All scheduled CT and MR studies will be assessed by a central core lab neuroradiologist. 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 calcualed either by multiplying the number of CT slices which depict the hematoma by the 
slide thickness or determined on coronal or sagittal reconstructions. 
Hemorrhage volumes will also be assessed using a manual volume measurement technique on the 
diagnostic scan and all subsequent scans, as defined in the Imaging Manual. Intraventricular hemorrhage 
will be assessed on each scan and graded according to a modified Graeb score (see the Imaging Manual 
and Manual of Procedures). 
Scheduled imaging studies include the diagnostic/admission scan, the stability scan(s) (at least 6 hours 
after the diagnostic scan), CT or MR angiogram (with either the diagnostic or stability scan), Post- 
operative post-presentation scan 7 day post presentation scan.

 
 
 
 
 
 
Table 1. Schedule of Events 
 
 
 
ACTIVITY 
SCREENING 
/BASELINE 
STABILITY 
SCAN (at least 
6 hours post 
initial CT) 
TREATMENT 
24 hour post -
MIES (+/-12) 
DISCHARGE 
AND /OR 7 
DAYS (+/- 1 
day) 
3 MONTHS 
(+/- 14 
days) 
6 MONTHS 
(+/- 21 
days) 
1 YEAR or 
END OF 
STUDY (+/- 
35 days) 
Informed Consent 
X 
Inclusion/ Exclusion 
Criteria 
X 
Medical History 
X 
Focused Exam 
X 
X 
X 
X 
X 
X 
X 
Standard of Care Labs 
X 
X 
X 
X 
Standard of Care 
CT/MR 
X 
X 
X  
 
X 
CTA or MRA 
X (or at 
stability) 
X (if not done 
with Baseline) 
Barthel 
Historic 
X 
X 
X 
NIHSS 
X 
X 
X 
X 
X 
X 
X 
GCS 
X 
X 
X 
X 
X 
X 
X 
mRS 
Historic 
X 
X 
X 
X 
X 
Stroke Impact Scale 
(QOL) 
X 
X 
X 
ED-5D-5L 
X 
X 
X 
Pregnancy Test if 
childbearing potential 
X 
Or X 
Con Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Apollo / Artemis MIES 
under general 
anesthesia within 24 
hours of sx onset  
 
 
X 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
All brain imaging sent to 
central core lab 
within 48 hours 
of test 
within 48 
hours of test 
within 48 
hours of test 
within 48 
hours of test 
within 48 
hours of test 

16 
 
 
5.9.3 Serious Adverse Events 
 
All serious adverse events occurring during the 365 days of study participation will be recorded. Adverse 
events and serious adverse events are critical endpoints and will be assessed as they occur and at the 
scheduled clinic visits. A serious adverse event is one that is fatal or life-threatening, is permanently or 
substantially disabling, requires or prolongs hospitalization, or any event that the treating clinician judges 
to be a significant hazard. For each recorded serious adverse event, the patient’s attending physician will 
be asked to classify the causal relationship of the event to the study treatment as probable, possible, 
unlikely, and unrelated. Detailed form and narrative reports of the following specific adverse events will 
be obtained: 
 
• Death (all cause) within 90 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 90 days 
associated with an increase of 4 or more points on the NIHSS or GCS increase > 2 persisting for 
at least 24 hours and/or requiring emergency surgical decompression or resulting in death5, 6. 
• Symptomatic Evolution of Perihematomal Edema: Edema with increased mass effect or 
uncontrolled ICPs within 90 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 increase > 2 persisting for at least 24 hours, and/or 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 90 days 
associated with an increase of 4 or more points on the NIHSS or GCS increase > 2 persisting for 
at least 24 hours and/or requiring emergency surgical decompression or resulting in death. 
• Surgical complications related to Apollo / Artemis MIES: 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 90 
days. 
 
 
A medical monitor will review these specific categories of events as they are reported. The DSMB will also function 
as the CEC and will review all of these specified categories of events at regularly scheduled DSMB meetings, which 
will occur at approximately 6-month intervals during the study. 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 trial be placed on hold and request additional analyses of the trial 
dataset. The DSMB will issue reports for each meeting. The DSMB will be composed of three cerebrovascular 
specialists and a statistician. Safety stopping rules for the primary safety endpoint will be developed and used to help 
the DSMB make its safety assessments. Additional details of the monitoring plan will be included in the study MOP. 
Additional details regarding the DSMB structure and stopping rules will be included in the DSMB charter. 
 
