A Prospective, Multi-centered, Assessor-blinded Clinical Performance Study to Evaluate the Sensitivity and Specificity of the cCeLL-Ex Vivo Device for Intraoperative Brain Tumor Diagnosis.
Phase: NA
Conditions: Benign Brain Tumor, Malignant Brain Tumor
Sponsor: VPIX Medical

Study No.: cCeLL - Ex vivo_01 
 
Protocol Version: 1.3/Date: 6MAR2024 
 
  
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CLINICAL PROTOCOL COVER PAGE 
 
A prospective, multi-centered, assessor-blinded clinical performance study to evaluate 
the sensitivity and specificity of the proposed cell/tissue histopathology image 
processor cCeLL – Ex vivo (Confocal Fluorescence Endomicroscopy) for 
intraoperative brain tumor diagnosis. 
 
Sponsor Protocol No.: 
cCeLL_BT_2022 
Site Protocol No.: 
22-VEHSV-01 
Version: 
1.3 
Protocol Date: 
6 March 2024 
 Sponsor: 
VPIX Medical Inc. 
 
 
 
 
 
 
CONFIDENTIAL 
The information provided in this document is confidential data and is a property of VPIX 
Medical Inc. The information in this document may not be disclosed unless federal or state 
law or regulations require such disclosure. Subject to the foregoing, this information may be 
disclosed only to those persons involved in the study who have a need to know it, with the 
obligation not to further disseminate this information.  
 
 

Study No.: cCeLL - Ex vivo_01 
 
Protocol Version: 1.3/Date: 6MAR2024 
 
  
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Protocol Revisions 
No. 
Version 
No. 
Date 
Description of Changes 
1 
1.0 
19 January 2022 
N/A 
2 
1.1 CA 
23 MAY 2023 
This version is a Canadian specific version. 
 • Addition of ISO 14155 compliant sections 
 • Changes to sample size calculation and statistical 
methods  
• Refinement of eligibility criteria  
• Changes to some secondary endpoints  
• Addition of normal tissue and margin tissue  
• Removal of neurosurgeon assessment of images  
• Change of Canadian Primary Investigator and 
CRO 
3 
1.2 
July 11, 2023 
Number of specimens and basis for calculation, 
modification of secondary endpoints changed 
4 
1.3 
March 6, 2024 
• 
Correction to study summary: objective and 
secondary endpoints. 
• 
Updated the informed consent section (6.4) 
to indicate that patients will first be 
approached for the study by a clinical staff 
member not part of the research study, and 
that ICF will be obtained by a study team 
member not part of the circle of care. 
• 
Overall improved consistency of term and 
symbol use. 
 
   
 
 

Study No.: cCeLL - Ex vivo_01 
 
Protocol Version: 1.3/Date: 6MAR2024 
 
  
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Table of Contents 
PROTOCOL REVISIONS ........................................................................................................................... 2 
TABLE OF CONTENTS .............................................................................................................................. 3 
SYNOPSIS ..................................................................................................................................................... 5 
1. 
STUDY TITLE .................................................................................................................................... 12 
2. 
STUDY ORGANIZATION ................................................................................................................. 12 
2.1. 
STUDY SITES ....................................................................................................................................... 12 
2.2. 
SPONSOR ............................................................................................................................................. 12 
3. 
BACKGROUND AND PURPOSE OF THE INVESTIGATION .................................................... 12 
3.1 
STUDY OBJECTIVE .............................................................................................................................. 12 
3.2 
BACKGROUND .................................................................................................................................... 12 
4. 
INVESTIGATIONAL DEVICE ......................................................................................................... 15 
4.1 
DEVICE STANDARD ............................................................................................................................. 15 
4.2 
APPEARANCE OF THE DEVICE ............................................................................................................. 16 
4.3 
OPERATING MECHANISM .................................................................................................................... 18 
4.4 
INTENDED USE .................................................................................................................................... 19 
4.5 
TARGET HEALTH CONDITION ............................................................................................................. 19 
4.6 
DEVICE ACCOUNTABILITY .................................................................................................................. 19 
5. 
INCLUSION AND EXCLUSION CRITERIA AND SAMPLE SIZE DETERMINATION ......... 21 
5.1  INCLUSION CRITERIA .......................................................................................................................... 21 
5.2  EXCLUSION CRITERIA ......................................................................................................................... 21 
5.3  TISSUE ELIGIBILITY ............................................................................................................................ 21 
5.4  SAMPLE SIZE ...................................................................................................................................... 21 
5.5  STUDY DURATION ............................................................................................................................... 22 
6. 
STUDY PROCEDURES ..................................................................................................................... 22 
6.1  STUDY DESIGN ................................................................................................................................... 22 
6.2  STUDY ASSESSMENTS AND PROCEDURES ........................................................................................... 22 
6.3  SAMPLE IMAGE NUMBER AND BLINDING ........................................................................................... 25 
6.4  INFORMED CONSENT .......................................................................................................................... 26 
6.5  DEMOGRAPHICS AND ANTHROPOMETRIC’S PROFILE.......................................................................... 26 
6.6  TIMING DATA ...................................................................................................................................... 26 
6.7  ASSESSMENT DATA ............................................................................................................................. 26 
7. 
RISKS AND PROCEDURES TO MINIMIZE RISK ...................................................................... 27 
7.1  ANTICIPATED RISKS ............................................................................................................................ 27 
7.2  PRECAUTIONS OF USE ......................................................................................................................... 27 
8. 
STUDY EVALUATION ...................................................................................................................... 28 
8.1  PRIMARY ENDPOINT ........................................................................................................................... 28 
8.2  SECONDARY ENDPOINTS ..................................................................................................................... 28 
8.3 
STATISTICAL ANALYSIS AND INTERPRETATION ................................................................................... 28 
9. 
OPERATIONAL CONSIDERATIONS ............................................................................................. 31 
9.1  REGULATORY, ETHICAL AND STUDY OVERSIGHT ............................................................................... 31 
9.2  CONFIDENTIALITY AND PRIVACY ........................................................................................................ 32 
9.3  SPONSOR RESPONSIBILITIES ............................................................................................................... 32 
9.4  INVESTIGATOR RESPONSIBILITIES ...................................................................................................... 33 
9.5  CLINICAL MONITORING ...................................................................................................................... 34 
9.6  SOURCE DOCUMENTATION ................................................................................................................. 35 
9.7  DATA HANDLING ................................................................................................................................ 35 
9.8  PROTOCOL DEVIATIONS ...................................................................................................................... 36 

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9.9  QUALITY ASSURANCE AND QUALITY CONTROL ................................................................................. 36 
9.10  PUBLICATION POLICY ......................................................................................................................... 37 
9.11  FINANCIAL DISCLOSURE ..................................................................................................................... 37 
10. SAFETY OVERSIGHT ...................................................................................................................... 37 
10.1  DEFINITION AND ASSESSMENT OF SAFETY RELATED EVENTS .............................................................. 37 
10.2  DEVICE DEFICIENCY (DD) .................................................................................................................. 38 
10.3  REPORTING OF SAFETY RELATED EVENTS .......................................................................................... 38 
11. REFERENCES .................................................................................................................................... 40 
 
 
 

Study No.: cCeLL - Ex vivo_01 
 
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Synopsis 
Protocol 
Title 
A prospective, multi-centered, assessor-blinded clinical performance study to 
evaluate the sensitivity and specificity of the proposed cell/tissue histopathology 
image processor cCeLL – Ex vivo (Confocal Fluorescence Endomicroscopy) for 
intraoperative brain tumor diagnosis. 
Sponsor 
VPIX Medical Inc. 
Sites 
Korea University Anam Hospital, Seoul, S. Korea 
Seoul National University Hospital, Seoul, S. Korea 
Samsung Medical Center, Seoul, S. Korea, 
Unity Health- St. Michael’s Hospital, Toronto, ON, Canada 
Coordinating 
Investigator 
Shin-Hyuk Kang MD M.M.Sc Ph.D 
Korea University College of Medicine 
 
 
Study 
Objective 
The purpose of this clinical study is to confirm sensitivity and specificity of the 
cCeLL – Ex vivo in intraoperative brain tumor diagnosis as compared to analysis 
with frozen section. 
Background 
○ The existing workflow for intraoperative brain tumor diagnosis involves tissue 
biopsy, processing, analysis and confirmation by a pathologist using a frozen 
section, and relaying the result back to the surgeon.  
○ The current intraoperative diagnosis based on frozen section analysis is time-, 
resource-, and labor-intensive. The process takes over 40 minutes on average, but 
may take longer if biopsied specimen is insufficient or requires repeated analysis. 
Thereby the development of an efficient device that allows intraoperative real-
time diagnosis is enforced. 
○ The “Digital Biopsy” imaging method, using micro-sized confocal laser 
endomicroscopy, is an emerging technology that enables intraoperative 
visualization of real-time high-resolution brain tumor tissue images.  
○ Neoplastic brain tissue biopsied from participant will be visualized and images 
will be captured using cCeLL – Ex vivo. The corresponding biopsy samples will 
be examined with standard frozen-section analysis (H&E slide), to evaluate the 
sensitivity and specificity of cCeLL – Ex vivo in the diagnosis of brain tumors. 
This study will also be able to verify the potential of Confocal Endomiicroscopy 
to replace the current standard frozen-section analysis, in intraoperative brain 
tumor diagnosis. 
Study Design Prospective, multi-centered, assessor-blinded, clinical performance study 
Sample Size 
The sample size refers to the number of analyzable tissue samples collected 
from participants. There may be multiple samples collected from each 
participant. As it is expected that the 30% of tissue samples will be non-
analyzable, the collection of tissue samples will be larger than the target sample 
size. 
 
