ANET Electrosurgery Applicator Pilot Evaluation Study
Phase: NA
Conditions: Lung Cancer, Lung Cancer Metastatic
Sponsor: Olympus Corporation of the Americas

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Gyrus ACMI 
CPR-05394, Revision AD,  
ANET Electrosurgery Applicator 
Pilot Evaluation Study 
Gyrus ACMI, Inc., d/b/a Olympus Surgical Technologies America (OSTA) 
(formerly Spiration, Inc.) 
6675 185th Avenue NE 
Redmond, WA 98052 USA 
CERTIFICATION AND CONFIDENTIALITY AGREEMENT: 
I have read and agree to conduct this study in compliance with the approved 
investigational plan, Good Clinical Practices, and applicable regulatory requirements, as 
indicated by the investigator and the ethics committee. This investigational plan 
contains confidential proprietary information with respect to Gyrus ACMIproducts and 
this clinical study. 
______________________________________________ 
Print Name  
______________________________________________ 
________________ 
Signature of Investigator 
 
 
 
 
 
Date 
______________________________________________ 
Institution Name 
NCT03400748
11-Sep-2020

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ANET ELECTROSURGERY APPLICATOR PILOT 
EVALUATION STUDY
STUDY OBJECTIVES 
Evaluate the preliminary safety and performance of the ANET 
Electrosurgery Applicator (ANET) during and after 
bronchoscopic ablation of a target pulmonary nodule/tumor. 
PRIMARY 
ENDPOINT 
Safety provided by the evaluation of peri-procedural, device-
related adverse events produced by the ANET device used to 
ablate a target pulmonary nodule/tumor. 
SECONDARY 
ENDPOINTS 
1. Pathological and histological evaluation of the acute
thermal effect, produced by the ANET device, on targeted
pulmonary nodule/tumor and surrounding tissue to
determine if the observed zone of ablation is localized and
consistent with the predicted zone of ablation.
2. Characterize any effects on surrounding tissue outside the
zone of predicted ablation.
OBSERVATIONAL 
ENDPOINT 
Characterization of possible immune response changes. 
STUDY POPULATION 
Adult subjects with confirmed Stage I or Stage II primary lung 
cancer with a pulmonary nodule/tumor suitable for ablation by 
the ANET device via EBUS bronchoscopy, prior to planned 
surgical resection (lobectomy or greater). 
STUDY SIZE 
Up to 10 subjects will be treated, at up to 5 sites. 
STUDY DESIGN 
This is a first in human use pilot study. Study subjects who 
are already scheduled for a surgical resection of their target 
nodule/tumor will be treated with the ANET RF Applicator. 
Blood will be drawn pre and post ablation, and at 2-4 weeks 
post surgery. Following ANET ablation, the subject will 
undergo lung resection as scheduled. The ablated target 
nodule/tumor will undergo gross histopathologic assessment. 
and may undergo immuno-histochemical assessment and 
microenvironment assessment for immune response. 
INCLUSION 
CRITERIA  
1. Subject with Stage I or Stage II primary lung cancer
2. Pathological proof of target nodule/tumor type and
malignancy with specimen considered adequate for
mutational analysis per institutional laboratory standards
3. Target nodule/tumor which can be accessed via EBUS
bronchoscopy
4. Resection/surgical candidate (lobectomy or greater) as
standard of care
5. Participants must be at least 22 years old and able to
provide consent

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EXCLUSION 
CRITERIA 
1. Subjects in whom flexible bronchoscopy is contraindicated
2. Target nodule < 1.0 cm
3. Prior radiation or neo adjuvant chemotherapy of the target
nodule/tumor
4. Any comorbidity that the investigator feels would interfere
with the safety of the subject or the evaluation of study
objectives
5. Pacemaker, implantable cardioverter, or other electronic
implantable device
6. Patients with coagulopathy
7. Patients in other therapeutic lung cancer studies
8. Subject is pregnant or breastfeeding
9. Known or suspected sensitivity or allergy to nickel
TREATMENT 
ALGORITHM 
The target nodule/tumor depth will be measured under EBUS 
visualization. The applied energy will be determined based on 
the nodule/tumor size using guidance from the Instructions 
for Use (IFU) to create a measurable and predictable ablation 
zones. A single ablation zone will be created in the first 3 
subjects. The applied energy and number of ablation zones 
for the remaining subjects will be determined based on the 
nodule/tumor size and physician defined target ablation 
zone(s). 
PATHOLOGY 
ASSESMENT 
The ablated target nodule/tumor and surrounding tissue will 
be resected. The specimens will be examined by gross, 
histopathologic, and may be assessed by immuno-
histochemical methods. Routine staining will be performed 
with hematoxylin and eosin (H&E). Analysis of cellular vitality 
may be performed with different methods of immunostaining 
which may include one or more of the following: including 
mouse antihuman mitochondria monoclonal antibody (MAB 
1273), TUNEL, Ki167 PHH3, and Masson’s trichrome. 
The pathology assessment will be performed by an 
experienced pathologist. 
IMMUNE RESPONSE 
Blood will be drawn pre and post ablation to assess for 
immune response indicators 
The micro environment of the resected tissue may have 
pathological assessment for immune cell population to 
explore a potential mechanistic effect of immune response. 
FOLLOW-UP 
Subjects will be followed peri-operatively for safety. There is 
no long-term follow-up since the ablated tissue will be 
resected during the scheduled post-ablation surgical 
procedure, however adverse events will be captured 30 days 
post-procedure. 

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There will be a blood draw 2-4 weeks following surgery, 
during the standard post-surgery visit, 
STUDY DURATION 
Approximately 2 years 

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Table of Contents 
 
1 
INTRODUCTION ...................................................................................................... 7 
2 
DEVICE DESCRIPTION .......................................................................................... 9 
2.1 Device Overview ................................................................................................ 9 
2.2 Handle ............................................................................................................. 10 
2.3 Needle Electrode ............................................................................................. 11 
2.4 Coil Electrode .................................................................................................. 11 
2.5 Ancillary Supplies............................................................................................. 12 
2.6 Packaging and Sterilization .............................................................................. 12 
3 
PRIOR ANIMAL STUDIES ..................................................................................... 13 
4 
STUDY OBJECTIVES ............................................................................................ 17 
4.1 Objectives ........................................................................................................ 17 
4.1.1 Primary Endpoints ....................................................................................... 17 
4.1.2 Secondary Endpoints ................................................................................... 17 
5 
STUDY PLAN......................................................................................................... 18 
5.1 Study Design ................................................................................................... 18 
5.2 General Description of Study ........................................................................... 18 
5.3 Study Duration ................................................................................................. 19 
6 
SUBJECT POPULATION ....................................................................................... 20 
Adult subjects with confirmed Stage I or Stage II primary lung cancer with a 
pulmonary nodule/tumor suitable for ablation, by the ANET device via EBUS 
bronchoscopy, prior to planned surgical resection. ...................................... 20 
6.1 Eligibility Criteria .............................................................................................. 20 
6.1.1 Inclusion Criteria .......................................................................................... 20 
6.1.2 Exclusion Criteria ......................................................................................... 20 
6.2 Assignment of Subject Identification ................................................................ 21 
7 
STUDY PROCEDURES AND PATHOLOGY METHODS ...................................... 22 
7.1 Informed Consent ............................................................................................ 22 
7.2 Procedure ........................................................................................................ 22 
7.2.1 Pre-ablation CT ............................................................................................ 22 
7.2.2 ANET Procedure .......................................................................................... 22 
7.2.3 Post-ablation bronchoscopic evaluation and CT .......................................... 23 
7.2.4 Surgical Resection ....................................................................................... 23 
7.2.5 Pathology ..................................................................................................... 24 
8 
RISK/BENEFIT ANALYSIS .................................................................................... 26 
8.1 Justification for Investigation ............................................................................ 26 
8.2 Benefits ............................................................................................................ 26 
8.3 Risks ................................................................................................................ 26 
8.3.1 Risk Management ........................................................................................ 26 
9 
ADVERSE EVENTS ............................................................................................... 28 
9.1 DEFINITIONS (from ISO/FDIS 14155) ............................................................ 28 
9.1.1 Adverse Event (AE) ..................................................................................... 28 
9.1.2 Adverse Device Effect (ADE) ....................................................................... 28 
9.1.3 Device deficiency ......................................................................................... 28 