6. 
Study Primary Endpoints 
 
The primary objective is to assess the impact of Apollo / Artemis MIES upon clinical outcomes in patients with 
supratentorial intracranial hemorrhage with primary endpoints defined as: 
 
• Rate of recruitment over a two-year time span following first patient enrollment 
• Rate of successful 180 day follow up obtainment.  

17 
 
• Statistical details can be found in section 7.2. 
 
6.1 
Analysis of Primary Endpoint 
 
6.1.1 
Definition of Analysis Samples 
 
1. Target Population 
 
The target population for the Apollo / Artemis MIES trial are patients 22-84 years of age who have a 
diagnosis of spontaneous, non-traumatic, intracerebral hemorrhage (ICH) ranging in volume between 30 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. 
 
 
7. 
General Statistical Considerations 
General Design 
The Apollo / Artemis MIES Trial is a multicenter, single arm feasibility study investigating the potential efficacy of 
Apollo / Artemis MIES to improve clinical outcomes in patients with spontaneous, non-traumatic, ICH presenting 
within 24 hours. The primary hypothesis to be tested is that Apollo / Artemis MIS patients can be recruited and 
followed successfully for 180 days. 
 
 
7.1 
Sample Size Estimation for the Primary Outcome 
 
Sample Size Calculation 
 
 
The Apollo / Artemis MIES Trial is a prospective, multi-center, single-arm feasibility trial investigating enrollment 
of the Apollo / Artemis MIES in patients with spontaneous, non-traumatic, ICH presenting within 24 hours. Up to 
50 subjects will be enrolled in this study. The primary outcome assessed at trial completion will be successful 
capture of 180 day modified Rankin score (mRS) for those 50 patients enrolled in the study.  Additionally, we will 
analyze the proportion of patients achieving mRS of 0-3 and 90 day mortality. 
 
 
 
7.2 
Statistical Evaluation  
 
Statistical Analysis of Primary Outcome 
 
Two-sided 95% confidence intervals will be calculated for the proportion of subjects with captured mRS scores at the 
180-day follow-up visit using the exact binomial distribution.  
 
Statistical Analysis of Secondary Outcomes 
 
Secondary efficacy analyses will include 180-day global disability assessed via mRS, analyzed as the proportion of 
patients achieving mRS of 0-3.  Two-sided 95% confidence intervals will be calculated for the proportion of 
subjects with mRS scores of 0-3 at the 180-day follow-up visit using the exact binomial distribution. The Kaplan-
Meier Curve will be generated to assess the 90 day mortality. With the date of enrollment set at day 0, and any 
death occurring on or before day 90 will be included as a death. 

18 
 
 
Subsequent Statistical Analysis 
 
Statistical analysis of the SIS-ADL, SIS-mobility, EQ-5D-5L, and Length of Stay will be analyzed with confidence 
intervals. 
 
Other pre-specified analyses will be performed as outlined in the statistical plan. 
 
7.3 
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). The number and proportion of 
subjects eligible for and compliant with each follow-up examination will be presented. Subjects who withdraw from the study 
will be tabulated with reasons for withdrawal. Additional details will be provided in the Statistical Analysis Plan (SAP).  
 
7.4 
Secondary Statistical Analysis 
 
Statistical analysis of the raw Rankin outcome scores of 0 to 6 (with 5 and 6 collapsed) will be conducted with an 
adjusted ordinal logistic regression model (proportional odds model). This analysis will be adjusted using key 
baseline variables. The odds ratio and corresponding 95% confidence interval will be presented for the treatment 
effect. 
 
Group differences will be analyzed by the non-parametric Wilcoxon rank sum test for the following: 
• SIS-ADL 
• SIS-mobility 
• EQ-5D-5L 
• Length of Stay 
 
Other pre-specified analyses will be performed as outlined in the statistical plan. 
 
 
7.5 
Safety Analysis 
 
7.5.1 
Safety Outcomes 
Safety outcomes 
Several specific adverse events are monitored throughout the study. However the primary safety outcome to be 
assessed at completion of the trial will be death within 90 days. 
 
 
7.5.2 
Interim Safety Monitoring 
 
7.5.2.1 
Stopping the Trial Based on Interim Safety Data 
 
The Trial Operating Committee (TOC) and Data Safety Monitoring Board (DSMB) will receive periodic safety 
reports of all AEs and SAEs. In addition, the following specific endpoints will be assessed by the medical monitor 
and presented: 
 
• Death (all cause) within 90 days of enrollment 
• Death within 7 days of enrollment: Immediate periprocedural death 

19 
 
• 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 90 days 
associated with an increase of 4 or more points on the NIHSS or GCS increase > 2 persisting for 
at least 24 hours and/or requiring emergency surgical decompression or resulting in death5, 6. 
• Symptomatic Evolution of Perihematomal Edema: Edema with increased mass effect or 
uncontrolled ICPs within 90 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 increase > 2 persisting for at least 24 hours and/or 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 9s 
associated with an increase of 4 or more points on the NIHSS or GCS increase > 2 persisting for 
at least 24 hours and/or requiring emergency surgical decompression or resulting in death. 
• Surgical complications related to Apollo / Artemis MIES: 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 90 
days. 
 
