Prospective Open Label, Pivotal Study of the Accuracy of The CapsoCam Colon (CV-3) in Detecting Colonic Polyps, Using Colonoscopy as the Reference
Phase: NA
Conditions: Colonic Polyp
Sponsor: Capso Vision, Inc.

 
 
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CLINICAL INVESTIGATIONAL PLAN 
PROSPECTIVE, OPEN LABEL, PIVOTAL STUDY OF THE ACCURACY OF THE 
CAPSOCAM® COLON (CV-3) IN DETECTING COLONIC POLYPS, USING COLONOSCOPY 
AS THE REFERENCE 
 
PIVOTAL CLN-CVI-5794 
Revision M 
August/2024 
 
 
CapsoVision 
18805 Cox Avenue, Suite 250 
Saratoga, CA 95070 
 
 
 
 
 
Principle Investigator’s Statement and Signature 
I agree to conduct this study following this protocol. Modifications to this protocol not permitted without agreement from 
CapsoVision and must be documented through the document control process. 
Investigator Name (Print): 
 
Investigator Signature: 
 
Date: 
 
 
 
 

 
 
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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ........................................................................................................................ 4 
1. 
INVESTIGATIONAL PLAN ......................................................................................................................... 4 
1.1 
Protocol Synopsis .................................................................................................................................... 4 
2. 
INTRODUCTION ........................................................................................................................................... 9 
2.1 
Background ............................................................................................................................................. 9 
2.2 
CapsoCam® Colon (CV-3) System ........................................................................................................ 9 
2.3 
Device Description ................................................................................................................................ 10 
2.4 
Proposed Indications for Use ................................................................................................................ 12 
2.5 
Early Clinical Investigations ................................................................................................................. 12 
2.5.1 
Safety ............................................................................................................................................. 12 
2.5.2 
Effectiveness ................................................................................................................................. 13 
2.6 
Rationale for This Study ....................................................................................................................... 13 
2.7 
Purpose and Objectives of the Investigation ......................................................................................... 14 
2.8 
Study Endpoints .................................................................................................................................... 15 
2.8.1 
Coprimary Endpoints .................................................................................................................... 15 
2.8.2 
Secondary Endpoints ..................................................................................................................... 15 
2.8.3 
Safety Assessment ......................................................................................................................... 16 
2.8.4 
Exploratory Endpoints................................................................................................................... 16 
2.9 
Study Design ......................................................................................................................................... 16 
2.10 
Duration and Extent of Investigation .................................................................................................... 17 
3. 
CLINICAL PROTOCOL .............................................................................................................................. 17 
3.1 
Site Selection ......................................................................................................................................... 17 
3.2 
Number of Subjects ............................................................................................................................... 17 
3.3 
Subject Population ................................................................................................................................ 17 
3.4 
Inclusion/Exclusion Criteria:................................................................................................................. 17 
3.5 
Study Procedures ................................................................................................................................... 18 
3.5.1 
Subject Consent ............................................................................................................................. 18 
3.5.2 
Screening/Baseline (Day -14 to -3) ............................................................................................... 19 
3.5.3 
Pre-procedure Prep (Day -2 to 0) .................................................................................................. 19 
3.5.4 
Day of Procedure – Capsule Ingestion (Day 0) ............................................................................. 19 
3.5.5 
Follow-Up Phone Call (Day 3 ± 2 days)—can be completed in office if subject has opted for Day 
1 Colonoscopy ............................................................................................................................................... 20 
3.5.6 
Colonoscopy (Day 1 or Day 21-42) .............................................................................................. 20 
3.5.7 
2nd-look Colonoscopy (when warranted as described in section 2.10) .......................................... 20 

 
 