The total samples to be collected will be up to 358 samples (286 cancer 
samples, 72 normal samples) 
‐ 
Korea University Anam Hospital: 51 samples (cancer: 42 samples, 
normal: 9 samples)  

Study No.: cCeLL - Ex vivo_01 
 
Protocol Version: 1.3/Date: 6MAR2024 
 
  
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‐ 
Seoul National University Hospital: 82 samples (cancer: 72 samples, 
normal: 10 samples)  
‐ 
Samsung Medical Center: 82 samples (cancer: 72 samples, normal: 10 
samples)  
‐ 
St.Michael’s Hospital, Unity Health: 143 samples collected from a total 
of 65 participants (cancer: 100 samples, normal: 43 samples)  
 
After excluding the non-analyzable tissue samples, we expect to conclude the 
study with a total of 250 samples (200 samples for cancer, 50 samples for normal) 
-Korea University Anam Hospital: 36 samples (cancer: 30 samples, normal: 
6 samples)  
-Seoul National University Hospital: 57 samples (cancer: 50 samples, 
normal: 7 samples)  
-Samsung Medical Center: 57 samples (cancer: 50 samples, normal: 7 
samples)  
-St.Michael’s Hospital, Unity Health: 100 samples collected from a total of 
50 participants (cancer: 70 samples, normal: 30 samples) 
 
 
Basis for 
Calculating 
the Number 
of Acquired 
Images 
The data for agreement, sensitivity and specificity can be summarized as in the 
table below. For agreement, the terms agree and disagree are with respect to 
each other. For sensitivity and specificity, the terms agree and disagree are with 
respect to truth. So for sensitivity, truth is tumor and for specificity truth is not 
tumor.  
 
Agreement Table 
  
cC   
   
FS   
Results   
Agree   
DisAgree   
   
Agree   
a   
b   
a+b   
Disagree   
c   
d   
c+d   
   
a+c   
b+d   
nT   
 
 
The estimate of agreement is pAG = (a+d)/nT. It is desired to test the hypothesis 
that the agreement is greater than 80%. This is compatible with the expected 
result that both the sensitivity and the specificity will be about 90%. Thus the 
hypothesis to be tested is:  
 
H0: πAG  = 80% vs HA: πAG > 80%   
Where πAG  is the percent agreement between Frozen Section and cCeLL. This 
will be tested utilizing the exact binomial test. Estimates of agreement from the 
pilot study indicate that the agreement will be greater than 86%. In this study, 
there will be 250 subjects available for analysis for the estimation and testing of 
agreement. For outcome results, if the agreement is 86%, with the sample size 
of 250, the probability the estimated agreement will be greater than 80% is 
greater than 90%. 
 

Study No.: cCeLL - Ex vivo_01 
 
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Sensitivity Table – This is only tabulated when the truth standard is positive for 
tumor.   
Agreement Table with Tumor Truth 
   
cC   
   
FS   
Results   
Agree 
w/Truth   
DisAgree 
w/Truth   
   
Agree   
e   
F   
e+f   
Disagree   
g   
H   
g+h   
   
e+g   
f+h   
n1   
 
The sensitivity of the Frozen Section is given by pSenF = (e+f)/n1 and the 
sensitivity of cCeLL is given by pSenC=(e+g)/n1.  It is desired to demonstrate that 
the sensitivity of cCeLL is non inferior to that of Frozen section.   
 
The non inferiority of the sensitivity of cCeLL result versus the sensitivity of 
the Frozen Section is given as:   
H0: SenF -SenC  >  versus HA: SenF -SenC    
 
Here πSenF is the true sensitivity for Frozen Section and πSenC is the true 
sensitivity for cCell. Where  is the non inferiority limit.  In this study, it is 
proposed to utilize a =0.05 (5%).  If that  is used and the anticipated 
sensitivity is 90%, then with a sample size of 200 tumor positive samples the 
probability the difference between the estimated sensitivities is greater than 5% 
is greater than 90%.  
 
 
Eligibility 
Criteria 
Inclusion Criteria 
The biological specimens (hereafter referred to as ‘Tissue’) and/or images to be 
used in this trial must be collected from patients who satisfy all of the following 
inclusion criteria  
 
1. Male or female patients >19 years of age;  
2. Patient is suspected to have a brain tumor and has been scheduled 
for neurosurgery with a potential tumor resection;   
3. Patient is willing and able to provide informed consent and 
understand its content.  
 
Exclusion Criteria 
Tissue and/or images to be used in this trial must be collected from patients who 
do not meet any of the following exclusion criteria:   
  
1. Patients has undergone several surgeries on the lesion of interest.  
 
Study Device cCeLL - Ex vivo (Clearance No. 21-311) 
Study 
Duration 
18 months from the start date of the study    
Study 
Procedure 
1) Samples will be collected from consented participants who have satisfied 
the eligibility criteria.  

Study No.: cCeLL - Ex vivo_01 
 
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2) Tissue will be removed as part of the standard neurosurgical procedure. 
Normal tissue obtained from inevitable resection during the course of 
surgery. There will be no deviation from normal surgical practice to 
aquire tissue samples. 
3) Image recordings of sample tissue using cCeLL – Ex vivo are taken and 
the obtained data is stored (CC).  
4) cCeLL – Ex vivo image data of the collected samples is sent to the central 
core.  
5) The result of frozen section analysis (FS) will be collected from the 
pathology department of each site.  
6) The result of permanent section analysis (PS) of corresponding paraffin-
embedded tissue section (PS) will be collected from the pathology 
department of each site. PS will serve as a reference standard to the 
analysis result of CC and FS.  
7) An interpreting pathologist will analyze given images (CC-H) and is not 
allowed to review the reference standards (PS) until all interpretations 
have been completed.  
8) The cCeLL – Ex vivo image data will be anonymized such that only the 
unique reference numbers will be displayed in the images provided, and 
participant information including participant enrollment number and 
surgery information will be removed.  
9) The types of the images obtained from this procedure are as follows: 
cCeLL – Ex vivo will capture image data of a 
resected tissue, prior to frozen sectioning (FS) 
and permanent sectioning (PS). The biopsied 
samples can be used to evaluate the presence of 
tumors, and the tumor types. 
Method 
of 
analysis 
Image 
data 
Reference 
standard 
Result of 
analysis by 
a 
pathologist 
cCeLL – 
Ex vivo 
CC 
PS 
CC-H 
Permane
nt section 
PS 
PS 
 
Frozen 
Section 
FS 
PS 
 
CC : Analysis of images obtained by cCeLL  
FS : Frozen section analysis  
PS : Permanent section analysis  
H : Pathologist   
 
 
 
10) Data will be analyzed by a statistician. Sensitivity and specificity will be 
calculated as follows: 

Study No.: cCeLL - Ex vivo_01 
 
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- 
The probability of interpretation results by the interpreting physician 
(1 pathologist) being positive given that the reference standards is 
positive 
- 
The probability of interpretation results by the interpreting physician 
(1 pathologist) being negative given that the reference standards is 
negative 
Study 
Endpoints 
Primary Endpoint 
The primary endpoints in this study are the agreement between cCeLL Ex vivo 
and frozen section, the sensitivity of cCeLL ex vivo and frozen section, and the 
specificity of cCeLL ex vivo and frozen section. These endpoints will be assessed 
by a single pathologist in the analysis of tumor tissue.   
Secondary Endpoints 
1. 
Comparison of time taken in tissue scanning, visualization, and 
interpretation using cCeLL – Ex vivo to time taken in frozen section 
analysis.  
2. 
Accuracy in determining the tumor type  
3. 
Required image counts for adequate analysis and diagnosis 
using cCeLL – Ex vivo  
4. 
Non-diagnostic Image  
5. 
AUC value  
 