Additional details of the monitoring plan will be included in the study MOP. Additional details regarding the DSMB 
structure and stopping rules will be included in the DSMB charter. 
 
 
7.6 
Blinding 
 
This study is not blinded. Blinding is difficult, if not impossible, from a clinical perspective. It is not possible to 
blind the Investigator who treats the patient, the clinical staff or the research team. Additionally, physicians treating 
subjects who experience an adverse event after must know how the hemorrhage was treated in order to effectively 
report the adverse event and plan further treatment. Blinding the study is not required for interpretation of study 
outcomes. 
 
 
8. 
Study 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 withdrawal of consent will be maintained in the study database. 
• Lost to follow-up –– defined as a subject who is more than one month late to a study visit and for whom 5 
documented telephone attempts to contact the subject and at least one certified letter were unsuccessful. 
• Subjects may also be withdrawn at the investigator’s discretion if within their best interest. 
 
8.1 
Unattended 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). If the missed visit was due to a serious adverse event, (e.g., re- 
hospitalization) an AE Case Report Form (CRF) must be completed and any reporting requirements met. 
 
 
9. 
Data Safety Monitoring Board (DSMB) 
A DSMB will be comprised of 4 members not participating in the trial and will include neurovascular specialist 
physicians and a statistician. The DSMB will exercise review of the overall safety of the trial, periodically review all 
adverse events occurring in the trial, and make recommendations to adjustments in the study protocol, should any be 

20 
 
considered necessary for safety or other related reasons. Additional details will be specified in the DSMB charter. 
 
 
10. 
Trial Operating Committee (TOC) 
The TOC will consist of the study PIs, statistical PI, project managers, data managers, and others deemed necessary 
in overseeing the day-to-day operations of the trial. The TOC will review study progress, study conduct at 
individual clinical sites, other clinical site performance measures, and blinded DSMB reports. 
 
 
11. 
Steering Committee (SC) 
The SC will be comprised of the trial PI’s and selected principal investigators from participating centers. The SC 
will be responsible for overall supervision and execution of the trial including adherence to protocol, progress of 
enrollment, patient safety and consideration of new information. Daily trial management is the responsibility of the 
TOC. It will provide key input to the SC for study planning, execution and data presentation. 
 
 
12. 
Study Management 
 
As the study Principal Investigators, J Mocco MD, David Fiorella MD PhD, and Adam Arthur MD, have overall 
responsibility for the conduct of the study according to 21 CFR 812, 21 CFR Part 50, Good Clinical Practice (GCP) 
Guidelines (Guidance for Industry, E6 Good Clinical Practice Consolidated Guidance, ICH, April 1996), ISO 
14155: Part 1 and 2, the Declaration of Helsinki, Medical Device Directive, Annex X, FDA and all applicable 
regulatory requirements. For this study, the PIs will have certain direct responsibilities and will delegate other duties 
to appropriately qualified individuals.  All personnel participating in the conduct of this clinical trial will be 
qualified by training, education, and experience to perform his or her respective tasks. 
 
*NOTE: A complete list of participating investigators will be maintained and will be available upon request. 
 
 
13. 
Investigator Responsibilities 
The Investigator(s) shall be responsible for the day-to-day conduct of the investigation as well as for ensuring that 
the investigation is conducted according to all signed agreements, applicable elements of ISO 14155, the Clinical 
Investigational Plan, applicable FDA regulations, and the principles that have their origin in the Declaration of 
Helsinki. 
 
The investigator is also responsible for having control of the device under investigation, for protecting the rights, 
safety and welfare of subject’s under the investigator’s care and for obtaining informed consent in accordance with 
21 CFR Part 50. Each Investigator must sign the Investigator Agreement (or an equivalent and a Financial 
Disclosure) prior to becoming eligible to enroll subjects in this trial. 
 
Responsibilities of the Investigator include, but are not limited to: 
Ensuring that IRB approval is obtained prior to undertaking the trial at a clinical site; and, that participation of a 
subject in a clinical trial includes obtaining written informed consent prior to enrollment, and/or other non- 
standard of care study-related assessments; 
 
Providing the TOC with accurate and complete financial information per 21 CFR Part 54; Ensuring that all 
personnel assisting with the clinical trial are adequately informed and understand their trial-related duties and 
functions; 
 
It is recommended that each site identify a study coordinator for this study. Working with and under the authority of 
the clinical site Principal Investigator, the study coordinator assures that all study requirements are fulfilled, and is 
the contact person at the site for all aspects of study administration. 