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9.1.4 Investigational medical device ..................................................................... 28 
9.1.5 Serious Adverse Device Effect (SADE) ....................................................... 28 
9.1.6 Serious Adverse Event (SAE) (see Table 3.0 of Protocol Defined Serious 
Adverse Events, below).......................................................................................... 28 
9.1.7 Unanticipated Serious Adverse Device Effect (USADE) .............................. 29 
9.2 Protocol Defined Potential Adverse Events ..................................................... 29 
9.1 Adverse Event (AE) Reporting by Investigator ................................................. 31 
9.2 Serious Adverse Event (SAE) Reporting by Investigator ................................. 32 
9.3 Unanticipated Serious Adverse Device Effect (USADE) Reporting by Sponsor
 ..................................................................................................................... 33 
10 PROTOCOL DEVIATIONS AND VIOLATIONS ..................................................... 33 
11 Study Management ................................................................................................ 33 
11.1 
Investigator Reports ..................................................................................... 33 
11.2 
Sponsor Reports .......................................................................................... 34 
11.3 
Clinical Study Monitoring Plan ..................................................................... 35 
11.3.1 Study Initiation Visits .................................................................................... 36 
11.3.2 Study Interim Visits ...................................................................................... 36 
11.3.3 Study Closeout Visits ................................................................................... 37 
11.4 
Data Management Plan ............................................................................... 38 
12 STATISTICAL METHODS AND ANALYSIS .......................................................... 38 
 
 
 

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1 
INTRODUCTION 
The American Cancer Society's estimates for lung cancer in the United States for 2013 
are:  
• About 228,190 new cases of lung cancer will be diagnosed (118,080 in men and 
110,110 in women).  
• There will be an estimated 159,480 deaths from lung cancer (87,260 in men and 
72,220 among women), accounting for about 27% of all cancer deaths.  
Lung cancer is by far the leading cause of cancer death among both men and women. 
Each year, more people die of lung cancer than of colon, breast, and prostate cancers 
combined. 
Early detection, diagnosis and treatment of lung cancer is the largest unmet need in 
pulmonary medicine. Surgical resection is the treatment of choice for patients with 
Stage I and Stage II lung cancer1. However, over 20%2 are not suitable for resection 
due to comorbidities3. 
Localized energy destruction of tumors (ablation or coagulation) in other organs is a 
well-established technique, and initial feasibility pre-clinical and clinical evaluations have 
been performed in lungs.4,5 Percutaneous RF ablation is currently a therapeutic option 
for patients not appropriate for surgery, particularly individuals with poor pulmonary 
reserve6, however, treating central and hilar nodules and tumors with percutaneous RF 
is a contraindication for this therapy. 
Bronchoscopic ablation of lung cancer may provide benefits for patients not appropriate 
for or who decline surgery with Stage I or Stage II hilar/central tumors and nodules. 
 
1 Dennis A. Casciato, ed., Manual of Clinical Oncology, Seventh edition (Philadelphia: LWW, 2012). 
2 Amgad El-Sherif et al., “Outcomes of Sublobar Resection versus Lobectomy for Stage I Non-Small Cell 
Lung Cancer: A 13-Year Analysis,” The Annals of Thoracic Surgery 82, no. 2 (August 2006): 408-
415; discussion 415-416, doi:10.1016/j.athoracsur.2006.02.029. 
3 Jean Deslauriers MD FRCPS, F. G. Pearson MD, and Farid M. Shamji MD, Lung Cancer, Part I: 
Screening, Diagnosis, and Staging, An Issue of Thoracic Surgery Clinics, 1e, 1 edition (London: 
Elsevier, 2013). 
4 Hidemi Suzuki et al., “Innovative Technique of Transbronchial Radiofrequency Ablation for 
Intrapulmonary Tumors: A Preliminary Study in a Rabbit Model,” Journal of Bronchology & 
Interventional Pulmonology 18, no. 3 (July 2011): 211–17, doi:10.1097/LBR.0b013e318229671b. 
5 Ralf Eberhardt, Nicolas Kahn, and Felix J. F. Herth, “‘Heat and Destroy’: Bronchoscopic-Guided 
Therapy of Peripheral Lung Lesions,” Respiration 79, no. 4 (2010): 265–73, doi:10.1159/000284015. 
6 Thierry de Baere, Geoffroy Farouil, and Frederic Deschamps, “Lung Cancer Ablation: What Is the 
Evidence?,” Seminars in Interventional Radiology 30, no. 2 (June 2013): 151–56, doi:10.1055/s-
0033-1342956. 

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Lethal RF ablation zones extending beyond a tumor cannot adequately be 
characterized by imaging7. Therefore, “Treat and Resect” studies have been used to 
characterize tissue response to RF ablation of lung tissue. Jaskolka, et al8 studied 
patients in which metastases were resected 2-4 weeks after percutaneous RF treatment 
and demonstrated support for RF ablation as an effective treatment for select 
pulmonary metastases. Clasen, et al9 characterized the pathomorphology of tissue 
response for pulmonary malignancies treated with RFA, followed by resection 3 days 
later confirmed in their study that 10 (90.9%) cases of the tumor tissue was completely 
ablated, however in 2 cases a safety margin was absent. Schneider, et al10,11 
completed studies in which RF neoplasms were treated with RF intraoperatively, then 
immediately resected. In both studies they were able to histopathically characterize the 
ablation zone. Local control of the neoplasms was determined effective in 38% and 89% 
of the tumors treated, demonstrating that it should not replace surgery, but RFA was 
safe and may be an option for patients who are not candidates for surgery.  
 
 
 
7 Sophie Chheang et al., “Imaging Features Following Thermal Ablation of Lung Malignancies,” 
Seminars in Interventional Radiology 30, no. 2 (June 2013): 157–68, doi:10.1055/s-0033-1342957. 
8 Jeffrey D. Jaskolka et al., “Pathologic Assessment of Radiofrequency Ablation of Pulmonary 
Metastases,” Journal of Vascular and Interventional Radiology: JVIR 21, no. 11 (November 2010): 
1689–96, doi:10.1016/j.jvir.2010.06.023. 
9 Stephan Clasen et al., “Pathomorphologic Evaluation of Pulmonary Radiofrequency Ablation,” Cancer 
113, no. 11 (December 1, 2008): 3121–29, doi:10.1002/cncr.23882. 
10 Thomas Schneider et al., “Intraoperative Radiofrequency Ablation of Lung Metastases and Histologic 
Evaluation,” The Annals of Thoracic Surgery 87, no. 2 (February 2009): 379–84, 
doi:10.1016/j.athoracsur.2008.10.088. 
11 Jaskolka et al., “Pathologic Assessment of Radiofrequency Ablation of Pulmonary Metastases.” 

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2 
DEVICE DESCRIPTION 
2.1 Device Overview 
The Active Needle Endoscopic Treatment (ANET) Applicator is a disposable 
bipolar electrosurgical applicator used for the coagulation and necrosis of soft 
tissue. Each Applicator consists of a 19 gauge needle (proximal electrode) with a 
coil (distal electrode). The needle and coil serve as the bipolar electrodes, so there 
is no need for an external ground pad.  
The ANET Applicator works with ancillary equipment which include an ultrasound 
endoscope and a compatible electrosurgical generator. The ANET Applicator has 
been shown to be compatible with the previously cleared/approved Olympus ESG-
100 or Olympus ESG – 300 Electrosurgical Generator. Other radiofrequency 
generators will be added as compatibility is established. 
A standard infusion pump can be used to infuse small quantities of saline during 
active ablation. Saline is administered to cool the electrodes during ablation, and to 
prevent the tissue surrounding the target tissue from dehydration.  
To perform ablation, the flexible portion of ANET device is first inserted into an 
ultrasound endoscope with a working channel of 2.2mm or greater, then locked 
onto the adapter biopsy valve on the endoscope using the endoscope adapter on 
the handle. The handle facilitates advancement of the sheath and needle/proximal 
electrode during puncture of the target tissue. Once the needle is positioned in 
place, the handle is used to facilitate advancement and of the coil. The coil in the 
target tissue and helps to hold the device in place during treatment.  
To perform ablation, the bipolar plug on the ANET Applicator is connected to the 
compatible electrosurgical generator. The generator is set to the appropriate power 
level included in the Instructions for Use (IFU). During ablation, radiofrequency 
(RF) current is passed between the distal electrode and the proximal electrode to 
thermally coagulate the tissue. Once the target energy has been reached, ablation 
is stopped, and the electrodes are retracted from the target. Additional ablations 
can be performed to achieve a larger coagulation zone. 
  