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3.5.8 
Capsule retrieval and return .......................................................................................................... 20 
3.6 
Moment of Enrollment .......................................................................................................................... 22 
3.7 
CapsoCam® Video Reading ................................................................................................................. 22 
3.8 
Colonoscopy and Biopsy (follow these procedures for initial and/or repeat colonoscopy) .................. 23 
3.9 
Second-colonoscopy determination and subject exit from study .......................................................... 25 
3.10 
Reference Polyp Size Determination .................................................................................................... 25 
3.11 
Adverse Events (AEs) ........................................................................................................................... 26 
3.11.1 
Clinical Events Committee (CEC) ................................................................................................ 27 
3.12 
Device Malfunction ............................................................................................................................... 28 
3.13 
Subject Withdrawal ............................................................................................................................... 28 
3.14 
Data Collection and Reporting .............................................................................................................. 29 
3.14.1 
Reporting of Protocol Deviations: ................................................................................................. 29 
3.14.2 
Confidentiality of Data: ................................................................................................................. 29 
3.14.3 
Lost to Follow Up ......................................................................................................................... 29 
3.14.4 
Quality Assurance of the Data ...................................................................................................... 29 
3.15 
Study Termination ................................................................................................................................. 29 
4. 
STATISTICAL CONSIDERATIONS .......................................................................................................... 30 
4.1 
Analysis Population .............................................................................................................................. 30 
4.2 
Study Endpoint Analyses ...................................................................................................................... 31 
4.3 
Polyp Matching Rules ........................................................................................................................... 32 
4.4 
Safety Assessment ................................................................................................................................. 33 
4.5 
Sample Sizes ......................................................................................................................................... 33 
4.6 
Hypotheses ............................................................................................................................................ 34 
4.7 
Multiple Comparisons ........................................................................................................................... 34 
4.8 
Masking Procedures .............................................................................................................................. 34 
5. 
PERSONNEL RESPONSIBILITIES ............................................................................................................ 34 
5.1 
Principal Investigator Responsibilities .................................................................................................. 34 
5.2 
Sponsor Responsibilities ....................................................................................................................... 35 
6. 
RISK/BENEFIT ANALYSIS ....................................................................................................................... 35 
6.1 
Potential Risks to Study Subjects .......................................................................................................... 35 
7. 
MONITORING PROCEDURES .................................................................................................................. 38 
7.1 
Clinical Study Monitors ........................................................................................................................ 38 
8. 
REFERENCES .............................................................................................................................................. 40 
9. 
Appendix A ................................................................................................................................................... 42 

 
 
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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with the appropriate sections of the following:  
• United States (US) Code of Federal Regulations (CRF) applicable to clinical studies (21 CFR 
812, 21 CFR Part 50and 21 CFR Part 56) 
The protocol, informed consent form, recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval. Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled. Any amendment to 
the protocol will require review and approval by the IRB before the changes to the study are 
implemented. All IRB requested changes to the consent form will be approved by the study Sponsor 
prior to subject enrollment. In addition, all changes to the consent form occurring as a result of 
protocol amendments will be IRB-approved. 
 
1. 
INVESTIGATIONAL PLAN 
1.1 Protocol Synopsis 
Sponsor 
CapsoVision, Inc., Saratoga, CA 
Title 
Prospective, Open Label, Pivotal Study of the Accuracy of the CapsoCam® Colon (CV-3) in 
Detecting Colonic Polyps, Using Colonoscopy as the Reference 
Study device 
CapsoCam® Colon (CV-3) 
Design 
Prospective, open-label, non-significant risk, multicenter study comparing the polyp 
detection of the study device to that of the colonoscopy reference. The study device videos 
will be read in a crossover design, both with and without computer assisted detection 
(CADe), so that the benefit of CADe can be assessed.   
Purpose 
 
The purpose of this study is to evaluate the safety and effectiveness of CapsoCam® Colon 
(CV-3) endoscope system for the detection of colonic polyps and to show that AI-based 
CADe improves the polyp-detection accuracy and efficiency of capsule video readers. It is 
anticipated that the data from this clinical trial will be used to support marketing 
authorizations to commercialize the CapsoCam® Colon (CV-3). 
Study 
Population 
Subjects referred for colonoscopy. 
Clinical Sites 
Up to 30 US clinical sites will participate in the study.   
Inclusion 
Criteria 
 
1. 45-75 years of age 
2. Committed to undergo a colonoscopy. 
3. Choose to participate and must have signed the IRB-approved informed consent 
document and agreed to release colonoscopy images and results report to Sponsor 
Exclusion 
Criteria 
1. Colonoscopy or CT-colonography within the past 5 years that demonstrated no polyps 
2. Has contraindication for capsule endoscopy or colonoscopy 
3. Subject is suspected or diagnosed with familial adenomatous polyposis, hereditary non 
polyposis colon cancer, or any high-risk genetic syndrome 
4. Subject is suspected or diagnosed with inflammatory bowel disease such as ulcerative 
colitis or Crohn’s disease 
5. History of incomplete colonoscopy 
6. Type I or uncontrolled II Diabetes (Uncontrolled defined as HbA1C>6.4 within the past 
3 months and/or with history of constipation or gastroparesis). 
7. Impaired cardiac function assessed as greater than NYHA Class II  