21 
 
 
The Investigator will allow direct access to source data/documents for trial related monitoring, audit, IRB/EC review 
and regulatory inspection. Also, the investigator will allow auditing of their clinical investigational procedure(s). 
 
 
14. 
Required Documents from the Investigator 
At a minimum, the investigational site will provide the following documents to the TOC: 
 
1) Signed Investigator Agreement 
 
2) Written and dated IRB/EC approval, 
 
3) Written and dated IRB/EC approval for ICF document 
 
4) IRB/EC approval for any other written documents to be provided to the study subject (e.g., advertising), 
 
5) HIPAA documentation, 
 
6) *Investigator and Co-Investigators’ current Curriculum Vitae, 
 
7) Current medical licenses, 
 
8) Any other relevant documents requested by the TOC or the reviewing IRB/EC or other regulatory 
authorities, 
9) FDA Form 3454 or 3455 (or equivalent) regarding financial interests 
 
10) Fully executed contract. 
 
11) Ongoing IRB approval documents 
 
12) Source Documents for data verification 
 
13) Site Delegation of Authority Log 
 
A site may not begin study participation until all of the above listed documents have been provided to the study 
management team. 
* With regard to the Sub-Investigators current CVs, the study may begin once the CV of the site PI, IRB approval 
and IRB approved consent and privacy statement, the investigator’s agreement, Medical License, and financial 
disclosures, fully-executed contract, and others listed above, have been received. No additional Investigators may 
participate in the study, however, until a copy of their CV and all other required documents have been provided to 
the TOC. 
 
 
15. 
Investigator Records 
The Investigator must ensure that all study subject records are stored for at least 6 years after the end of the clinical 
study. To avoid error, the study site should contact J Mocco MD prior to the destruction of study records to ensure 
that they no longer need to be retained. In addition, J Mocco MD should be contacted if the Investigator plans to 
leave the investigational site so that arrangements can be made for the handling or transfer of study records. 
 
The Investigator will also maintain original source documents from which study-related data are derived, which 
include, but are not limited to: 
 

22 
 
• Clinic progress notes recording subject’s medical history and medications; 
 
• Medical charts with operative reports and condition of subject upon discharge; 
 
• Medical records regarding AEs/SAEs, including treatment and clinical outcome; 
 
• Results of diagnostic examinations, imaging (such as x-rays, MRIs), as well as the report of the radiologist’s 
reading/interpretation of diagnostic imaging; 
 
• Signed notes of phone calls and/or correspondence indicating investigational site’s attempts to follow study 
subjects at the required follow-up visits until subject’s participation in the study is complete or terminated; 
 
• Records relating to patient death (e.g., death certificate, autopsy report, if available, or terminal medical 
records). 
 
15.1 
Data Collection 
 
15.1.1 
Data Management Overview 
Data management will be handled by the MSMC Stroke Clinical Research Group, which is housed in the Department 
of Neurological Surgery at the Mt. Sinai Medical Center (MSMC), and its representatives. All activities will be 
conducted in coordination with the study PI, the sites, and the TOC. The data validation procedure will be 
implemented in two stages. First, the automated data checks will flag items that fail a rule, and the rule violation 
message will appear on the data entry screen at the time of data entry. The Study Coordinator at a site will see these 
rule violations and will be required to provide a response. His/her choices are to: (1) correct the entry immediately; 
(2) correct the entry at a later time; or (3) if the entered data are confirmed to be correct, dismiss the rule by checking 
that option provided by the Research Electronic Data Capture, REDCap system. Any changes made to the data will 
have a full audit trail. Second, for some checks that are more complicated, additional consistency checks will be run 
periodically after data entry occurs at the site. All data items that fail the programmed consistency checks will be 
queried via the data clarification request (DCR) process initiated by the MSMC data managers and/or their 
representatives. Site Monitors will also be able to generate DCRs when discrepancies are found during source 
document verification. The DCRs will be generated, communicated to the sites, and resolved within the secure study 
database. 
 
In addition to the study database, MSMC will provide the site staff password protected access to a standard set of 
web-enabled tools, including subject visit calendar, subject accrual status, case report form completion status, and 
outstanding DCR status pertaining to their respective sites. 
 