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Figure 1: ANET Applicator with Identification of All Components 
 
2.2 Handle 
The handle consists of the electrical and fluid connectors, the coil control, the 
needle control, the sheath adjuster knob, and the endoscope adaptor (Figure 1). 
The handle includes error-proofing features assist the user in performing the 
advancement and retraction steps in sequence. 
An insulated bipolar plug connects the ANET to a compatible electrosurgical 
generator which delivers RF energy to the applicator. The saline line consists of a 
flexible silicon tube with standard luer fitting which delivers small quantities of 
saline through the needle tip during active ablation to cool the electrodes and to 
prevent tissue dehydration adjacent to the electrodes. The handle contains a 
saline manifold which routes saline from the saline line to the inside of the needle 
for delivery. 
The handle affixes to the endoscope via the endoscope adaptor, which locks the 
device onto the biopsy valve adapter. The needle control controls the needle’s 
extension out from the sheath. The needle can be advanced up to 35mm from the 
sheath. The position of the needle relative to the sheath is indicated by the depth 
indicator on the handle.  
The coil control advances and retracts the coil relative to the needle. Sheath  
The sheath, which houses the needle, consists of a single lumen, extruded PTFE 
tube. The sheath protects both the needle tip and endoscope during device 

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insertion into and retraction from the endoscope. The sheath also electrically 
insulates the electrodes from the endoscope (Figure 2). 
Figure 2: 
Sheath/Needle Tip 
2.3 Needle Electrode 
The needle electrode is a 19 gauge hypotube needle assembly located within the 
sheath. To penetrate the target tissue, the hypotube assembly is advanced beyond 
the sheath. The needle’s distal end is machined to a Huber point bevel form to 
easily penetrate through the tissue with minimal coring.  
The Huber tip is bent on the distal end to create a curved path. The curve is 
designed to orient the coil as it is advanced into the tissue. The 19G hypotube has 
several different laser cut patterns for added flexibility. A spiral cut on the distal 
portion of the 19G hypotube provides strength and flexibility during penetration into 
the target tissue. A laser cut “dog bone” pattern provides single plane bending and 
aligns the needle relative to the endoscope during penetration. The laser cut 
region is fully covered by a layer of heat-shrink tubing to prevent saline leakage 
through the laser cuts and ensure that saline is delivered to the very distal end of 
the needle, where ablation is occurring. The most distal 9mm of the 19G hypotube 
has a shallow spiral groove on the outer surface, which reflects the endoscope’s 
ultrasound waves. The echo-enhanced region is intended to increase visualization 
at the tip, e.g., where the needle is located within the target tissue, and thereby 
help prevent penetration beyond the targeted tissue. 
After the needle tip has been inserted into the target tissue, the coil is advanced. 
The position of the needle tip determines where the coil will penetrate tissue.  
2.4 Coil Electrode 
The coil electrode is composed of an insulated Nitinol flat wire and extends the 
entire length of the device, through the inner lumen of the handle and needle 
electrode.   
The distal end is formed into a coil shape to anchor the electrodes into the target 
tissue during coagulation. The tip of the coil is cut at a 45 degree angle to aid in 
tissue penetration. The coil has many shallow divot features, which reflects the 

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endoscope’s ultrasound waves. The echo-enhanced region is intended to increase 
the visualization of the coils, e.g., where the coil is located within the target tissue, 
and thereby help prevent penetration beyond the targeted tissue structure.  
The coil is gold plated from the proximal end point of the divots to the proximal end 
of the device; the purpose of the gold plating is to improve the conductivity of the 
coil. Due to the bipolar nature of the ANET device and the co-axial construction of 
the electrodes, the coil is electrically insulated from the needle with a polyethylene 
terephthalate (PET) heat shrink tubing.  
2.5 Ancillary Supplies 
• 
Electrosurgical generator - The ANET Applicator is compatible with the 
Olympus ESG-100 and Olympus ESG-300 Electrosurgical Generator.  
• 
Ultrasound endoscope – The ANET Applicator is compatible with an ultrasound 
endoscope with an inner working channel of 2.2mm or greater.  
• 
Olympus biopsy valve – Model # MAJ-1414  
2.6 Packaging and Sterilization 
In its packaged configuration, the device is held in a plastic tray with a lid (made of 
LDPE and HDPE [Tyvek]).The sealed tray is packaged inside a dust cover box. 
Each dust cover box contains one device inside and an Instruction for Use (IFU).  
The device is sterilized by ethylene oxide (EO) sterilization.  
 
 

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3 
PRIOR ANIMAL STUDIES  
These GLP studies were conducted in a swine model with lung pseudotumors for 
early evaluation of the ANET-RFA Applicator, produced by Spiration Inc. (test 
device) via bronchoscopy access.  The primary goal of these studies was to 
evaluate the ability of the test device (ANET RF applicator) to deliver energy into 
pseudo-tumors in swine lungs and produce a thermal effect without substantial 
concurrent damage to the surrounding healthy tissue. Two studies were 
performed.  A short term study, in which the animals were followed for 7 days post 
ANET ablation procedure, and a long term study, in which the animals were 
followed for 3 months post procedure.  After the follow-up period, the animals were 
euthanized and the treated tissue was resected and underwent pathologic 
assessment. 
Study Limitations 
There are no large animal lung cancer models available for testing, therefore a 
pseudotumor model was used. The pseudotumors used in the animal model for 
these studies are mostly a dense proliferation of macrophages, which do provide a 
dense tissue target but are not cancer and therefore, while representative of the 
thermal cytocidal response pattern, may not represent the actual ablation of cancer 
cells. 
These studies were done in a small number of healthy animals (6). This number is 
too small for any meaningful statistical analysis.  
Short Term Study 
This GLP study was conducted under an IACUC approved protocol, SP-1602 GLP: 
RF Energy Ablation of Lung Pseudotumors Study in Yorkshire-Cross Farm Swine 
via Bronchoscopy (One Week Evaluation) and in accordance with Spiration’s 
protocol NCS-05097.AA. The study was conducted at the Care Research and 
Colorado Histo-Prep facilities in Fort Collins, CO.  
The test subjects were 6 domestic swine with induced pseudo-tumors in the lungs. 
A total of 6 pseudo-tumors were ablated, 1 in each swine with 1 pseudo-tumor left 
un-ablated in the opposite lung as a control. One extra animal was kept in reserve 
for the duration of the study as a backup. The pseudo-tumors were located and 
measured by EBUS bronchoscope and one per animal selected for RF ablation 
using the ANET RF applicator. The amount of energy delivered was based on the 
depth of the lesion as measured by EBUS, and determined by a predefined 
algorithm. During the thermal ablation the applicator electrodes are cooled with a 
flow of sterile physiological saline solution which conducts some of the heat away 
from the center of the bipolar ablation zone while also helping to maintain 
conductivity of the ablated tissue. With the rapid cooling of the saline as it expands 
away from the electrodes, no addition thermal tissue damage can be detected and 
the saline is absorbed by the tissue vasculature. The ANET applicators all 
functioned properly, and delivered the pre-determined amount of energy to the 
target location. Placement, visualization and subsequent removal of the electrodes 
in the pseudotumor targets was accomplished without complication. 