 
 
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8. History of small- or large-bowel obstructive condition 
9. Known history of swallowing disorder, and/or ischemic bowel disease neuropathies 
and/or radiation enteritis 
10. Known history of NSAID enteropathy and stricture resulting from taking NSAIDs on a 
regular basis that, in the opinion of the Investigator, would put the subject at greater risk 
for capsule endoscope retention  
11. Known allergy to ingredients used in bowel preparation and boosters 
12. Daily and/or regular narcotic use 
13. Decompensated cirrhosis 
14. Prior abdominal radiation therapy 
15. Diagnosis of anorexia or bulimia 
16. History of or suspicion of any of the following: strictures, volvulus or intestinal 
obstruction, or internal hernias or abdominal surgeries that the Investigator believes 
should exclude the patient from study participation 
17. Known or suspected megacolon 
18. Scheduled to undergo MRI examination within 7 days after ingestion of the capsule  
19. Has known slow gastric-emptying time or confirmed diagnosis of gastroparesis 
20. Pregnant or nursing or of child-bearing potential and does not agree to practice medically 
acceptable methods of contraception. Women of child bearing potential (WOCBP) must 
have a negative urine pregnancy test at screening.  
21. Unable to follow or tolerate fasting, bowel preparation, and other study procedures 
22. Any documented medical or psychological condition or significant concurrent illness 
which, in the Investigator’s opinion, would make it unsafe for the subject to participate 
in this research study or would affect the validity of the study results 
23. Are currently enrolled in an interventional clinical study or currently enrolled in or 
within the last 30 days, a pharmaceutical clinical study 
24. Chronic constipation as defined by <3 bowel movements per week, or the use of routine 
laxatives (other than fiber) to attain regular bowel movements  
Pre-Enrollment 
Screening 
Eligible subjects who have been referred for colonoscopy will adhere to the following 
protocol procedures: 
Screening (Day -14 to -3):  
• 
Informed consent completion and verification of eligibility  
• 
Detailed medical history and medications, including assessment of GI health  
• 
Site will dispense bowel prep regimen along with detailed dosing instructions 
 
Pre-Procedure Preparation (Day -2 to 0):  
• 
Subject starts the pre-determined bowel prep that has been provided   
• 
Adhere to dietary requirements 
Intervention 
and Follow-up 
Periods 
Procedure (Day 0):  
• 
Confirmation of adherence to pre-procedure prep via bowel prep visual aid (subject 
reported) 
o 
Subjects that do not report acceptably clean bowel preparation (picture 1 or 
picture 2 on visual aid) will be considered screen failures or will be 
permitted to re-attempt bowel preparation and capsule swallow described in 
detail in section 3.5.4. 
• 
Recording of Anticipated Observations/Adverse Events  
• 
Ingestion of pro-kinetic medication 30 – 60 minutes prior to ingestion of capsule  
• 
Ingestion of capsule 

 
 
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• 
Post-procedure instructions provided to study subject: 
o 
Very clear liquid diet until capsule is excreted or until 8:00am the next day, 
whichever comes first, or as directed by a Principal Investigator (PI) 
o 
Booster regimen until capsule is excreted or 8 hours post ingestion, 
whichever comes first 
o 
Suppository use at bedtime and next morning if capsule hasn’t been 
excreted within the first hour of arising 
o 
Retrieval kit and instructions to return CapsoCam® Colon (CV-3) to the 
Sponsor who will download the CapsoCam® images to a secure server. All 
image readings and interpretations will be performed by independent 
colonoscopists /endoscopists. 
o 
Discharge from clinic upon confirmed understanding of at-home 
instructions 
Follow-up Phone Call (Day 3 +/- 2 days): 
• 
Excretion of capsule and retrieval of CapsoCam® Colon (CV-3) verification 
• 
Instruct subject to return CapsoCam® Colon (CV-3) to Sponsor (if not yet 
completed) 
• 
Assessment of adverse events related to capsule ingestion 
 