 
15.1.2 
Data Acquisition and Central Study Database 
The entire study will be conducted using an electronic data acquisition method where all clinical data on enrolled 
subjects will be data entered (single-keyed) by the site personnel into a web-based data management system, 
REDCap. In order to provide user-friendly and easy-to-navigate interfaces, the REDCap data capture screens are 
designed based upon individual CRFs. Prior to study start, the system is validated to ensure the data entry screens 
mirror the CRFs and that the pre- programmed data rules appropriately detect incorrect data. The data will be 
managed after data entry via data queries from the MSMC. 
The latest version of each CRF and source documents will be available as a PDF file on the REDCap website for use 
by study personnel. This process facilitates version control of these study related documents, particularly since 
documents may evolve over the course of the study. 
 
This user friendly web-based database system, developed and validated by the MSMC, will be used for subject data 
entry, data validation, project progress monitoring, subject tracking, user customizable report generation and secure 
data transfer. 

23 
 
 
 
 
 
15.2 
Reporting Module 
The REDCap system also has a real-time reporting component that allows authorized users to view protocol specific 
reports as data listings and in a summary format, overall and by site, at any time during the study via the password 
protected system. The Reporting Module is developed based on input from the TOC and includes reports on 
enrollment, SAEs, CRF processing, and subject progress. The reports will be presented to the TOC in a manner that 
protects the integrity of the study (e.g., blinded). 
 
MSMC will provide the TOC and authorized study personnel access to a standard set of web-enabled tools within 
REDCap. These tools allow the authorized research personnel to track trial progress by reviewing accrual status and 
CRF status of enrolled subjects. Other assistive tools and available information includes subject enrollment logs, basic 
subject demographics, CRF completion rate and number of data queries outstanding and resolved.  
 
 
15.3 
Security, Privacy, and Confidentiality 
 
The MSMC employs several layers of data protection to ensure data security. 
 
The first part of security is physical protection of the hardware systems employed by the MSMC. The facility 
housing the MSMC hardware is protected 24/7 by multiple layers of security. By limiting access, ensuring only 
authorized personnel have access, and tracking all entry, the risk of a security breach is minimal. All communication 
with the web server and client is encrypted. To help protect and secure the data stored in REDCap’s back end 
database, the software application employs various methods to protect against malicious users who may attempt to 
identify  and exploit any security vulnerabilities in the system. In REDCap, all incoming data gets intentionally 
filtered, sanitized, and escaped. Server environment variables that are vulnerable to forgery by end-users are also 
checked  and sanitized. To specifically protect against Cross-Site Request Forgery (CSRF), which is another method 
of attack, REDCap utilizes a “nonce” (a secret, user-specific token) on every web form used in the application. The 
nonce is generated as a unique value for each new REDCap session 
 
To maintain electronic records in the database as adequate and accurate, the REDCap system tracks all changes 
made to any dynamically managed electronic records. REDCap has a built-in audit trail that automatically logs all 
user activity and logs all pages viewed by every user, including contextual information (e.g. the project or record 
being accessed). The logging record can itself be viewed within a project by users that have been given privileges to 
view the Logging page. The Logging page allows such users to view or export the entire audit trail for that project, 
and also to filter the audit trail in various ways based upon the type of activity and/or user. This audit-trail 
information is created with a computer generated time-stamp and the user name in chronological order, when the 
original data is modified or deleted. 
 
 
16. 
Adverse Events 
Adverse events (AEs) may occur at any time after enrollment. Pre-existing conditions will be documented in the 
subject’s medical record as part of prior medical history but will not count against either study procedure unless 
there is a worsening of the condition during the study. Adverse events (serious and non-serious) will be documented 
on an Adverse Event CRF. Non-serious adverse events will be recorded from enrollment through hospital discharge 
or 7 days whichever is earlier. Serious adverse events will be recorded from enrollment through the end of study 
(i.e., 90 day follow-up). 
 
Investigators will record characteristics of each adverse event on an Adverse Event CRF. Each adverse event will be 
judged by the Investigator as to its level of relatedness to the investigational devices and investigational procedure. 

24 
 
In addition, the Investigator will identify the date of onset, severity, required treatment, relatedness and duration of 
the event. Severity will be judged using the scale noted in Table 10. All adverse events will be monitored until they 
are adequately resolved or explained or until the subject reaches the end of the study.  
 
Table 10. Definition of event severity for judgment by Investigator. 
 