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After ablations, the swine were recovered and monitored for peri- or post-
procedural complications and general health for 7 days, which according to the 
study pathologist was the optimal time to observe any cytocidal effects in the 
tissue. Each animal was then euthanized and a gross necropsy performed by the 
Study Board Certified Veterinary Pathologist. Lung tissue was removed, fixed, 
trimmed and processed into stained slides. The Study Pathologist then performed 
histopathological and histomorphometric evaluations of the H&E and trichrome 
stained slides and evaluated a panel of health screen organs for any findings.  
The animals were healthy for the duration of the study; all gained weight, and had 
hematology and clinical chemistry values which were consistent with animals in 
good health. 
The bronchoscopic follow up at 7 days revealed normal airways with only minimal 
hyperemia noted at the ablation penetration sites. At necropsy, direct observation 
of the thoracic cavity revealed no significant findings in 5 of the 6 swine, with only 
mild irregular consolidations in the lungs which were determined by the pathologist 
to be related to anesthesia and not the ablation procedure. One swine (1506) had 
chronic resolved pleuritis with adhesions and chronic resolved pericarditis with 
adhesions, both of which resulted from a prior infection that had resolved with no 
adverse effect on this study. This animal also had marked bilateral peri-acute 
alveolar hemorrhage with dorsal gravitational congestion due to the animal being 
on its back terminally. These findings were compatible with a terminal overdose of 
IV heparin with an extended period between the injection and euthanasia. No other 
gross findings were detected in either the thorax or the abdomen of the animals.  
Histopathology of the ablated pseudotumors and surrounding tissues revealed a 
localized thermal ablation effect with no evidence of adverse effects. There was 
some variation in the pattern of the thermal effect between different swine, 
however the surrounding vascularized pulmonary tissue rapidly cools the infused 
saline so that the ablation effects are limited to the target area and immediate 
vicinity. There was no evidence of secondary bacterial infection in any of the 
bronchus penetration sites or in the ablated areas of the induced pulmonary 
pseudotumor. Where bronchoscopic observations implied thermal damage to the 
mucosa at the ANET penetration site, there was healing of the bronchus wall with 
active mucosal re-epithelization. This study demonstrates that even with site to site 
variation there is overall consistency in the ablation effects. These changes were 
focal and limited to the pseudotumor itself and the immediately surrounding 
tissues.  
 
Long Term Study 
This study was a long-term version of CARE Study SP-1602 that evaluated 
minimally invasive interventions over a short term (one week). This GLP 3 month 
study employed 6 (plus 1 extra) female Yorkshire-Cross farm swine from a 
previous Non-GLP study conducted at CARE (SP-1601). In that study, 
bronchoscopic techniques and instrumentation were used along with fluoroscopy 
to inject paste mixtures of barium sulfate and talcum powder into accessible lung 

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parenchyma locations of female Yorkshire-Cross farm swine to produce lung 
pseudotumors. Six of these animals that had been identified as having a minimum 
of one 1 – 3 cm in diameter pseudotumor accessible in both the right and left lung 
were assigned to this study. Details regarding the creation of the lung 
pseudotumors are in the CARE Non-GLP protocol and Summary Document for 
that project (CARE Study SP-1601).  
RFA with the test device was performed by the sponsor in 2 staggers with Study 
Day 1 as the day that each animal was subjected to the ablation procedure as 
follows: Each animal was anesthetized. Fluoroscopy was used to identify the 
location of the lung pseudotumors and bronchoscopic examination of the airways 
was done using a diagnostic scope. Lung pseudotumors in the lung parenchyma 
were located and their depth determined by ultrasound techniques using the EBUS 
bronchoscope. Any targets that could be accessed and seen by the ultrasound 
function of the EBUS bronchoscope were selected for possible bronchoscopic 
ANET- RFA Applicator treatment. Energy was delivered to one pseudotumor per 
animal per a predefined algorithm based on the size of the lesion as determined by 
EBUS, using the applicator (ANET-RFA) developed by the sponsor (test device) to 
the test pseudotumor. A similar pseudotumor was selected in the opposite lung 
and left untreated (non-ablated) to serve as control. Once completed, the energy 
device was retracted and removed. No treatment was provided to the selected 
pseudotumor in the opposite lung. No acute adverse events were observed or 
recorded. Each animal was recovered from anesthesia and kept alive for 3 months 
before being euthanized 85 days post-ablation for animal 1501 and 86 days for 
animals 1502-1506. Prior to euthanasia, each animal was anesthetized and 
subjected to bronchoscopy and fluoroscopy to observe and document the 
condition of the ablated and non-ablated control pseudotumor locations. Clinical 
observations were conducted daily. Body weights were recorded on Study Day 1, 
3, and weekly thereafter post-RFA, excluding Week 12. 
Following euthanasia, the pathologist conducted the necropsy and tissue 
collection, and grossly evaluated the tissue samples, including those collected 
from the pseudotumor treated with the ANET-RFA Applicator and the non-ablated 
control sites. The extent of thermal effects to the ablated pseudotumor and 
pulmonary parenchyma tissue surrounding the primary treatment site were 
characterized for comparison with the non-ablated control sites by gross 
examination, pre-fixation fluoroscopic imaging and post histology examination. 
This included any possible effects due to the perfusion of heated saline coolant 
within the lung parenchyma. Other evaluations included blood hematology and 
chemistry, and standard tissue pathological evaluations.  
Based on the results of this study, the minimally invasive bronchoscopic 
radiofrequency ablation (RFA) of induced lung pseudo-tumors in female Yorkshire-
Cross farm swine using the ANET-RFA Applicator (test device) was well tolerated 
when the animals were evaluated for 3 months following the ablation procedure. 
This study demonstrates that even with site to site variation there was overall 
consistency in the ablation effects, and the rapid cooling of the heated saline by 
the surrounding pulmonary tissue so any complete or selective ablation effects 
were limited to the BNTM target area and immediate vicinity. All animals remained 

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essentially normal throughout the study and did not exhibit abnormal clinical signs, 
body weight effects, hematology or chemistry changes from Day 1 to the end of 
the study, or toxicologically relevant gross necropsy observations. In addition, 
pathology evaluation of health screen tissues that were collected (included 
kidneys, liver, gallbladder, spleen, urinary bladder, adrenals, stomach, small 
intestine, pancreas, large intestine, heart, lung, parabronchus lymph nodes, and 
mesenteric lymph nodes) did not reveal adverse treatment related effects.  
The gross pathology and histopathological analysis of the lung tissues in this study 
indicates that the ANET RFA Applicator provided by Spiration was safe and 
effective in this BNTM model of pseudotumors when evaluated 3 months after its 
use. The ANET ablation of the BNTM histiocytic granulomas had similar 
predictable identifiable patterns of localized thermal ablation effects. During the 
thermal ablation the coil area of the device was flushed with sterile physiological 
saline as a coolant to prevent overheating of the device tip. This very small amount 
of heated saline flowed along a path of least resistance, and as it flowed it is 
cooled rapidly by the viable vascularized pulmonary tissue and the movement of 
air through the respiratory tree. Within a short distance from the ANET electrodes, 
the heated saline cooled uniformly and destroyed tissue by thermal coagulation, 
and then as the saline cooled to the tumoricidal temperature, the thermal damage 
became selective, and created a zone where only the most sensitive cells such as 
carcinoma, skeletal, and smooth muscle cells were selectively destroyed. With the 
rapid cooling of the saline no additional morphological thermal tissue damage 
could be detected, and the saline was absorbed by the tissue vasculature. The 
flow of this cooled saline appeared to contain proteinaceous debris from the "up-
stream" ablated tissue, which stimulated the alveolar macrophages and fibroblast 
in the lung parenchyma to slightly thicken without any thermal effects, and this 
morphological change allowed the tracking of the cooled saline flow pattern in the 
pulmonary tissue; however, this subtle change was almost completely resolved in 
this long term chronic study as compared to the short term study conducted earlier 
SP-1602. There was no evidence of secondary bacterial infection in any of the 
bronchus penetration sites or in the ablated areas of the induced BNTM pulmonary 
pseudo-tumor. Where sections were collected through the bronchus wall at the 
ANET RF Applicator penetration site, there was occasionally bronchus mucosal 
thermal damage due to back flow of the heated saline along the needle electrode, 
but this was limited to the immediate site of penetration, and there was early 
healing of the bronchus wall with active mucosal re-epithelization and submucosal 
fibrosis.  
 