Analysis 
Methods 
Primary Endpoints 
Comparison of the sensitivity/specificity of cCeLL-Ex vivo reading results, and 
the sensitivity/specificity of the frozen section reading results in one pathological 
inquiry for brain tumor tissue  
• 
Sensitivity of cCeLL-Ex vivo reading result in 1 patient in 
pathological inquiry for brain tumor tissue: Probability that PS is 
positive if CC-H positive  
• 
Specificity of cCeLL-Ex vivo reading result in 1 patient in 
pathological inquiry for brain tumor tissue: Probability that PS is 
negative if CC-H is negative  
• 
Sensitivity of frozen section reading results for brain tumor 
tissue: Probability that FS is positive if PS is positive  
• 
Specificity of frozen section reading results from brain tumor 
tissue: Probability that PS is negative if FS is negative   
 
The ratio of the clinical sensitivity/specificity of a cCeLL Ex-vivo image and the 
sensitivity/specificity of the frozen section image of 1 patient in the pathological 
inquiry for the total reading results is presented, respectively. To identify a 95 % 
bilateral confidence interval for the difference between cCeLL- Ex vivo and the 
frozen section sensitivity/specificity.   
  
The statistical significance of the difference between cCeLL-Ex vivo and the 
frozen section sensitivity/specificity ratio is tested by the McNemar test.   
 
Secondary Endpoints 
1. 
Comparison of cCeLL-Ex vivo imaging and reading time with frozen 
section reading time  
i. 
The cCeLL-Ex vivo imaging time is measured and recorded in 
minutes from the time the fluorescent dye is applied to the specimen 
for image acquisition   

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ii. 
The cCeLL-Ex vivo reading time by the pathologist is measured and 
recorded in minutes from the time of capturing the cCeLL-Ex vivo 
image of each brain tumor to the time of the final reading.   
iii. 
The imaging and reading time for frozen section is measured in 
minutes from the time of resecting the specimen undergoing frozen 
section in the operating room to the time when the pathology 
department of each institution obtains a frozen section image and 
reports the findings.   
iv. Format: ___Hours ___Minutes  
2. 
Comparison of cCeLL accuracy of evaluating the tumor types via 
Ex-vivo imaging with the accuracy using frozen section  
i. 
Evaluation of tumor types via cCeLL-Ex vivo images by 1 
pathologist : Agreement between the result of CC-H and the result 
of PS   
ii. 
Evaluation of tumor types via frozen section: Agreement between 
the result of FS and the result of PS  
3. 
cCeLL – Time and number of images required to diagnose Ex vivo 
imaging  
i. 
The number of images required for the pathologist to read the brain 
tumor cCeLL – Ex vivo image will be measured and averaged.  
ii. 
cCeLL – Ex vivo reading time uses that of secondary endpoint 1.  
iii. 
*Average number of images required for cCeLL – Ex vivo image 
reading of 1 brain tumor specimen: __ _  _  
4. 
Non-diagnostic image  
i. 
The total number of cCeLL Ex-vivo images among the images 
confirmed in the vivo reading, and the proportion of the number of 
images that cannot be read are stated as a percentage (%).  
ii. 
The number of images that cannot be read is recorded when the 
reader reads it.  
5. 
 AUC value  
i. 
Based on the results of each endpoint, the sensitivity and false 
positive rate (1-specificity) are used to draw the ROC (Receiver 
Operating Characteristic) Curve to evaluate the performance of the 
diagnosis to distinguish between positive and negative, and the 
accuracy of the diagnosis is evaluated through the AUC (Area Under 
the Curve) value obtained from the area below the ROC curve.  
 
  
 

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List of Abbreviations and Terms 
 
ADE 
 
Adverse Device Effect  
AE 
 
Adverse Event   
AUC   
Area under the curve  
CC 
 
Analysis of images obtained by cCeLL  
eCRF 
 
Electronic Case Report Form  
DD 
 
Device Deficiency  
FAS 
 
Full Analysis Set  
FS 
 
Frozen section analysis  
GCP 
 
Good Clinical Practice  
ICF 
 
Informed Consent Form  
ISO 
 
International Organization for Standardization  
ITT 
 
Intent-To-Treat  
LOCF  
Last Observation Carried Forward  
MAST  
Multiple Allergen Simultaneous Test  
PBS 
 
Phosphate Buffered Saline  
PP 
 
Per Protocol   
PS 
 
Permanent section analysis  
REB 
 
Research Ethics Board  
SAE 
 
Serious Adverse Event  
SADE  
Serious Adverse Device Effect  
SOC 
 
System Organ Class  
SOP 
 
Standard Operating Procedure  
UADE  
Unexpected Adverse Device Effect  
 
 
 
 

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1. Study Title 
A prospective, multi-centered, assessor-blinded clinical performance study to assess the 
sensitivity and specificity of the proposed cell/tissue histopathology image processor cCeLL – 
Ex vivo (Confocal Fluorescence Endomicroscopy) in diagnostic yield during brain tumor 
surgery 
 
2. Study Organization 
2.1. Study Sites 
Study Site 
Location 
Korea University 
Anam Hospital 
73 Goryeodae-ro, Seongbuk-gu, Seoul, 
Republic of Korea 
Seoul National 
University Hospital 
101 Daehak-ro, Jongno-gu, Seoul, Republic 
of Korea 
Samsung Medical 
Center 
81 Irwon-ro, Gangnam-gu, Seoul, Republic 
of Korea 
Unity Health- St. 
Michael’s Hospital  
36 Queen St E, Toronto, ON Canada  
*The Sponsor  will obtain Health Canada 
authorization for an Investigational Testing 
application for this site..  
 
2.2. Sponsor  
Company 
CEO 
Location 
Phone 
VPIX Medical Inc. 
Kyungmin Hwang 
2F, 774 Gyeryong-ro, 
Jung-gu, Daejeon, 
Republic of Korea 
 
010-4366-3519 
 
3. Background and Purpose of the Investigation 
3.1 Study Objective 
The purpose of this clinical study is to confirm sensitivity and specificity of the cCeLL – Ex 
vivo in intraoperative brain tumor diagnosis as compared to analysis with frozen section.  
3.2 Background  
Cancer is a leading cause of death, accounting for nearly 1 out of 6 death worldwide (Ferlay et 
al., 2020; de Martel et al., 2020; WHO, 2020).  
The existing workflow for intraoperative brain tumor diagnosis involves tissue biopsy, 
processing, analysis and confirmation by a pathologist using frozen section, and relaying the 
result back to the surgeon. The current intraoperative diagnosis based on frozen section analysis 
is time-, resource-, and labor-intensive. The process takes over 40 minutes on average but may 

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take longer if biopsied specimen is insufficient or requires repeated analysis. Thereby the 
development of an efficient device that allows intraoperative real-time diagnosis is enforced. 
Confocal Laser Endomicroscopy is a promising diagnostic tool to replace current standard 
‘frozen section analysis’ by allowing intraoperative real-time high-resolution visualization of 
tissue of interest. Confocal Fluorescence Endomicroscopy follows the general principles of 
fluorescence, which is the characteristic of fluorescence-stained specimen (‘tissue’) that absorb 
light of short-wavelength and emits light of long-wavelength. This medical device visualizes 
the intensity of light emitted from a specimen which varies according to the specimen’s degree 
of light absorbance (White et al., 1987; Amos and White, 2003). 
When the probe of the device, which contains optical fibers, is placed in contact with the 
specimen or close to within several hundred ㎛ of the specimen, the optical signal generated 
from the main body gets transmitted to the specimen through the probe and then absorbed by 
the specimen. The specimen then gets activated and emits fluorescent light, and this fluorescent 
light returns to the main body of the device through the optical fibers of the probe. The 
mechanism behind optical fibers is that light incident at a specific angle proceeds to total 
reflection due to the inside and outside of the optical fibers each being made with differing 
densities and refractive indices. The optical signal which returned to the main body through 
the optical fibers is detected as an electronic signal by the photodetector in the main body. The 
electric signal is then converted to a digital signal by the converter inside the main body of the 
device, and the digital signal is then processed by the PC through its software and exported as 
an image onto the monitor.   
Several global medical device companies have developed promising digital-biopsy devices 
based on confocal microscopy for past few years and commercialized micro-probe-based 
optical fusion imaging devices that can be placed in contact with the patient's organs directly. 
However, technological barrier in micro-miniaturization of probe still exist as seen in marketed 
devices, which limits its use in various human organ systems›. These limitations are observed 
as the probe being too large for intraoperative use (Vivascope, USA) (Mavig GmbH, 2019), 
limited number of optic fiber bundles leading to inadequate resolution of images for pathologic 
diagnosis (Cellvizio, France) (Mauna Kea Technologies, 2021), or difficulty in compensating 
body movements for respiratory/circulatory activities due to limited laser scanning speed of 
the probe (Convivo, Germany) (Carl Zeiss Meditec AG, 2019). The proposed investigational 
device designed with an innovative optic probe and image-processing technology to enable 
detection and capture of high-resolution images whilst in operating room. 
 