Term 
Definition 
Mild 
Patient is aware of a sign or symptom, but that sign or 
symptom does not interfere with normal activity or symptom 
is both transient and resolved 
Moderate Symptoms interfere with the subject’s usual activity or 
symptoms 
require treatment 
Severe 
Symptom(s) cause either severe discomfort or have a 
significant impact 
of the subject’s usual activity and symptoms require treatment 
 
 
 
16.1 
Serious Adverse Events 
An adverse event is considered serious if it is life-threatening, prolongs hospitalization, requires a re-hospitalization, 
inpatient hospitalization, results in significant disability, or leads to death. Additionally, an important medical event 
that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse event 
when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events 
include (but are not limited to): allergic bronchospasm requiring intensive treatment in an emergency room or at 
home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; or, the development of drug 
dependency or drug abuse. Serious adverse events should not be reported for hospitalization or prolonged 
hospitalization in the following scenarios: for a diagnostic or elective surgical procedure related to a pre-existing 
condition; to allow for an efficacy measure for the study; or, for a planned surgical procedure that was not the result 
of a condition worsening due to participation in the study. 
 
An assessment should be made regarding the seriousness, severity and relationship to the investigational devices and 
investigational procedure.  The following factors should be considered when evaluating causality of adverse events: 
1) the temporal sequence from the study procedure; 2) patient's response after discontinuation or re-introduction; 
and, 3) severity of the event. The investigators, on the basis of their clinical judgment and guided by the following 
definitions, should determine the relationship of an adverse event to the administration of the investigational device, 
and/or study procedure(s) as: definitely related, i.e. following in a reasonable temporal sequence, known to be a 
complication, and having no other explanation; probably related, i.e. following in a reasonable temporal sequence 
and not reasonably explained by the patient’s clinical state or other therapies; possibly related, i.e. could have been 
explained by other therapies or patient’s clinical state; or not related. 
 
16.2 
Reporting and Review of Adverse Events 
 
To provide for consistent reporting of adverse events, serious and non-serious adverse events will be recorded on the 
Adverse Event CRF. Non-serious adverse events will be recorded from enrollment through Day 7 or hospital 
discharge (whichever occurs first). Serious adverse events will be recorded from enrollment through the end of study 
(i.e., 90 day final follow-up visit, death, or withdrawal of consent). 
 

25 
 
In order to ensure prompt reporting of adverse events, we require that all adverse events be entered into the REDCap 
web-based database (REDCap) within five working days of their becoming aware of the event during the initial 
admission. For all serious adverse events (SAEs), we require that they be reported in the REDCap within 24 hours of 
the study site staff first being made aware of the occurrence of the SAE. The 24- hour reporting requirement for 
SAEs applies to all study phases. 
 
Reporting of serious or life-threatening adverse events will trigger notification of the event to the Medical Monitor 
(MM). The MM will conduct an independent review of these specific SAE. If the MM believes the adverse event is 
serious, unexpected and either definitely, probably, or possibly related to the investigational device(s) and/or study 
procedures, the TOC staff will forward a Safety Report (pre-filled with as much data as possible) to the clinical site 
Investigator to be completed with any additional information that may be relevant to the SAE. The Safety Reports 
will be included in the reports prepared for the DSMB. The principal investigator, at each clinical site, will be 
responsible for reporting to his/her own IRB/EC according to individual IRB/EC policies. After the submission of 
the initial Safety Report, the principal investigator at the corresponding clinical site will be responsible for obtaining 
follow-up information about the event, in order for it to be reported it to the TOC. 
 
If it is determined that an unanticipated adverse device effect presents an unreasonable risk to subjects, the Principal 
Investigator will recommend the termination of all investigations or parts of investigations presenting that risk as 
soon as possible. The PI and SC shall make a determination regarding termination not later than 15 working days 
after the sponsor first receives notice of the effect. Termination of all investigations or the parts of investigations that 
have been deemed to present the risk(s) shall occur not later than 5 working days after the PI and SC makes this 
determination. 
 
The trial will resume only after determining there is sufficient evidence to reinstate the trial, and after each clinical 
site obtains IRB/EC approval. 
 
 
17. 
Ethical Considerations 
 
The rights, safety and well-being of clinical investigation subjects shall be protected consistent with the ethical 
principles laid down in the Declaration of Helsinki. This shall be understood, observed and applied at every step in 
this clinical investigation. 
 
It is expected that all parties will share in the responsibility for ethical conduct in accordance with their respective 
roles in the investigation. The Sponsor and the Investigator(s) shall avoid improper influence or inducement of the 
subject, monitor, the clinical investigator(s) or other parties participating in or contributing to the clinical 
investigation. 
 
18. 
Protection of Patient Confidentiality 
At all times throughout the clinical investigation, confidentiality will be observed by all parties involved. All data 
shall be secured against unauthorized access. Privacy and confidentiality of information about each subject shall be 
preserved in study reports and in any publication. Each subject participating in this study will be assigned a unique 
identifier. 
 