 

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4 
STUDY OBJECTIVES 
4.1 Objectives 
Evaluate the preliminary safety and performance of the ANET Electrosurgery 
Applicator (ANET) during and after bronchoscopic ablation of a target pulmonary 
nodule/tumor. 
4.1.1 Primary Endpoints 
Safety provided by the evaluation of peri-procedural device related adverse 
events produced by the ANET device used to ablate a target pulmonary 
nodule/tumor. 
4.1.2 Secondary Endpoints 
1) Pathological and immuno-histochemical evaluation of the acute 
thermal effect, produced by the ANET device, on targeted 
pulmonary nodule/tumor and surrounding tissue to determine if 
the observed zone of ablation is localized and consistent with the 
predicted zone of ablation. 
2) Characterize any effects on surrounding tissue outside the zone 
of predicted ablation. 
4.1.3 Observational Endpoint 
Characterization of possible immune response changes. 
 

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5 
STUDY PLAN 
5.1 Study Design 
This is a first in human use pilot study. Study subjects who are already scheduled 
for a surgical resection (lobectomy or greater) of their target nodule/tumor, as 
standard of care, will be treated with the ANET device. The target ablation zone 
will be entirely within the planned resection. Following ANET ablation, the subject 
will undergo their scheduled lung resection. The ablated target nodule/tumor will 
undergo gross, immuno-histochemical and histopathologic assessment.  
5.2 General Description of Study 
After consent and evaluation of all inclusion and exclusion criteria, subjects will be 
enrolled in the study. The subject will undergo standard pre-operative testing, per 
the study institutional requirements. At that time, subject vital signs will be 
recorded. The subject will be prepped for bronchoscopy.  
A pre-ablation chest CT will be taken. The target nodule/tumor will be accessed via 
EBUS bronchoscopy, which may be guided and confirmed with Cone Beam CT, 
Intra-operative CT, or fluoroscopy, and ablated using the ANET Electrosurgical 
Applicator. Following ablation, there will be a bronchoscopic exam of the treated 
region and repeat chest CT will be taken.    
Immediately following bronchoscopy and ablation of the target tissue, the subject 
will undergo the planned surgical resection. The ablated tumor will be prepared for 
histopathological and immuno-histochemistry evaluation to assess the area of 
ablated tissue. Subjects will be followed peri-operatively. There is no long-term 
follow-up since the ablated tissue will be resected during the surgical procedure, 
however adverse events will be captured through 30 days post procedure. 
Blood will be drawn pre and post-ablation and 2-4 weeks post-surgery, per the 
ANET Blood Draw Lab Manual, DN0042775, to evaluate for potential immune 
response indicators. Blood specimens will be analyzed by a core laboratory to 
characterize cells important in immune responses and the disease process.  
  
 
 
 

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A study diagram is shown in Figure 4 below. 
 
 
5.3 Study Duration 
The study duration is anticipated to be approximately 2 years.  
 

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6 
SUBJECT POPULATION 
Adult subjects with confirmed Stage I or Stage II primary lung cancer with 
a pulmonary nodule/tumor suitable for ablation, by the ANET device via 
EBUS bronchoscopy, prior to planned surgical resection. 
6.1 Eligibility Criteria 
The criteria listed below shall be used to determine if an individual is eligible for 
enrollment in this clinical study. 
6.1.1 Inclusion Criteria 
1. Subject with Stage I or Stage II primary lung cancer  
2. Pathological proof of target nodule/tumor type and malignancy 
with specimen considered adequate for mutational analysis per 
institutional laboratory standards 
 
3. Target nodule/tumor which can be accessed via EBUS 
bronchoscopy 
4. Resection/surgical candidate (lobectomy or greater) as standard 
of care 
5. Participants must be at least 22 years old and able to provide 
consent 
6.1.2 Exclusion Criteria 
1. Subjects in whom flexible bronchoscopy is contraindicated 
2. Target nodule < 1.0 cm  
3. Prior radiation or neo adjunctive chemotherapy of the target 
nodule/tumor 
4. Any comorbidity that the investigator feels would interfere with 
the safety of the subject or the evaluation of study objectives 
5. Pacemaker, implantable cardioverter, or other electronic 
implantable device  
6. Patients with coagulopathy 
7. Patients in other therapeutic lung cancer studies  
8. Subject is pregnant or breastfeeding 
9. Known or suspected sensitivity or allergy to nickel 

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6.2 Assignment of Subject Identification 
Each subject who has signed an informed consent will be assigned a subject ID 
number unique to the subject and study site.  
 
 

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7 
STUDY PROCEDURES AND PATHOLOGY METHODS 
7.1 Informed Consent 
Subjects must sign the informed consent prior to enrollment. The original consent 
form will become an integral part of each case report form file. One copy will be 
retained with the subject’s medical records and one copy will be provided to the 
subject.  
7.2 Procedure 
All study eligible subjects will be prepared for the bronchoscopic/surgical 
procedure according to the policies and procedures established by the institution.  
Before starting the procedure, a “time out” review will take place. During the “time 
out” session, the nodule/tumor to be treated will be noted by all in attendance.  
7.2.1 Pre-ablation CT and blood draw 
A pre-ablation chest CT will be taken prior to ANET ablation, may be 
performed while the subject is under general anesthesia. 
A pre-ablation blood draw will be taken to assess for immune response 
indicators  
 
7.2.2 ANET Procedure 
The ANET Applicator and RF generator will be prepared for use per the 
ANET Instructions for Use (IFU). ASA guidelines for the Prevention and 
Management of Operating Room fires will be followed, including: 
• Discuss the use of RF prior to the procedure with the 
anesthesiologist and collaborate with procedure team throughout the 
procedure 
• Use cuffed tracheal tube 
• Before RF ablation: 
o Announce the intent to start RF ablation 
o Reduce the oxygen concentration to the minimum required to 
avoid hypoxia, guided by patient monitoring 
o Stop the use of nitrous oxide 
• Wait a few minutes before authorizing the use of RF ablation 
• Refer to institutional requirements 

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The nodule/tumor will be accessed via EBUS bronchoscopy. If the 
nodule/tumor cannot be accessed via EBUS, or nodule/tumor is considered 
inappropriate for ablation by the treating physician, the subject will proceed 
to surgery and will not count against enrollment. 
Under visualization with the EBUS bronchoscope, the ablation zone path 
length of the nodule/tumor will be measured using the EBUS measurement 
tool. If the path length is less than 1 cm, then a new ablation zone in the 
target nodule/tumor will be identified. The center of the ablation zone, 
should be at least 2 cm away from any critical structures, as determined by 
the investigator. 
If an acceptable ablation zone cannot be determined, the subject will be 
considered a treatment failure. Tissue ablation parameters will be 
determined by the IFU. 
The ANET applicator will be advanced to the target nodule/tumor under 
EBUS visualization. After the needle has been advanced into the target 
location, position may be confirmed using cone beam CT, intra-operative CT 
or fluoroscopy. The needle should be deep enough in the tissue and not 
extend past the distal margin of the target nodule/tumor. If it is not possible 
to place the needle appropriately, the subject will be considered a treatment 
failure.  
Once the needle is placed correctly, a fixed electrode spacing of 1mm 
should be maintained for ablation.  The target nodule/tumor can then be 
ablated per the energy application guidelines in the IFU. Saline flow post-RF 
delivery must be maintained to bring the tissue next to the electrode to 
baseline temperatures (~ ≥ 120 s) and to arrest thermal damage to stated 
margins. 
If the tumor is greater than 3.1 cm, than the energy parameters for no 
greater than a 3.1 cm ablation zone will be used.  
7.2.3 Post-ablation bronchoscopic evaluation and CT 
A post-ablation bronchoscopic evaluation and chest CT will be taken 
following ANET ablation, while the subject is under general anesthesia. 
7.2.4 Post-ablation blood draw 
A post-ablation blood draw will be taken to assess for immune response 
indicators. The blood draw should occur prior to the surgical resection. 
 