Colonoscopy – (Day 1 or Day 21-42):  
• 
Day 21-42 option: Colonoscopy will be performed from 3-6 weeks following 
CapsoCam® Colon (CV-3) ingestion.   
• 
Day 1 option: Only if it is in the best interest of the subject, as determined by the 
Investigator, a study subject may have colonoscopy the day after CapsoCam 
ingestion. See section 3.5 for further details.       
• 
Recording of Anticipated Observations 
Coprimary 
Effectiveness 
Endpoints 
• 
Positive Percent Agreement (PPA) of the study device with computer assisted 
detection (CADe) for detecting the presence in a subject of the largest polyp detected 
by optical colonoscopy (OC) if that polyp is ≥ 6 mm, where a match is considered to 
have occurred if a polyp detected by the device is assessed as having a size within 
plus or minus 50% of the size of the polyp detected by OC and as having a location 
within the same or an adjacent colon segment. 
• 
Negative percent agreement (NPA) of the study device with CADe for not detecting 
any polyp ≥ 6 mm in a subject for whom OC did not detect any polyp ≥ 6 mm. 
 
Secondary 
Effectiveness 
Endpoints 
• 
Study-device PPA with a random reader relying on CADe versus not using CADe 
for detecting the presence in a subject of the largest polyp detected by optical 
colonoscopy (OC) if that polyp is ≥ 6 mm, where a match is considered to have 
occurred if a polyp detected by the device is assessed as having a size within plus 
or minus 50% of the size of the polyp detected by OC and as having a location 
within the same or an adjacent colon segment. 
• 
Study-device NPA with a random reader relying on CADe versus not using CADe 
for not detecting any polyp ≥ 6 mm in a subject for whom OC did not detect any 
polyp ≥ 6 mm. 
• 
Sensitivity of the study device with CADe for detecting in a subject an advanced 
neoplasia (AN) detected by OC and histopathology, defined as an adenoma ≥ 10 
mm, or containing villous growth or high-grade dysplasia, or cancer, where a lesion 
in the subject detected by the device is assessed to be at least 6 mm in size. 

 
 
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• 
Specificity of the study device with CADe for not detecting any lesion ≥ 6 mm in a 
subject for whom OC detected no polyps ≥ 6 mm and no AN of any size. 
• 
Specificity of the study device with CADe for not detecting any lesion ≥ 6 mm in a 
subject for whom OC detected no polyps. 
• 
PPA of the device with CADe for detecting the presence in a subject of the largest 
polyp detected by optical colonoscopy (OC) if that polyp is ≥ 10 mm, where a 
match is considered to have occurred if a polyp detected by the device is assessed 
as having a size within plus or minus 50% of the size of the polyp detected by OC 
and as having a location within the same or an adjacent colon segment. 
• 
NPA of the device with CADe for not detecting any polyp ≥ 10 mm in a subject for 
whom OC did not detect any polyp ≥ 10 mm. 
• 
PPA of the device with CADe for detecting the presence in a subject of the largest 
polyp detected by optical colonoscopy (OC) if that polyp is ≥ 6 mm and < 10 mm, 
where a match is considered to have occurred if a polyp detected by the device is 
assessed as having a size within plus or minus 50% of the size of the polyp detected 
by OC and as having a location within the same or an adjacent colon segment. 
• 
Sensitivity of the device with CADe for detecting the presence of a polyp ≥ 6 mm 
in a subject with OC as the reference (without regard to polyp matching). 
• 
Sensitivity of the device with CADe for detecting the presence in a subject of a 
polyp ≥ 10 mm with OC as the reference (without regard to polyp matching).  
• 
PPA of the device with CADe for detecting the presence in a subject of the largest 
sessile serrated polyp (SSP) detected by OC if that polyp is ≥ 6 mm, where a match 
is considered to have occurred if the size of a polyp detected by the device is 
assessed as having a size within plus or minus 50% of the size of the polyp assessed 
by OC and as having a location within the same or an adjacent colon segment. 
• 
Sensitivity of the study device with CADe for detecting in a subject a SSP detected 
by OC and histopathology, where a polyp in the subject detected by the device is 
assessed to be at least 6 mm in size. 
• 
PPA of the device with CADe for detecting the presence in a subject of a cancerous 
polyp biopsied by OC and diagnosed by histopathology, where a match is 
considered to have occurred if the size of a polyp detected by the device is assessed 
as having a size within plus or minus 50% of the size of the cancerous 
polyp assessed by OC and as having a location within the same or an adjacent colon 
segment. 
• 
Sensitivity of the study device with CADe for detecting in a subject a cancer 
detected by OC and histopathology, where a lesion in the subject detected by the 
device is assessed to be at least 6 mm in size. 
• 
The above secondary endpoints will also be assessed for the device without CADe. 
• 
The paired within-subject difference in video reading time with and without CADe 
(time with CADe – time without CADe). 
 