The Investigator will maintain a confidential study subject list identifying all enrolled subjects. This list will contain 
the assigned study subject’s unique identifier and name. The Investigator bears responsibility for keeping this list 
confidential. 
 
Monitors and auditors will have access to the study subject list and other information that personally identifies study 
subjects to ensure that data reported in the CRF corresponds to the person who signed the ICF and the information 
contained in the original source documents. Such personal identifying information may include, but is not limited to 
the subject’s name, address, date of birth, and medical record number. 

26 
 
 
 
19. 
Ethics Committee/Institutional Review Board Approval 
Institutional Review Board (IRB) / Ethics Committee (EC) approval is required prior to study commencement. The 
Investigator must also obtain renewal of IRB/EC approval as dictated by local requirements (but at least annually) 
during the entire duration of the study. The Investigator is responsible for fulfilling any conditions of approval 
imposed by the reviewing IRB/EC, such as regular reporting, study timing, etc. Study data required to be included in 
IRB/EC reports (e.g., Continuing Reviews) must be obtained from the SDMC; in order to ensure that accurate and 
consistent data are presented. 
 
The Investigator will provide the Project Management (PM) team with copies of such approvals and reports. 
Withdrawal of IRB/EC approval must be reported to the PM team immediately following the investigator’s 
knowledge of the withdrawal. 
 
The reviewing Independent Review Board (IRB) / Ethics Committee (EC) must review and approve an Informed 
Consent Form (ICF) specific to this study. Prior to the start of the trial, the PM team will provide each study center 
with a sample ICF. The study center, to meet specific requirements, may modify this sample ICF; however, the ICF 
must contain all of the elements required by the protocol, regulations, and GCP. Each investigational site will submit 
a copy of their ICF to the TOC prior to submission to their IRB; and, the IRB/EC approved ICF and renewal 
approvals to the PM team as required for the duration of the study. The original, signed and dated ICF should be 
retained by the investigational site for monitoring, and a copy provided to the subject. 
 
 
20. 
Informed consent 
Upon confirmation of patient’s eligibility, a written informed consent document must be obtained prior to any study- 
specific evaluations being conducted. In accordance with US FDA regulations (21 CFR 50) and ICH-GCP 
Consolidated Guidelines (Federal Register, May 9, 1997, Vol. 62, Number 90), a witnessed, IRB-approved, 
informed consent will be required from all subjects or their legal representative (LAR) or family member, as  
defined in 21 CFR 50.3(m), prior to participating in this trial. At the initial contact with a potential candidate, the 
investigator(s) will provide an adequate explanation of the purpose, procedures, possible risks/benefits, and 
participant responsibilities; in addition to the fact that his/her participation is voluntary, that he/she may withdraw 
from the study at any time, and that the decision not to participate or to withdraw will not affect subject’s care in any 
way. Potential participants or their legal representative or family member will be given ample opportunity to ask 
questions and to consider their decision. If the subject expresses a sustained interest, a signed and dated written 
informed consent will be obtained. A copy of the consent form will be given to the participant or their legal 
representative or family member, and another copy will be placed in his/her medical record. The informed consent 
must be obtained by either the clinical site PI or other members of the study team who have been delegated the 
authority to obtain informed consent. Each of the study team members with this delegation must be qualified in 
terms of education, experience, and training to obtain informed consent. 
 
The written informed consent document (and any other written information to be provided to the study subject) 
should be updated whenever new information becomes available that may require significant revisions to the 
informed consent document previously signed by a subject. Any such revision or update must be approved by the 
reviewing IRB/EC before being provided to the study subject. Previously consented subjects will be made aware of 
the changes and depending on the extent and/or severity of the new information a subject may be asked to “re- 
consent” to continued participation in the trial. 
 
 
21. Quality Assurance 
To ensure monitoring responsibilities are performed to the fullest extent possible on a real-time basis through the 
REDCap system, an experienced clinical research group will perform on-site and centralized monitoring for the trial. 
Sites will be responsible for uploading all applicable source documents into the REDCap system. MSMC staff and 

27 
 
their representatives will manage the assignment of monitors to performance sites, the coordination of monitoring 
visits, and provide support to monitors while they are in the field. In addition to on-site monitoring, centralized 
monitoring (per the FDA’s most recent monitoring guidance developed in August 2013) reflects a modern, risk-
based approach. Centralized monitoring focuses on critical study parameters and relies on a combination of 
monitoring activities. In this recent guidance, the FDA has encouraged the implementation of centralized 
monitoring due to its ability to ensure quality and integrity of data. Centralized monitoring is also very effective at 
identifying data fraud, data fabrication, and data errors. 
 