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7.2.5 Surgical Resection 
Surgical resection will be performed as scheduled, per institutional 
guidelines.  
Following resection, the ANET ablated tumor will be grossly evaluated and 
prepared for histopathologic and immuno-histochemistry evaluation of the 
treated tumor. 
7.2.6 Pathology 
The tumors will be bisected through the largest diameter in a right angle 
referring to the RFA electrode direction and marked to determine orientation 
of coagulation electrode immediately after the resection procedure. The 
specimens will be fixed in 10% neutral buffered formalin-solution and 
prepared for routine diagnostics and immuno-histochemistry. 
The specimens will be examined by gross pathology, histopathology, and 
may be examined by immuno-histochemical methods. Routine staining will 
be performed with hematoxylin and eosin (H&E). Analysis of cellular vitality 
may be performed with different methods of staining, which may include one 
or more of the following: mouse antihuman mitochondria monoclonal 
antibody (MAB 1273; Millipore UK, Hertfordshire, UK)12,13, Terminal 
deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL; 
Boehringer Ingelheim, Germany),14 antibody MiB1(Ki67; Dianova, Hamburg 
Germany),15 ,16 PHH317, and Masson’s trichrome1819 The immuno-
histochemical criterion for cell death in is the lack of expression or 
proliferation/mitotic index markers in the treated and surrounding tissue. The 
intent of the pathology assessments is to determine if the observed zone of 
ablation is consistent with the predicted zone of ablation and to characterize 
any effects on surrounding tissue outside the zone of predicted ablation. 
 
12 Schneider et al., “Intraoperative Radiofrequency Ablation of Lung Metastases and Histologic 
Evaluation.” 
13 Thomas Schneider et al., “The Efficacy of Bipolar and Multipolar Radiofrequency Ablation of Lung 
Neoplasms - Results of an Ablate and Resect Study,” European Journal of Cardio-Thoracic Surgery: 
Official Journal of the European Association for Cardio-Thoracic Surgery 39, no. 6 (June 2011): 
968–73, doi:10.1016/j.ejcts.2010.08.055. 
14 Clasen et al., “Pathomorphologic Evaluation of Pulmonary Radiofrequency Ablation.” 
15 Ibid. 
16Pelosi et al. J Thorac Oncol. 2014;9: 273–284 
17 Ozturk Sari et al. Endocr Pathol. 2016 Jun;27(2):162-70 
18 Jie Ouyang et al. Utility of desmin and a Masson’s trichrome method to detect early acute 
myocardial infarction in autopsy tissues, Int J Clin Exp Pathol 2010;3(1):98-105. 
19 T.D. Koreckij et al., Low Dose, Alternating Electric Current Inhibits Growth of Prostatic 
Cancer, The Prostate, Accepted 5 October 2009, Published online in Wiley InterScience 
(www.interscience.wiley.com). 

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The micro environment of the resected tissue may have pathological 
assessment for immune cell population to explore a potential mechanistic 
effect of immune response.20. 
The pathologic and immuno-histochemical effect of RFA on nodules/tumors 
and surrounding tissue will be evaluated by an experienced pathologist.  
7.2.7 Post-surgical blood draw 
A post-surgical blood draw will be taken 2-4 weeks post-surgery to assess 
for immune response indicators. 
 
 
 
 
20 M.A.J. Gorris, et al. Eight-Color Multiplex Immunohistochemistry for Simultaneous Detection 
of Multiple Immune Checkpoint Molecules within the Tumor Microenvironment J Immunol 
January 1, 2018, 200 (1) 347-354 

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8 
RISK/BENEFIT ANALYSIS 
Spiration has conducted an analysis of the potential benefits and risks of the ANET 
procedure and device operation on the patient population as defined in section 6 of this 
protocol. 
 
8.1 Justification for Investigation 
The safety of subjects participating in first in man studies is the paramount 
consideration in proceeding to clinical trials in man. Such subjects would not 
normally be expected to derive any therapeutic benefit.  
The lack of observed safety effects from the pre-clinical studies have provided 
the benchmark for safety in this first in human study.  The study has been 
designed to optimize knowledge gained regarding ablation therapy in human 
cancerous tissue without involving excessive numbers of subjects and while 
ensuring the safety of patients. 
The study design is a treat/resect design wherein the ablated tissue is fully within 
the part of the lung being surgically removed and represents the standard of care 
for these patients with primary lung cancer. 
Lastly, the study has limited the number of trial sites being used to incorporate 
centers of excellence in the treatment of lung cancer.  All of these sites will be 
further trained on the use of the ANET device to minimize safety events. 
 
8.2 Benefits 
There are no direct benefits to patients in this study.  However, information from 
this study may help patients in the future with Stage  I, II lung cancer and with 
pulmonary metastasis who are not suitable for surgical intervention.   
8.3 Risks 
• Risks of ANET ablation procedure and device are listed in Table 2, 
section 9.2 of this protocol. 
• Patients will receive up to 3 additional CT’s as a result of this study. 
These include a CT prior to and after ANET ablation. An additional CT 
may be taken to confirm needle location during the ANET ablation 
procedure. 
8.3.1 Risk Management 
Risks associated with the use of the ANET device are minimized through 
device design, Investigator selection and training, pre-specified subject 
eligibility requirements and study monitoring to ensure adherence to this 
investigational plan.  Specific strategies include: 
• Clearly defining the subject inclusion/exclusion criteria 

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• Prior to treatment, adequate cancer specimen sufficient for 
mutational analysis will be collected  
• AEs will be reported per section 9 of this investigational plan and will 
be reported and monitored throughout the course of the study 
• The sites will be notified if unexpected adverse device effects and 
other safety concerns that could negatively impact the safety of 
subjects if such issues arise 
• Ensuring that treatment and follow-up of subjects is consistent with 
standard and current medical practice. 
 
 

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9 
ADVERSE EVENTS 
9.1 DEFINITIONS (from ISO/FDIS 14155) 
9.1.1 Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or  
untoward clinical signs (including abnormal laboratory findings) in subjects, 
users or other persons, whether or not related to the investigational medical 
device which includes:  
a. 
events related to the investigational medical device or the 
comparator; and 
b. 
events related to the procedures involved 
For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
9.1.2 Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical device. 
NOTE 1- This includes any adverse event resulting from insufficiencies or 
inadequacies in the instructions for use, the deployment, the implantation, 
the installation, the operation, or any malfunction of the investigational 
medical device. 
NOTE 2- This includes any event that is a result of a use error or intentional 
misuse. 
9.1.3 Device deficiency 
Inadequacy of a medical device related to its identity, quality, durability, 
reliability, safety or performance, such as malfunction, misuse or use error 
and inadequate labeling. 
9.1.4 Investigational medical device 
Medical device being assessed for safety or performance in a clinical 
investigation 
NOTE: This includes medical devices already on the market that are being 
evaluated for new intended uses, new populations, new materials or design 
changes. 
9.1.5 Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
9.1.6 Serious Adverse Event (SAE) (see Table 3.0 of Protocol Defined Serious 

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Adverse Events, below) 
Adverse event that: 
a) led to a death, 
b) led to a serious deterioration in health that either: 
1) resulted in a life-threatening illness or injury, or 
2) resulted in a permanent impairment of a body structure or a body 
function, or 
3) required in-patient hospitalization or prolongation of existing 
hospitalization, or 
4) resulted in medical or surgical intervention to prevent life 
threatening illness or injury or permanent impairment to a body 
structure or a body function. 
c) led to fetal distress, fetal death or a congenital abnormality or birth defect. 
NOTE 1: This includes device deficiencies that might have led to a serious 
adverse event if a) suitable action had not been taken or b) intervention had 
not been made or c) if circumstances had been less fortunate. These are 
handled under the SAE reporting system. 
NOTE 2: A planned hospitalization for pre-existing condition, or a procedure 
required by the Clinical Investigation Plan, without a serious deterioration in 
health, is not considered to be a serious adverse event. 
9.1.7 Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or 
outcome has not been identified in the current version of the risk analysis 
report. 
NOTE: Anticipated: an effect which by its nature, incidence, severity or 
outcome has been previously identified in the risk analysis report.  Adverse 
events listed in Table 2 below are considered anticipated for this study. 
9.2 Protocol Defined Potential Adverse Events 
The following list of adverse events are anticipated given the nature of the EBUS 
procedure and the investigational device. Potential adverse event terms in Table 2 
are referenced from MedDRA release Version 23.0. All terms are Preferred Terms 
(PT). 
Table 2: Potential Adverse Events 
MedDRA term  
 