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Anticipated Economic/Industrial Impact and Advancement – Establishment of Digital 
Histopathology System 
 
① cCeLL – Ex vivo allows rapid scanning, capturing, and storing of high-resolution images of biopsy 
specimen, without undergoing lengthy standard procedure, as a complete Digital Histopathology 
System. Hospitals are suffering from the increased burden in storing pathology tissue slides, hence in 
process of converting originals into digital slides and storing into digital image repository. 
 
② cCeLL – Ex vivo enables capturing of digital images without producing physical tissue slides, which 
is a  labor-,time- and cost-intensive process, as well potentially reduces carbon emission. As the digital 
images created by cCeLL – Ex vivo are saved as electronic files without requiring utilization of separate 
viewer system, it allows efficient data management and accelerates conversion rate and smooth 
adaptation into digital histopathology system. 
 
 
 

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4. Investigational Device 
4.1 Device Standard 
 
Item 
Specification 
Electrical 
Specification 
Maximum power 
consumption at the 
maximum output 
300VA 
Electrical rating input 
100-240VAC, 50/60Hz 
Protection degree for electric 
shock 
Class 1 equipment 
Performance 
specification 
Laser 
Output wavelength 
1. CX100-2W2C488775: 480- 492 
nm, 770- 785 nm 
2. CX100-1W1C488: 480-492 nm 
3. CX100-1W1C785: 770 -785 nm 
Laser Class 
3R 
Output power 
1. CX100-2W2C488775 
a. 488 nm: max. 2.5 mW 
b. 775 nm: max.  3.5 mW 
2. CX100-1W1C488: max. 2.5 mW 
3. CX100-1W1C785: max. 3.5 mW  
Operation mode 
Continuous mode 
Laser medium 
Laser diode (semiconductor) 
Imaging 
Field-of-View 
(FOV) 
500㎛(±10%) x 500㎛(±10%) 
Frame count per 
second 
2 - 10fps 
Storage and 
Maintenance 
In-Use 
Temperature 
15℃ - 35℃ 
Humidity 
30% - 75% 
Storage 
Temperature 
-10℃ - 50℃ 
Humidity 
10% - 90% 
 
 
 
 
 
 

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4.2 Appearance of the Device 
Item 
Description 
Main 
device 
 
Probe 
 

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Stage 
 

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Main screen 
(Software) 
 
 
 
4.3 Operating Mechanism 
The investigational medical device visualizes cells of a biological specimen which has been 
resected from the body and to which dye has been applied by measuring the intensity of the 
fluorescence signal that is generated by shooting a laser onto the specimen. The device is 
capable of capturing images of regions several ㎛ wide of a specimen at depth of several 
hundreds of ㎛, and visualizing them in 2D through its complementary software.  Confocal 
Fluorescence Endomicroscopy follows the general principles of fluorescence. Fluorescence 
refers to a phenomenon in which a fluorescent object emits light of long wavelength by 
absorbing light of short wavelength. This device visualizes the intensity of light emitted from 
a specimen which varies according to the specimen’s degree of light absorbance. 
When its probe, which contains optical fibers, is placed in contact with the specimen or close 
to within several to several hundred ㎛ of the specimen, the optical signal generated from the 
main body gets transmitted to the specimen through the probe and then absorbed by the 
specimen. The specimen then is activated and emits fluorescent light.  This fluorescent light 
returns to the main body of the device through the optical fibers of the probe. The mechanism 
behind optical fibers is that light incident at a specific angle proceeds to total reflection due to 
the inside and outside of the optical fibers each being made with differing densities and 
refractive indices. The optical signal which returned to the main body through the optical fibers 
is detected as an electronic signal by the photodetector in the main body. The electric signal is 
then converted to a digital signal by the converter inside the main body of the device, and the 
digital signal is then processed by the PC through its software and exported as an image onto 
the monitor.  
 

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4.4 Intended Use 
This investigational medical device is a diagnostic tool that aims to provide rapid and precise 
intraoperative assessment of biopsied neoplastic tissue specimen from a brain tumor. By 
enabling the fluorescence staining, visualizing, capturing and storing image data while in the 
operation room, standard time-consuming and labor-intensive preparation of specimen 
sectioning may not be necessary.   
4.5 Target Health Condition 
Benign/Malignant Brain Tumor 
4.6 Device Accountability 
4.6.1 Labeling 
The investigational medical device will be labelled according to the requirements of ICH-GCP, 
ISO 14155, and all other applicable regulatory guidelines. The device label will contain the 
following information in required official languages (i.e. English and French in Canada; 
Korean in Korea): 
 
a. 
Name of the device 
b. 
Name and address of manufacturer 
c. 
Identifier of the device 
d. 
Package content 
e. 
Expiry date 
f. 
Specification (as necessary for proper use) 
g. 
Directions for use 
h. 
Warning and cautions 
i. 
Contraindications 
j. 
Storage condition 
 
All investigational devices used in Canada will be labelled “Investigational Device” and “To 
be Used by Qualified Investigators Only” and “Instrument de recherche” and “Réservé 
uniquement à l’usage de chercheurs compétents” accordingly to Health Canada regulations.  
 
4.6.2 Maintenance, Handling, and Record Keeping 
The investigational medical device will be provided by Sponsor only after obtaining written 
approval/authorization from the REB and regulatory authorities. Access to investigational 
devices shall be controlled and the investigational devices shall be used only in the clinical 
investigation and according to the study plan. Device accountability will be maintained and 
will document the physical location of all investigational devices from shipment of 
investigational devices to the investigation sites until return or disposal. The Sponsor must 
document and retain all records related to device manufacture, shipping, receipt, return, or 
disposition. The investigator/investigator’s designee will acknowledge receipt upon reception.  

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Sponsor or Sponsor’s designee must identify and document the SOP procedures for the return 
of investigational device upon study completion or in case of issue related to device.  
The Sponsor or manufacturer must not provide or dispense any parts of investigational medical 
device to any other study site or investigator. The device must not be used other than for the 
intended use specified in the trial protocol.   
4.6.3 Receiving, Storage, and Return 
Device accountability will be maintained and will document the physical location of all 
investigational devices from shipment of investigational devices to the investigation sites until 
return or disposal. The principal investigator or an authorized designee shall keep records 
documenting the following:   
a. 
name(s) of person(s) who received, used, returned, or disposed of the device;   
b. 
the date of receipt, identification, and quantity of each investigational device 
(lot number);   
c. 
the expiry date, if applicable;   
d. 
the date or dates of use;   
e. 
the date on which the investigational device was returned;   
f. 
the date of return of unused, expired, or malfunctioning investigational devices, 
if applicable.  
A site monitor will review the inventory and accountability log during site visits and at the 
completion of the study. If the study is completed, prematurely terminated, or suspended, the 
Sponsor shall promptly inform the investigators, the REB, the regulatory authorities of the 
reason for termination or suspension, as specified by the applicable regulatory requirements; 
and the investigational medical device will be return to the Sponsor or alternative disposition 
of used/unused products as per request by the Sponsor. The investigational medical device is 
intended for use by qualified investigators only.   
 
 

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5. Inclusion and Exclusion Criteria and Sample Size Determination 
5.1 Inclusion Criteria 
The biological specimens (hereafter referred to as ‘tissue’) and/or images to be used in this trial 
must be collected from patients who satisfy all of the following inclusion criteria:  
 
1. Male or female patients ≥ 19 years of age.  
2. Patient is suspected to have a brain tumor and has been scheduled for neurosurgery 
with a potential tumor resection.  
3. Patient is willing and able to provide informed consent and understand its content.  
 
5.2 Exclusion Criteria 
Tissue and/or images to be used in this trial must be collected from patients who do not meet 
any of the following exclusion criteria:   
1. Patient has undergone several surgeries on lesion of interest.  
 