For the first subject enrolled at any site, 100% of the data will be verified to source documents. For subsequent 
subjects, at minimum, key outcome and safety data will be reviewed against source documents. Source documents 
verifying each data point collected in the trial will be uploaded into REDCap for all study subjects. This will allow 
for data to be monitored in a real-time fashion and for any errors in data to be identified more quickly. A target of no 
less than 50% of the trial data submitted to the REDCap database will be verified against source documents from the 
performance sites prior to final data analysis.  Safety and efficacy variables represent approximately half of the data 
to be verified. The remaining half of source monitored data include: 100% of deaths and 100% of serious adverse 
events and all MSMC requested source data reviews based on the per-subject evaluation of safety parameters defined 
in the protocol. All data monitored are verified for accuracy and thoroughness using the most appropriate source 
documents for all subjects. 
 
Signed informed consent documents and HIPAA policies are monitored for all subjects. Additional monitoring 
verification will include: ongoing evaluation of the adequacy of site facilities and staff, site recruitment,  
the presence of regulatory documents, and specific review of documents and data as requested by the MSMC staff 
and their representatives. Each site will be monitored on a real-time basis through the uploading of all source 
documents into the REDCap system. Sites are evaluated in an ongoing manner by site monitors and MSMC staff 
and their representatives to determine if there is a need to monitor more frequently and/or more thoroughly or via on-
site evaluation. 
 
Any omissions and corrections to data submitted to the database are noted and queries are generated by the monitor 
on site via the REDCap system. All queries will be stored in REDCap’s logging and audit trail so that all data 
changes or questions regarding data accuracy are tracked and permanently recorded. The auditing trail will contain 
information regarding which monitor issued the query, which user was assigned the query at each site, the complete 
free text conversations discussing data questions and/or changes, and will provide time and date stamps for all query 
related processes. 
 
Monitors will perform closeout-monitoring evaluations at the completion of subject enrollment. The monitor will 
again review all regulatory files and verify documents for accuracy and completeness as directed by the MSMC 
staff and their representatives. Sites are instructed in the record retention of all trial documents. Principal 
Investigators are directed to close the trial and issue a final report to their IRB/EC following resolution of any and 
all outstanding issues at that site. Finally, any additional special considerations for the auditing of any additional 
safety issues will be made. 
 
All documents and data shall be produced and maintained in such a way to assure control of documents and data to 
protect the subject’s privacy as far as reasonably practical. Only users with password-protected REDCap access will 
have the ability to view study data within the secure REDCap database. The Primary Investigator, Sponsor, the 
Sponsor’s representatives, and representatives of regulatory authorities are permitted to inspect the study documents 
(e.g., study protocol, CRFs, and original study-relevant medical records/files) as needed. All attempts will be made 
to preserve subject confidentiality. 
 
 
22. 
Protocol Deviations 
A protocol deviation is defined as any study action taken by the clinical Investigator or site personnel in conflict 
with the Study Protocol. All protocol deviations will be entered into REDCap within 48 hours of the deviation. 

28 
 
These will be tracked within the REDCap system. 
 
Deviations must be reported to the PM team regardless of whether medically justifiable, or taken to protect the 
subject in an emergency. Investigators will also adhere to procedures for reporting study deviations to their IRB/EC 
in accordance with their specific IRB/EC reporting policies and procedures. 
 
Good Clinical Practice Guidelines require that Investigators maintain accurate, complete and current records, 
including documents showing the dates of and reasons for each deviation from the protocol. 
 
 
23. 
Final Report 
A final report will be completed, even if the study is prematurely terminated. At the conclusion of the trial, 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 trial is not allowed until the aggregate study results have been published, unless 
there is written consent from the study PI. 
 
 
24. 
Information Confidentiality 
All information and data generated in association with this study will be held in strict confidence and remain the sole 
property of the Principal Investigator. 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 Trial Operating Committee. 
 
 
25. 
Trial Registration 
The study will be registered in a publicly accessible trial database (e.g., clinicaltrials.gov) prior to study initiation. 
 
26. 
Risk Analysis 
A thorough risk analysis was performed as part of design control recommendations of the Quality System 
Regulation (21 CFR 820). 
 
 
27. 
Publication Policy 
Publication of the results of this trial will be governed by the policies and procedures developed by the Trial 
Operations Committee. The Publication Policy will be fully compliant with the voluntary NIH Public Access 
Policy mandated by the Consolidated Appropriations Act of 2008 (Division G, Title II, Section 218 of PL 110- 
161). 

29 
 
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