Ablation site reactions   

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MedDRA term  
 
(MedDRA term: 
Administration site 
reactions) 
Abscess formation 
(MedDRA term: 
Wound Abscess) 
 
Anaesthetic 
complication 
 
Arrhythmia 
 
Atelectasis 
 
Bronchial obstruction 
 
Bronchopulmonary hemorrhage 
Bronchospasm 
 
Burning or charring – 
unintended (MedDRA 
term: Burn local) 
 
Cardiac arrest 
 
Death 
 
Device failure 
 
Dyspnea 
 
Electric shock 
 
Esophageal 
hemorrhage 
 
Hematoma (MedDRA 
term: Post-procedural 
hematoma) 
 
Haemolysis 
 
Haemoptysis 
 
Hemorrhage 
 
Hemothorax  
 
Hypoxemia 
 
Infection (acute) 
 
Laryngeal spasm 
 
Localized allergic 
reaction or irritant 
reaction (MedDRA 
term: Administration 
site hypersensitivity) 
 
Microbubble/air 
embolism 
 
Pleural effusion 
 
Pleuritic pain 
 
Pneumo-mediastinum 
 
Pneumonia  
 
Pneumonitis  
 
Pneumothorax  
 
Post-procedural 
hemorrhage 
 
Postoperative thoracic procedure complication 

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MedDRA term  
 
Pulmonary edema  
 
Pulmonary embolism 
 
Pulmonary fistula 
 
Respiratory failure 
 
Systemic toxicity 
 
Soft tissue necrosis 
 
Tumor recurrence 
(MedDRA term: 
Neoplasm recurrence) 
 
Tumor seeding 
(MedDRA term: 
Treatment related 
secondary 
malignancy) 
 
 
Table 3: Adverse Event Categories 
 
 
9.1 Adverse Event (AE) Reporting by Investigator 
Peri-procedural adverse events, defined as from the start of the EBUS 
bronchoscopy through the planned surgical resection, will be collected up to 
30 days post procedure using the AE paper case report form. AEs shall be 
reported in accordance with study institution requirements, local vigilance 
systems, 21CFR 803 21CFR 812.46, 21CFR 812.140, and 21CFR 812.150, 
and ISO 14155:2011, sections 8.2.5 and 9.8.  
Since this is a limited pilot study, there is no Data Safety Monitoring Board.  
In the event of an incidence of massive hemoptysis, acute respiratory 
distress, or a death that is device or ANET procedure related, as defined by 
the Principal Investigator, the study will be paused and the IRB and FDA will 
be notified. 
Onset of Multiple Adverse Events  

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If AEs occur concurrently, each event should be recorded on separate AE 
case report forms.  However, if known at the time of reporting, a diagnosis 
should be recorded on the case report form rather than individual signs and 
symptoms (e.g., record congestive heart failure rather than dyspnea, rales 
and cyanosis).  If a diagnosis is established from subsequent follow-up 
information post initial SAE reporting, the event term should be updated on 
the corresponding case report form to reflect the final diagnosis term. 
If a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, 
each individual adverse event should be recorded as a separate AE.  Signs 
and symptoms that are considered unrelated to an encountered syndrome 
or disease should be recorded as individual AEs (e.g., if congestive heart 
failure and severe headache are observed at the same time, each event 
should be recorded as an individual AE on separate AE case report forms). 
AEs occurring secondary to other events (e.g., sequelae) should be 
identified by the primary cause; a "primary" event, if clearly identifiable, and 
generally represents the most accurate clinical term to record as the AE 
event term. 
Event Causality 
 
All AEs will be assessed for relationship to the investigational device and/or 
the procedure on 2-point scale as follows: 
 
Related: 
The AE has a timely relationship to the device or 
procedure.   
 
Not related:  
There is no clear evidence that the AE has a 
relationship to the investigational device or 
procedure.  
 
9.2 Serious Adverse Event (SAE) Reporting by Investigator 
Investigators are required to report a serious adverse event (see criteria in 
Section 9.1.6), regardless of whether the event is considered anticipated or 
unanticipated to the Spiration Clinical Field Specialist (i.e. site monitor) 
assigned to investigational site within 2 working days from the time of initial 
awareness.  

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9.3 Unanticipated Serious Adverse Device Effect (USADE) Reporting by 
Sponsor 
All SAEs that satisfy USADE criteria (see Section 9.1.7) will be reviewed by 
the study Medical Monitor, an independent physician consultant with subject 
matter expertise. The sponsor must report the results of an evaluation of an 
USADE to FDA and all reviewing IRBs and investigators within 10 working 
days after the sponsor first receives notice of the adverse device effect. 
 
10 PROTOCOL DEVIATIONS AND VIOLATIONS 
During the course of the study, any deviations or violations from this protocol will be 
properly logged and documented by the site. 
 
11 Study Management 
The clinical study will be conducted in accordance with the applicable Sponsor SOPs.  
The sponsor will establish a clinical study plan that is appropriate to this study and that 
ensures compliance with Food and Drug Administration (FDA and Health Canada) 
regulations, Good Clinical Practice (GCP), and any other applicable regulations. 
 
The clinical study plan will establish and document practical working methods for the 
management and execution of the pivotal study.  The plan will address study-specific: 
definitions, roles, responsibilities, documents, clinical site and investigator selection, site 
qualification, training, inventory management, CRO management, data management, 
clinical data and CRFs, safety reporting/AEs/SAEs, monitoring, randomization, record 
retention, clinical complaints and product returns, and applicable sponsor SOPs and 
work instructions. 
11.1 Investigator Reports 
All study investigators shall prepare and submit the following complete, accurate, and 
timely reports per 21 CFR 812.150(a): 
1) Serious Adverse Events. Please see Section 9.2 for reporting parameters. 
2) Withdrawal of IRB approval. An investigator shall report to the sponsor, within  
5 working days, a withdrawal of approval by the reviewing IRB of the 
investigator's part of an investigation, 
3) Progress. An investigator shall submit progress reports on the investigation to the 
sponsor, and the reviewing IRB at regular intervals, but in no event less often 
than yearly, 
4) Deviations from the investigational plan. An investigator shall notify the sponsor 
and the reviewing IRB (see 56.108(a) (3) and (4)) of any deviation from the 
investigational plan to protect the life or physical well-being of a subject in an 
emergency. Such notice shall be given as soon as possible, but in no event later 

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than 5 working days after the emergency occurred.  Except in such an 
emergency, prior approval by the sponsor is required for changes in or deviations 
from a plan, and if these changes or deviations may affect the scientific 
soundness of the plan or the rights, safety, or welfare of human subjects, FDA, 
and IRB approval is also required, 
5) Informed consent. If an investigator uses a device without obtaining informed 
consent, the investigator shall report such use to the sponsor and the reviewing 
IRB within 5 working days after the use occurs, 
6) Final report. An investigator shall, within 3 months after termination or completion 
of the investigation or the investigator's part of the investigation, submit a final 
report to the sponsor and the reviewing IRB, and 
7) Other. An investigator shall, upon request by a reviewing IRB or FDA, provide 
accurate, complete, and current information about any aspect of the 
investigation. 
11.2 Sponsor Reports 
The study sponsor shall prepare and submit the following complete, accurate, and 
timely reports per 21 CFR 812.812.150(b): 
1) Unanticipated adverse device effects.  Please see section 9.3 for reporting 
parameters. 
2) Withdrawal of IRB approval. A sponsor shall notify FDA and all reviewing IRBs 
and participating investigators of any withdrawal of approval of an investigation or 
a part of an investigation by a reviewing IRB within 5 working days after receipt of 
the withdrawal of approval, 
3) Withdrawal of FDA approval. A sponsor shall notify all reviewing IRBs and 
participating investigators of any withdrawal of FDA approval of the investigation, 
and shall do so within 5 working days after receipt of notice of the withdrawal of 
approval, 
4) Current investigator list. A sponsor shall submit to FDA, at  
6-month intervals, a current list of the names and addresses of all investigators 
participating in the investigation.  The sponsor shall submit the first such list  
6 months after FDA approval, 
5) Progress reports. At regular intervals, and at least yearly, a sponsor shall submit 
progress reports to all reviewing IRBs.  In the case of a significant risk device, a 
sponsor shall also submit progress reports to FDA,  
6) Recall and device disposition. A sponsor shall notify FDA and all reviewing IRBs 
of any request that an investigator return or otherwise dispose of any units of a 
device. Such notice shall occur within 30 working days after the request is made 
and shall state why the request was made, 
7) Final report. In the case of a significant risk device, the sponsor shall notify FDA  
within 30 working days of the completion or termination of the investigation and 
shall submit a final report to FDA  and all reviewing the IRBs and participating 
investigators within 6 months after completion or termination,  