5.3 Tissue Eligibility 
Eligible tissue will meet all of the following: 
1. Tissue from an eligible and consented patient at a participating site  
2. Any normal tissue obtained from inevitable resection during standard surgery 
5.4 Sample Size  
The sample size refers to the number of analyzable tissue samples collected from participants. 
There may be multiple samples collected from each participant.  
There will be 250 analyzable tissue samples required (200 tumor positive and 50 normal) for 
this study.  
5.4.1  Number of Specimens 
A total of 250 analyzable samples (200 samples for cancer, 50 samples for normal) are 
required.   
• 
Korea University Anam Hospital: 36 samples (cancer: 30 samples, normal: 6 
samples)  
• 
Seoul National University Hospital: 57 samples (cancer: 50 samples, normal: 
7 samples)  
• 
Samsung Medical Center: 57 samples (cancer: 50 samples, normal: 7 samples)  
• 
St.Michael’s Hospital, Unity Health: 100 samples collected from a total of 65 
participants (cancer: 70 samples, normal: 30 samples)  

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With an expected dropout rate of 30%, the number of samples to be collected is 358 samples 
(286 cancer samples, 72 normal samples)  
• 
Korea University Anam Hospital: 51 samples (cancer: 42 samples, normal: 9 
samples)  
• 
Seoul National University Hospital: 82 samples (cancer: 72 samples, normal: 
10 samples)  
• 
Samsung Medical Center: 82 samples (cancer: 72 samples, normal: 10 
samples)  
• 
St.Michael’s Hospital, Unity Health: 143 samples collected from a total of 50 
participants (cancer: 100 samples, normal: 43 samples)  
5.5 Study Duration 
It is expected that the study will run for about 18 months in total from the time the study sites 
are activated. Enrollment is expected to 8 months in Korea and up to 12 months in Canada. 
There will be additional time for data collection, data cleaning and analysis.   
 
6. Study Procedures 
6.1 Study Design 
Prospective, multi-center, assessor-blinded clinical study. Samples will be paired and 
compared against the current standard of assessment.  
6.2 Study Assessments and Procedures 
There will be up to three (3) tissue sample types assessed for each participant: 1- center-of-
tumor, 2- normal tissue (collected from inevitable standard resection), and 3- margin tissue. 
Depending on each participant’s circumstance, the number of sample tissues harvested will 
differ from minimum of one to maximum of three. All tissue samples will be assessed with the 
investigative device and compared against frozen section analysis.  
 

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1. Samples will be collected from consented participants who have satisfied the 
eligibility criteria.  
2. Tissues will be removed as part of the standard neurosurgical procedure. Normal 
tissues obtained from inevitable resection during the course of surgery.    
3. Collected samples will be processed as follows:  
1. Wash the biopsied tissue with Phosphate Buffered Saline (PBS)  
2. Place the tissue on a glass slide  
3. Apply dye onto the tissue  
4. After 1 minute, wipe on gauze and then scan (i.e., cCeLL imaging) the tissue 
using Pixecton (probe) connected to cCeLL – Ex vivo  
5. Send the processed tissue to pathology to obtain images in the form for frozen 
sections analysis (FS)/permanent sections analysis (PS)    
4. Image recordings of sample tissue using cCeLL – Ex vivo are taken and the obtained 
data is stored (CC).  
5. cCeLL – Ex vivo image data of the collected samples is sent to the central core.  
6. The result of frozen section analysis (FS) will be collected from the pathology 
department of each site.  
7. The result of permanent section analysis (PS) of corresponding paraffin-embedded 
tissue section (PS) will be collected from the pathology department of each site. PS 
will serve as a reference standard to the analysis result of CC and FS.  
8. An interpreting pathologist will analyze given images (CC) and is not allowed to 
review the reference standards (PS).  
9. The cCeLL – Ex vivo image data will be de-identified such that only the unique 
reference numbers will be displayed in the images provided, and participant 
information including participant enrollment number and surgery information will be 
removed.  
10. The types of the images obtained from this procedure are as follows:  
 
 
 
 

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cCeLL – Ex vivo will capture image data of a resected tissue, prior to frozen sectioning 
(FS) and permanent sectioning (PS). The sample is used to evaluate the presence or absence 
of tumors, and also to evaluate the tumor types.   
Method of 
analysis  
Image data  
Reference standard  
Result of analysis by a 
pathologist 1  
  
cCeLL – Ex 
vivo  
CC  
PS  
CC-H  
  
Permanent 
section  
PS  
PS  
  
Frozen Section  
FS  
PS  
  
CC : Analysis of images obtained by cCeLL  
FS : Frozen section analysis  
PS : Permanent section analysis  
H : Pathologist  
 
 
 

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6.3 Sample Image Number and Blinding 
6.3.1  Participant Number Assignment 
Participant No. will be assigned to participants satisfy the eligibility criteria and are included 
in the study.  
 
The following rules will apply to generating Participant No: 
Participant No.  
R - __ __ - __ __ __  
2 letter site acronym, 3-digit sequence  
(e.g., R-KO-001, R-KO-002)  
 
The following rules will apply to generating Specimen No.: 
Specimen No.  
Participant No. - __ - __  
1 
letter 
specimen 
classification, 
1-digit
sequence  
(e.g., R-KO-001-C-1, R-KO-001-P-1, R-KO-
001-N-1)  
 
Each selected image will be assigned an enrollment number in a sequential manner. The 
investigator will register the images by entering such information as the participant number, 
image type, and order.  
6.3.2 Reference Standard and Analysis Number Assignment 
Reference standard and analysis No. will be assigned according to type as follows:  
<Reference standard No.>  
• Permanent section analysis (PS): Participant number – Specimen 
number – permanent section (e.g., R-KO-001-C-PS-01)  
<Frozen section No.>  
• Frozen section analysis (FS): Participant number – Specimen 
number – Frozen section (e.g., R-KO-001-C-FS-01)  
<cCeLL image analysis No.>  
• Pathologist 1 analysis of cCeLL image: Participant number – 
Specimen number – cCeLL – pathologist (e.g., R-KO-001-C-01-CC-
H)  
 
 
 
 
 

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6.4 Informed Consent 
Informed consent must be obtained prior to conducting any study-related assessments. A clinical 
staff member within the patient's circle of care (known to the patient), who is not part of the research 
team, will make first contact with potential patients to assess whether or not they are interested in 
learning more about the study. Then, they will contact a research study team member (not part of the 
patient circle of care) to discuss the study with the patient and obtain informed consent to participate in 
the study. 
The research staff (not part of the patient’s circle of care) will explain the clinical study to each 
potential participant, including all aspects of the clinical study that are relevant to the 
participant’s decision to participate throughout the clinical study including, but not limited to, 
the following: purpose and nature of the study, study procedures, expected study duration, 
available alternative therapies, and the benefits and risks involved with study participation and 
the potential treatment. They shall avoid any coercion or undue improper influence on, or 
inducement of, the participant to participate and will not waive or appear to waive the 
participant’s legal rights. Participants will be given a copy of the informed consent form and 
will be provided ample time to read and understand the document and the opportunity to ask 
questions. Participants will be informed of their right to withdraw from the study at any time 
without prejudice; consent forms will use local non-technical language and be provided in a 
language understandable to the participant.  After this explanation, and before any study-
specific procedures have been performed, the participant and the PI’s qualified designee (a 
member of the study team outside the patient’s circle of care), responsible for conducting the 
informed consent process will voluntarily sign and personally date the informed consent 
form.  Prior to participation in the study, the participant will receive a copy of the signed and 
dated written informed consent and any other written information provided to the participant.  
6.5 Demographics and Anthropometric Profile 
Demographic information relating to the participant’s age and sex will be recorded after 
enrollment.   
6.6 Timing Data 
Start and stop times and other similar data will be collected to determine the processing 
duration for each test from start to finish.   
6.7 Assessment Data 
Test results will be collected and compared from all three (3) modalities (cCell, FS, PS). 
Blinded assessments of cCell images will be documented from the site pathologist for each 
analyzable image.  
 
 

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7. Risks and Procedures to Minimize Risk  
7.1 Anticipated Risks  
The investigational medical device used in this prospective study is an ex-vivo diagnostic 
device which has no direct or indirect effect on the participant, and therefore there are no 
anticipated risks to be identified. Standard of care diagnostic images will be used to make 
clinical decisions in this study population.  
7.2 Precautions of Use  
7.2.1 General Precautions  
1. To be used for ex-vivo diagnostic purposes only (for trained professionals 
only).  
2. To be used by a trained professional only.  
3. The user must be fully aware of the user instructions prior to use.  
4. To be used with the parts and cables provided in accordance to the user 
instructions manual.  
5. Do not block the vent of the device.  
6. Not to be dissembled, repaired, or modified.   
7. If device failure or abnormal behavior is suspected, stop using the device 
immediately and contact the head office.  
  