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8) Informed consent. A sponsor shall submit to FDA a copy of any report by an 
investigator of use of a device without obtaining informed consent, within 5 
working days of receipt of notice of such use, and 
9) Other. A sponsor shall, upon request by a reviewing IRB or FDA, provide 
accurate, complete, and current information about any aspect of the 
investigation. 
11.3 Clinical Study Monitoring Plan 
Regular monitoring of study data at each site will be performed as defined by the study 
specific clinical plan.  Individual sites will be monitored to verify that enrollment rate, 
data recording, and protocol adherence are satisfactory.  The frequency of monitoring 
individual sites will fluctuate depending on enrollment rate and site performance.  The 
details of frequency of visits, activities to be performed at each visit, etc., are part of the 
conduct of the study, and will be implemented on an ongoing basis during the course of 
the study, in accordance with the monitoring procedures and the study specific clinical 
plan. 
 
Monitoring visits will be performed for the purposes of verifying adherence to the 
protocol and the completeness and accuracy of data entered on the CRF.  The study 
monitor will verify CRF entries by comparing them with the primary source documents 
(hospital/clinic/office records), which will be made available for this purpose.  The 
monitor will review the maintenance of regulatory documentation, device accountability, 
and any protocol deviations and/or violations.  The monitor will also review the progress 
of the study with the investigator and other site personnel on a regular basis.  At the end 
of the study, a close-out monitoring visit will be performed.  Monitoring visits will be 
arranged in advance with site personnel at a mutually acceptable time.  Sufficient time 
must be allowed by the site personnel for the monitor to review CRFs and relevant 
source documents.  The coordinator and/or investigator should be available to answer 
questions or resolve data clarifications. 
 
Monitoring visits will include study initiation visits, ongoing monitoring visits and study 
close-out visits, as described in the following sections. 
 
 

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11.3.1 
Study Initiation Visits 
The study monitor or designee will communicate with study site and identify a date, time 
and location to meet with the clinical investigator(s), coordinator, and other key 
personnel involved in the study.  A memo will be distributed to all key personnel 
confirming the date, time, location and purpose of the visit along with a detailed agenda. 
Prior to the study initiation site visit, the clinical site should submit the following 
documents to the study monitor, or have them available for collection during the visit: 
•
Signed Investigator Agreement,
•
Curriculum vitae of investigator,
•
Medical license of investigator,
•
Signed Financial Disclosure Form, and
•
IRB/Ethics committee approval documentation of protocol and informed consent
form.
The study monitor will review the study protocol requirements with special emphasis on 
the inclusion and exclusion criteria, study objectives, safety and efficacy endpoints, AE 
reporting, participant withdrawal criteria, the visit schedule and required assessments, 
special clinical procedures, study stopping rules, and other key site requirements for 
study support. 
The study monitor will review the site’s procedures for obtaining and documenting the 
participant’s informed consent, including who is responsible for this process and the 
location of the completed forms.  A thorough review of the regulatory binder with site 
staff and investigator will be performed for completeness.  The study monitor will review 
the protocol case report forms and the site’s plans for maintaining adequate source 
documentation.   
11.3.2 
Study Interim Visits 
The first monitoring visit after site activation normally will be conducted when the first 
few participants have been enrolled at the site.  Since study monitoring is based on the 
rate of patient enrollment, the number of patients enrolled at each site, and a number of 
other variables, monitoring will be adjusted to reflect the needs of the study and the 
participating sites.   
Prior to the site visit, the study monitor will review the protocol for critical aspects of the 
study for monitoring compliance.  The study monitor will also review outstanding queries 
and missing forms, unresolved issues from the previous site monitoring visit (if 

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applicable), study signature log, regulatory checklist, and device accountability log, as 
well as any other project specific documents. 
The study monitor will review demographic and eligibility criteria source documentation 
to ensure that all participants who have been enrolled in the trial were eligible.  All data 
or events that: 1) are critical to the reliability of the study findings, specifically those data 
that support primary and secondary endpoints, 2) are critical to the safety and ethical 
treatment of study subjects, or 3) affect the integrity of critical data will be 100% source 
verified.   
If possible, identified discrepancies will be corrected by the site staff during the visit, but 
may be corrected afterwards.  Documentation will also be reviewed for AEs.  Any 
protocol deviations or unreported AEs will be brought to the attention of the coordinator 
and/or investigator for immediate action.  The study documentation to be kept in the 
study regulatory binder will also be reviewed routinely. 
Informed consent forms will be reviewed to verify that the appropriate IRB/IEC approved 
consent has been signed by both patient and the person administering the consent, 
dated, and properly witnessed if this is required by the form used at the site.  
Test articles will be reviewed at each visit and compared to the test article accountability 
log.  The study monitor will be responsible to review the delivery and the inventory 
records to ensure that the quantity of the study product was shipped, received or 
returned as specified.  The test article records will be compared with the participant 
records to ensure that proper device was received.  The monitor will also verify that the 
test article is kept in a secure locked place.   
The study monitor will conduct a summary meeting with the study investigator and/or 
the study coordinator to discuss the findings of the monitoring team, discrepancies 
found, corrected, and remaining, and any recommendations to improve data quality for 
future site visits.  An attempt should be made to correct any discrepancies found on the 
case report forms or in the source documentation.  These discrepancies will still be 
included in the monitoring report, as well as whether resolved or in need of resolution 
after the monitoring visit.  In addition, the overall status of enrollment, amendments, and 
other protocol adherence issues are to be addressed. 
After the interim site monitoring visit, the site will receive a summary of any data 
discrepancies as well as any other issues encountered.  The summary will also describe 
any outstanding issues that will require the site’s attention. 
11.3.3 
Study Closeout Visits 
The study closeout visit will occur once all subjects have completed the study through 
the long-term follow-up phase.  A study closeout visit will include all of the elements 
identified as part of the interim monitoring visit information.  It will also include a review 
of data not previously audited. 
The study monitor will conduct a summary meeting with the study coordinator and the 
study investigator to discuss any discrepancies or other findings by the monitoring team. 

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At this meeting, an attempt should be made to resolve discrepancies in the source 
documentation requiring the investigator’s revision.  The study monitor will also review 
all regulatory requirements the site may have for closing this study with their IRBs and 
for the maintenance and retention period of study documentation. 
A closeout site visit report will be prepared, with all outstanding issues listed.  The site 
should resolve all issues within a reasonable time after the visit.  Once the study 
monitor verifies that all open issues are resolved, the site will be considered closed.   
11.4 Data Management Plan 
The sponsor will establish a data management plan that is appropriate to this study and 
that ensures the protection of human subjects, protocol compliance, data accuracy, and 
data integrity. 
12 STATISTICAL METHODS AND ANALYSIS 
This is a pilot study with primary outcomes aimed at collecting adverse event 
information. Summary results will be reported, as there is no proposed hypothesis. The 
sample size of 10 has been arbitrarily chosen to provide procedural and device related 
adverse event information. Subjects who are considered “Treatment Failures” will not be 
counted against the sample size of 10.