7.2.2  Installation Precautions  
1. 
Not to be used with cables other than the ones provided with the device.  
2. 
Do not turn on the device until installation is complete.  
3. 
Do not block the cooling fan of the device.  
4. 
Never use with ungrounded wall outlet.  
5. 
To be installed on flat surfaces only.  
  
7.2.3  Precautions Before Device Use  
1. 
Become fully aware of the device operation manual before use.  
2. 
Inspect all parts before use.  
 
7.2.4  Precautions During Device In-Use  
1. 
Never directly stare at the laser emitting part of the device.  
2. 
Do not use this device in places where combustible steam or explosive gases 
and chemicals are present or stored.   
3. 
If issues not listed in the user instruction manual have occurred, do not attempt 
to resolve them on your own; instead contact the head office.  
4. 
Keep this device and other electronic devices away from liquids.  
5. 
Do not bend, twist or shock the probe  

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6. 
Be careful not to touch the laser emitting part of the probe with bare hand as 
this will contaminate the lens.  
  
7.2.5 Laser Safety  
1. 
Do not expose yourself to the laser of this device.  
2. 
Never directly stare at the laser emitting end of the probe.  
  
7.2.6  Maintenance Precautions  
1. 
Back up data on a regular basis to avoid data loss.  
2. 
Update the software on a regular basis.  
3. 
Leave the device turned off during moving, washing, or maintenance.  
 
8. Study Evaluation  
8.1 Primary Endpoint  
The primary endpoints in this study are the agreement between cCeLL Ex vivo and frozen 
section, the sensitivity of cCeLL ex vivo and frozen section, and the specificity of cCeLL ex 
vivo and frozen section.  These endpoints will be assessed by a single pathologist in the 
analysis of tumor tissue.  
8.2 Secondary Endpoints  
1. Comparison of time taken in tissue scanning, visualization, and interpretation using 
cCeLL – Ex vivo to time taken in frozen section analysis.  
2. Accuracy in determining the tumor type  
3. Required image counts for adequate analysis and diagnosis using cCeLL – Ex vivo  
4. Non-diagnostic Image  
5. AUC value  
8.3 Statistical Analysis and Interpretation  
8.3.1  Methods and Sample Size  
The data for agreement, sensitivity and specificity can be summarized as in the table 
below.  For agreement, the terms agree and disagree are with respect to each other. For 
sensitivity and specificity, the terms agree and disagree are with respect to truth. So for 
sensitivity, truth is tumor and for specificity truth is not tumor.  It should also be noted that 
since the total sample size was chosen to be 250, no power calculations were done; however, a 
probability calculation that the estimated parameter is greater than the null hypothesis was 
presented.  
 
 

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Agreement Table  
  
cC  
  
FS  
Results  
Agree  DisAgree  
  
Agree  
a  
b  
a+b  
Disagree  
c  
d  
c+d  
  
a+c  
b+d  
nT  
 
The estimate of agreement is pAG = (a+d)/nT. It is desired to test the hypothesis that the 
agreement is greater than 80%.  This is compatible with the expected result that both the 
sensitivity and the specificity will be about 90%.  Thus the hypothesis to be tested is that the 
agreement is 80% (H0: Null hypothesis) versus the alternative hypothesis that the agreement 
is greater than 80% (HA: Alternative hypothesis).  
H0: πAG  = 80% vs HA: πAG > 80% 
Where πAG  is the percent agreement between Frozen Section and cCell. This will be tested 
utilizing the exact binomial test.  Estimates of agreement from the pilot study indicate that the 
agreement will be greater than 86%.  In this study, there will be 250 participants available for 
analysis for the estimation and testing of agreement.  For outcome results, if the agreement is 
86%, with the sample size of 250, the probability the estimated agreement will be greater than 
80% is greater than 90%.  That is, P(pAG > 80%) > 90%.  
 
Sensitivity Table – Sensitivity is only calculated when the truth standard is positive for tumor.  
Agreement Table with Tumor Truth 
  
cC  
  
FS  
Results  
Agree 
w/Truth  
Disagree 
w/Truth  
  
Agree  
e  
f  
e+f  
Disagree  
g  
h  
g+h  
  
e+g  
f+h  
n1  
 
The sensitivity of the Frozen Section is given by pSenF = (e+f)/n1 and the sensitivity of cCell is 
given by pSenC=(e+g)/n1. It is desired to demonstrate that the sensitivity of cCell is non inferior 
to that of Frozen section.  
The non inferiority of the sensitivity of cCell result versus the sensitivity of the Frozen Section 
is given as:  
H0: SenF -SenC >  versus HA: SenF -SenC   
Here πSenF is the true sensitivity for Frozen Section and πSenC is the true sensitivity for cCell. The 
parameter  is the non-inferiority limit.  In this study, it is proposed to utilize a =0.05 (5%).  If 
that D is used and the anticipated sensitivity for both Frozen Section and cCell is 90%, then 

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with a sample size of 200 tumor positive samples the probability the difference between the 
estimated sensitivities is less than 5% is greater than 90%.  That is P((SenF -SenC  5%) > 
90%.  
 
Specificity Table – Specificity is only calculated when the truth standard is negative for tumor.  
 
Agreement Table with Non-Tumor Truth  
  
cC  
  
FS  
Results  
Agree 
w/Truth  
Disagree 
w/Truth  
  
Agree  
r  
s  
r+s  
Disagree  
t  
u  
t+u  
  
r+t  
s+u  
n2  
 
The specificity of the Frozen Section is given by pSpeF = (r+d)/n2 and the specificity of cCeLL 
is given by pSpeC=(r+d)/n2.  It is desired to demonstrate that the specificity of cCeLL is non-
inferior to that of Frozen section.  
The non-inferiority of the specificity of cCell result versus the specificity of the Frozen Section 
is given as:  
H0: SpeCF -SpeC >  versus HA: SpeF -SpeC   
Here πSpeF is the true specificity for Frozen Section and πSpeC is the true specificity for cCell. 
The parameter  is the non-inferiority limit.  In this study, it is proposed to utilize a =0.10 
(10%).  If that  is used and the anticipated specificity for both Frozen Section and cCell is 
90%, then with a sample size of 50 tumor negative samples the probability the difference 
between the estimated specificities is less than 10% is greater than 80%.  That is P(SpeF -SpeC 
 10%) > 80%.  
The sensitivity and the specificity hypotheses will be tested using McNemar’s test by 
constructing an upper 97.5% confidence bound for the difference between the two methods.  If 
the upper bound is less than Δ (5% for sensitivity and 10% for specificity) then the two images 
are said to be non-inferior.  The upper confidence bound is given by:  
, where 
 
 
 
The standard error (se) for the difference depends on the number of discordant pairs (a and 
b).  Where a and b correspond to f and g from the sensitivity table and to t and s from the 
specificity table.  The estimates pFS and pcC correspond to the sensitivity of the Frozen Section, 

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pSenF , and the sensitivity of cCell, pSenC  when sensitivity is being tested and they correspond 
to the specificity of the Frozen Section, pSenF, and the specificity of cCell, pSenC,  when 
specificity is being tested.    
The secondary endpoints will be summarized via descriptive statistics.  No hypothesis testing 
will be performed for the secondary endpoints.  
8.3.2 Analysis Population  
The analyses described above will be performed on the intent to analyze population.  That is, 
all samples in that are collected and are analyzable by frozen section will be utilized in the 
analysis regardless of whether they were successfully analyzed by both methods.  
A secondary analysis will be done on the primary endpoints on the samples that were 
analyzable by both methods.  
8.3.3  Demographic Baseline Data  
Demographic data and other baseline characteristics will be summarized via descriptive 
statistics.  
9. Operational Considerations  
9.1 Regulatory, Ethical and Study Oversight  
It is the Sponsor’s responsibility to ensure that the study is conducted according to ISO 14155, 
the Declaration of Helsinki, other applicable regulatory requirements, the study protocol, and 
any conditions of approval imposed by the REB or Health Canada (HC). The Sponsor also will 
ensure proper clinical site monitoring.   
The Sponsor has taken out an insurance policy for the total duration of the study. This insurance 
policy covers the participants in respect of the risks involved in this study according to this CIP. 
In the case of injury or disability deriving from participation in the study, the participant is 
requested to inform the treating physician responsible for the study without delay.   
Prior to allowing the sites to start enrolling participants into the study, the Sponsor is 
responsible for selecting investigators, ensuring REB and HC approvals are obtained where 
applicable, and signing the Investigator Site Agreement with the investigators and/or hospitals. 
The study protocol (or amendment[s]), Informed Consent Form, and other applicable study 
related documents must be submitted to and approved by the REB and HC before enrolment 
of participants.   
A signed copy of the REB approval letter addressed to the investigator must be submitted to 
the sponsor certifying study approval prior to participant enrolment. The sponsor is responsible 
for notifying HC of the intention to perform a clinical investigation under this protocol and will 
ensure an official approval is obtained prior to starting the clinical investigation. The 
investigation will not start before the required approvals or favorable opinions from the REB 
and HC have been obtained.   

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Any substantial amendments to the protocol will require REB and HC approval before 
implementation of changes made to the study design, except for changes necessary to eliminate 
an immediate hazard to study participants.  
9.2 Confidentiality and Privacy  
All materials, information (oral or written) and unpublished documents provided to the 
participating physician (or any steps taken by the company on their behalf), including, but not 
limited to, the protocol, eCRFs, and IB are the sole property of the Sponsor.  
These materials and information (both global and partial) may not be provided or disclosed by 
the participating physicians or any person on their team to unauthorized persons without the 
prior written consent of the Sponsor.  
The participating physician considers all information received, obtained, or derived during the 
study to be confidential and will take all necessary steps to ensure that there is no breach of 
confidentiality, except for the information to be provided according to law.  
The participant's personal data (age, sex, cCeLL images, date of surgery) and participating 
physician’s personal data which may be included in Sponsor database shall be treated in 
compliance with all local and international applicable laws and regulations. When archiving or 
processing personal data pertaining to the physician and/or to the participants, Sponsor shall 
take all appropriate measures to safeguard and prevent access to this data by any unauthorized 
third-party.  
9.3 Sponsor Responsibilities  
The sponsor has the overall responsibility for the conduct of the study, including assurance that 
the study satisfies international standards and the regulatory requirements of the relevant 
regulatory authorities.  
The Sponsor will be responsible for:  
• Selection of clinical investigators and sites: The Sponsor will select qualified 
investigators and facilities which have adequate study population to meet the 
requirements of the investigation.  
• Training of investigators and site personnel and site monitoring: The training of the 
Investigator and clinical site personnel will be the responsibility of the Sponsor, or 
designee, and may be conducted during an investigator meeting, a site initiation visit, 
or other training sessions. Periodic monitoring visits will be conducted frequently 
enough to ensure that all clinical participant data are properly documented and that the 
study is properly conducted.  
• Documentation: The Sponsor will collect, store, guard and ensure completion of all 
study relevant documents by the relevant parties.  
o 
Signed and dated eCRFs  
o 
Records of any Serious Adverse Events (SAEs) reported to the Sponsor 
during the clinical investigation  

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• Any statistical analyses and underlying supporting data  
• Final report of the clinical investigation  
• Submitting Reports  
• Maintaining Records: The Sponsor will maintain copies of correspondence, data, SAEs 
and other records related to the clinical study according to requirements set forth by 
ISO 14155 and regulations.   
• Monitoring: The Sponsor is responsible for monitoring the study to ensure compliance 
with ISO 14155 and regulatory requirements.   
9.4 Investigator Responsibilities  
• Protocol acceptance: Prior to starting enrolment of participants, the Investigator must 
read and understand this study protocol, and must sign and date the Protocol Signature 
page. The Site Agreement documents agreement to all conditions of the study protocol 
and agreement to conduct the study accordingly. This study will be conducted in 
accordance the Declaration of Helsinki and other applicable regulatory requirements 
and standards, and any conditions of approval imposed by the REB or regulatory 
authorities.  
• Required documents: The following documents must be submitted to the Sponsor, or 
designee prior to participant enrolment:  
1. Signed Protocol Signature Page  
2. Recent (≤ 2 years old) signed and dated English Curriculum Vitae (CV) of 
the Principal Investigator and co-investigators of the clinical site. The CV 
should clearly show the Investigator/co-investigators’ qualifications and 
experience.  
3. Copy of the written confirmation of the REB regarding approval of the 
protocol including version number and date, ICF (including version and date) 
and other adjunctive participant material.  
4. List of voting REB members  
5. Signed Clinical Trial Agreement  
• REB approvals and notifications: According to the local requirements, the Investigator 
must have all necessary approvals, including written approval from the REB of the 
clinical site or other accepted REB prior to enrolling participants in the study. A copy 
of the written approval must be provided to the Sponsor.  
o Serious Adverse Event (SAE) reports as well as annual and final reports will 
be submitted to the REB as required.  
• Obtaining informed consent: A member of the study team, who is not part of the 
patient’s circle of care, will obtain informed consent in accordance with the procedure 
described in this study protocol and the requirements of the REB.  

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• Medical care of participants  
• Reporting requirements  
• Audits / Inspections: In the event that audits/inspections are initiated by the Sponsor (or 
its designee) or national/international regulatory authorities, the Investigator must allow 
access to the original medical records and must provide all requested information. In 
the event that audits are initiated by regulatory authorities, the Investigator will 
immediately notify the Sponsor.  
9.5 Clinical Monitoring  
The Sponsor will be responsible for ensuring that adequate monitoring at each site is completed 
to ensure protection of the rights of participants, the safety of participants, and the quality and 
integrity of the data collected and submitted.  Each clinical site will be monitored according to 
the study monitoring plan to ensure to verify that:  
• The rights and well-being of the participants are protected  
• The reported study data are accurate, complete and verifiable from source documents  
• The conduct of the study is in compliance with the currently approved CIP/ 
amendment(s), GCP, the applicable regulatory requirement(s) and applicable 
requirements of the REB  
• There is adequate participant enrollment  
• Investigational device accountability (if applicable) is maintained  
 
Monitoring visits will be performed remotely or onsite by qualified Sponsor representatives 
and will include, but not limited to, the following:  
• Verification of the protocol adherence  
• Source documentation verification and accuracy of the eCRFs  
• Verification that informed consent was obtained for all participants participating in the 
study in accordance with requirements described in the study protocol  
• The safety status of all participants (i.e. (S)AEs/(S)ADEs/DD)   
• Verification of completeness of the Site File  
• Verification of accuracy of all study logs such as the Delegation of Authority Log, etc.  
• Compliance with applicable regulations  
• Identification and action to resolve any issues or problems with the study.  
At the end of each visit the Monitor will meet with the PI and study site personnel to discuss 
any relevant findings. Failure by the PI/site staff to address adequately issues of non-
compliance may cause the Sponsor to put the Investigator or Site on probation or to withdraw 
the Investigator/Site from the study. The frequency of monitoring will be based upon 

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considerations such as enrollment levels, study duration, compliance, or suspected data 
inconsistency requiring further investigation.   
9.6 Source Documentation  
Regulations (Health Canada MDR; ISO 14155) require that Investigators maintain information 
in the participant’s medical records that corroborate data collected in the eCRF. In order to 
comply with these regulatory requirements, at minimum, the following is a list of information 
that should be maintained and made available as required by monitors and/or regulatory 
inspectors:  
1. Medical history/physical condition relevant to the inclusion/exclusion criteria 
2. Dated and signed notes on the day of entry into the study, protocol number, clinical site 
participant number assigned and a statement that informed consent was obtained and is 
on file in the participant medical chart 
3. Adverse events reported and categorized as Serious Adverse Device Effects (SADEs) 
their resolution, including supporting documents such as discharge summaries and lab 
results  
The Investigator and the head of the medical institution (where applicable) agree to allow the 
Clinical Monitor direct access to all relevant documents.  
9.7 Data Handling  
All eCRF information, study records, reports, and source documents that support the eCRF 
must be retained in the files of the responsible Investigator according to national requirements 
following notification by the Sponsor or designee that all investigations have been completed, 
and will further be retained in accordance with local and international guidelines as identified 
in the Investigator Site Agreement. This documentation must be accessible upon request by 
international regulatory authorities or the Sponsor (or designee). The Sponsor or designee must 
approve archiving or transfer of the documentation for relocation purpose of premises, in 
writing, prior to the actual file transfer. The Investigator must notify the Sponsor, in writing, 
of transfer location, duration, and the procedure for accessing study documentation. The 
Investigator must contact the Sponsor, or designee, in writing at least 30 days before the 
transfer location, duration, procedure for accessing study documentation or destruction of any 
records and reports pertaining to the study to ensure they no longer need to be retained.   
If the Investigator retires, relocates, or for other reasons withdraws from assuming primary 
responsibility for keeping the study records, custody per written notice must be submitted to 
the Sponsor, or designee, indicating the name and address of the person accepting primary 
responsibility. The REB must be notified in writing of the name and address of the new 
custodian.  
Data will be retained by the Sponsor for 15 years after the end of the study; or, where the 
investigational device is subsequently placed on the market, for 15 years after the last device 
has been placed on the market. Clinical data are to be retained by the study site in conformance 
with regional medical practice requirements.  

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All clinical study information will be recorded, handled and stored in a way that allows its 
accurate reporting, interpretation and verification. Data are to be submitted promptly via eCRF 
after collection. Missing or unclear data will be corrected as necessary throughout the study. 
The Sponsor will request further documentation such as physician a procedure notes when 
complications or malfunctions are observed and reported.  During monitoring visits, the 
findings from the review of source documents will be discussed with the Investigator.    
All documents shall be maintained in a secure location, protected from unauthorized access or 
damage, and they shall be archived as per local requirements.  
9.8 Protocol Deviations  
A protocol deviation is defined as any divergence from the study protocol.  PIs and site support 
staff must not deviate from the protocol.  Any deviations from clinical protocol requirements 
will be considered protocol deviations and need to be reported to the Sponsor within 24 hours. 
The Sponsor will not make any exceptions to the protocol and will not provide waivers to 
participants with any protocol deviations.   
Deviations from the protocol that may affect the rights, safety or well-being of human 
participants, or the scientific integrity of the study may not proceed without prior approval of 
the Sponsor and the REB. However, under emergency circumstances, deviations from the 
protocol to protect the rights, safety or well-being of human participants may proceed without 
prior approval of the Sponsor, the REB and the regulatory authorities as required. Such 
emergency deviations shall be documented by the Investigator and reported to the Sponsor 
within 24 hours.   
The Sponsor may disqualify an Investigator if, without having obtained prior written approval 
by the Sponsor, there is a deviation from this protocol in a manner that has affected or could 
affect the rights, safety or well-being of human participants, or the scientific integrity of the 
study.  
The Sponsor will determine the effect of the protocol deviation on the scientific value of the 
clinical study and participant safety and determine if additional reports or actions are required. 
Additional action may include site re-training, removal of the devices, and/or site termination.    
The Investigator is responsible for promptly reporting protocol deviations to the REB per the 
REB’s policies, and to the Sponsor.  
9.9 Quality Assurance and Quality Control  
The Sponsor will implement and maintain quality systems defined by written procedures to 
ensure that trials are conducted and data are generated, documented and reported in compliance 
with this Clinical Investigational Plan, Good Clinical Practices (ISO 14155), and the applicable 
regulatory requirements. Included in these procedures will be quality control measures to 
ensure that all data are reliable and have been processed correctly at each stage of handling.   
The PI will be responsible for ensuring that all personnel involved in the study are trained on 
such procedures. The Sponsor will secure agreement with all parties to ensure direct access to 

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the site, and to source data/documents and reports, for the purpose of monitoring and auditing 
by the Sponsor, REB review and for regulatory inspection. Such agreements will be verified 
as part of site initiation.  
9.10 Publication Policy  
The study will be registered in a publicly accessible database prior to participant inclusion, and 
the results of the study will be made publicly available upon conclusion in accordance with the 
Declaration of Helsinki. At the conclusion of the study, a report will be prepared for 
presentation and for publication. Authorship is based on the ICMJE (International Committee 
of Medical Journal Editors) guidelines.  
All parties should adhere to accepted guidelines for ethical reporting. Negative and 
inconclusive as well as positive results must be published or otherwise made publicly available. 
Sources of funding, institutional affiliations and conflicts of interest must be declared in the 
publication.  
9.11 Financial Disclosure  
The Sponsor will reimburse the site for participation in the study in accordance with the 
executed Clinical Study Agreement. No further compensation will be provided to the site or 
investigators. Additional details are provided in the Clinical Study Agreement.  
Investigators will provide the Sponsor with sufficient, accurate financial information as 
requested to allow the Sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the course of the study and for one year 
after completion of the study.  
10. Safety Oversight 
The Sponsor will be responsible for providing safety oversight and reviewing the information 
about the investigational product and reported safety events. This oversight includes reviewing 
safety information and providing applicable recommendations. This data and safety review 
facilitate early detection of safety signals and continued appropriateness of the research and 
protection of human study participants.  
10.1 Definition and assessment of safety related events 
  
Information on safety related events will be collected while the device is implanted (i.e., from 
implant up to and including explant) by the investigators or their designate. Classification of 
events is based on ISO 14155:2020. 1  
• 
Adverse Event (AE): any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including abnormal laboratory findings) in 
 
1 ISO 14155, 2020: Clinical investigation of medical devices for human subjects — Good clinical practice. 

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participants, users or other persons, whether or not related to the investigational 
device. This definition includes events related to the procedures involved.  
• 
Serious Adverse Events (SAE): An adverse event that led to death or led to serious 
deterioration in the health of the participant, that either resulted in:  
o Death  
o A life-threatening illness of injury, or  
o A permanent impairment of a body structure of a body function, or  
o In-patient or prolonged hospitalization, or  
o Medical or surgical intervention to prevent life-threatening illness or injury 
or permanent impairment to a body structure or a body function, or  
o Fetal distress, fetal death or a congenital abnormality of birth defect.  
Planned hospitalization for a pre-existing condition, or a procedure required by the clinical 
investigation plan without serious deterioration in health, is not considered a serious 
adverse event.  
• 
Adverse Device Effect (ADE): An adverse event related to the use of an 
investigational device. This definition includes adverse events resulting from 
insufficient or inadequate instructions for use, deployment, implantation, 
installation or operation, or any malfunction of the investigational device. This 
definition includes any event resulting from use error or from intentional misuse of 
the investigational medical device.  
• 
Serious Adverse Device Effect (SADE): Adverse device effect that has resulted in 
any of the consequences characteristic of a serious adverse event.  
For the purposes of this study, only (S)ADEs will be collected and reported. Since this is 
an ex vivo procedure, it is expected that the incidence of (S)ADEs will be low to none.  
10.2 Device Deficiency (DD)  
A DD is defined as any inadequacy of an investigational medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies include 
malfunctions, use errors, or inadequacy in information supplied by the manufacturer.    
All DDs must be reported to the Sponsor within 24 hours.  
 
10.3 Reporting of Safety Related Events  
Reporting of serious incidents to the regulatory authorities will be performed based on Health 
Canada regulations:  
• 
Incident means any malfunction or deterioration in the characteristics and/or 
performance of the study device, including use-error due to ergonomic features, 

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any inadequacy in the information supplied by the manufacturer and any 
undesirable side-effect.  
• 
Serious incident means any incident that directly or indirectly led, might have led 
or might lead to any of the following:  
o 
Death of a participant, user or other person,  
o 
Temporary or permanent serious deterioration of the participant’s, user’s or 
other person’s state of health,  
o 
Serious public health threat.  
Safety related events, which require preventive or corrective measurements intended to protect 
participants, may have to be reported to the local REBs. The Sponsor will report any (S)ADEs 
and DD(s) to Health Canada as required and within stipulated timelines.  
 
 

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11. References  
 
Amos WB, White JG. How the confocal laser scanning microscope entered biological 
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BIS Research Inc. Medical market data. Updated 2022. https://blog.bisresearch.com/bis-
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Carl Zeiss Meditec AG. Convivo: Putting in vivo cellular imaging at your fingertips. 
2019:Brochure. Available at: 
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Chand P, Amit S, Gupta R, Agarwal A. Errors, limitations, and pitfalls in the diagnosis of 
central and peripheral nervous system lesions in intraoperative cytology and frozen 
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de Martel C, Georges D, Bray F, Ferlay J, Clifford GM. Global burden of cancer attributable 
to infections in 2018: a worldwide incidence analysis. Lancet Glob Health. 
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Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, et al. Global Cancer 
Observatory: Cancer Today. Lyon: International Agency for Research on Cancer; 
2020 (https://gco.iarc.fr/today, accessed February 2021).  
 
IndustryARC. Oncology Market - Forecast (2020 - 2025). 2020.  
 
Mat Zin AA, Zulkarnain S. Diagnostic Accuracy of Cytology Smear and Frozen Section in 
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Mauna Kea Technologies. Cellvizio: Real-time in vivo cellular imaging platform. 
2021:Brochure. Available at: 
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MAVIG GmbH. Vivascope: Confocal laser scanning microscopy - In vivo histology for 
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2019:Brochure. Available at: https://www.vivascope.de/wp-
content/uploads/2019/06/Cosmeticbrochure.pdf  
 
Samal S, Kalra R, Sharma J, et al. Comparison between crush/squash cytology and frozen 
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Tofte K, Berger C, Torp SH, et al. The diagnostic properties of frozen sections in suspected 
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