Safety 
Assessment 
All adverse events (AEs) including serious adverse events (SAEs) and unanticipated adverse 
device effects (UADEs) will be assessed and reported at all visits. To ensure the accurate 
capture of device related events, side effects from bowel preparation, prokinetic booster and 
colonoscopy will be recorded as “Anticipated Observations” on the adverse event form.  
Incidence of all AEs for the discreet interval of capsule ingestion through excretion will be 
recorded and analyzed for seriousness, severity, and relatedness to the device. 

 
 
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Exploratory 
Endpoints 
• 
Accuracy of the detected polyp morphology assessed by the device. 
Hypotheses 
Secondary Endpoint #1 – The null hypothesis is that “true” difference in PPA for detecting 
polyps ≥ 6 mm with CADe versus without CADe (PPA with CADe – PPA without CADe) is 
≤ 0. The alternative hypothesis is that this difference is > 0.  
Secondary Endpoint #2 – The null hypothesis is that “true” difference in NPA for detecting 
polyps ≥ 6 mm with CADe versus without CADe (NPA with CADe – NPA without CADe) is 
≤ -10%. The alternative hypothesis is that this difference is > -10%.  
Secondary Endpoint #3 – The null hypothesis is that the sensitivity for detecting advanced 
neoplasia with CADe is < 65%. The alternative hypothesis is that it is ≥ 65%.  
Analysis 
Populations 
Evaluable population: This population will consist of all subjects who have both an evaluable 
colonoscopy and an evaluable CapsoCam® Colon (CV-3) exam, as defined in section 4.1. 
This population will be used for all effectiveness analyses. 
Safety population: This population will consist of all subjects who ingested the capsule and 
those who attempted but were unsuccessful at swallowing the capsule. It will be used for all 
safety analyses. 
Study Success 
Criteria 
The study will be considered a success if 
• 
The observed value of the PPA primary effectiveness endpoint with CADe is greater 
than or equal to the performance goal of 65.0%.  
• 
The observed value of the NPA primary effectiveness endpoint with CADe is greater 
than or equal to the performance goal of 75.0%. 
Sample Size 
Estimate 
A minimum of 700 evaluable subjects, of whom at least 192 have at least one ≥ 6 mm polyp 
and at least 432 do not, as determined by optical colonoscopy, and who meet the study 
eligibility criteria and consent to participate, will be enrolled in this study.  
Duration of 
Study 
It is expected to take approximately 12-24 months to complete enrollment. 

 
 
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2. 
INTRODUCTION 
2.1 Background         
The CapsoCam® Colon (CV-3) (hereinafter referred to as CapsoCam® or the study device) is intended 
to provide visualization of the colon and the detection of colon polyps in adults.  
 
The CapsoCam® is a capsule endoscope system that captures and stores image data onboard for 
subsequent download and review.  The system does not require the placement of external data 
receivers or a data recorder on the subject. In vivo image data are stored within the capsule, and it is 
retrieved by the subject after excretion and returned to a specified site for data download. A physician 
reviews the video on a computer using the CapsoView software, makes a diagnosis, and creates a 
report. 
 
The literature indicates colon capsule endoscopy  safe and a tolerable method for visualization of the 
large intestine.1-3 Most of the adverse events that have occurred in colon capsule endoscopy (CCE) 
studies have been associated with bowel preparation and not with the CCE itself.4  CCE’s high 
acceptability by subjects in various settings,3,5,6 coupled with the potential for out-of-clinic use,7 could 
increase patient adherence to CRC screening guidelines when offered as an alternative screening 
method.8 The main, but still rare, complication of capsule endoscopy is capsule retention.2,3,9  In the 
clinical studies reviewed, the incidence of capsule retention requiring endoscopic or surgical removal 
depended on the indication of the study and varied from 1-2% in subjects referred for obscure 
gastrointestinal bleeding (OGIB) to 2-5% for subjects with known Crohn’s disease.10,11  Capsule 
retention requiring endoscopic or surgical intervention may be beneficial since it often leads to a 
definitive diagnosis and therapy for the underlying cause of the retention, a tumor for example, that 
might have gone undetected without the capsule procedure.  
 
CCE provides a thorough visualization of the colon and is less invasive and more convenient for 
patients than optical colonoscopy (OC). It is especially suitable for patients at elevated risk for 
colonoscopy or associated sedation. The CapsoCam® has several potential advantages relative to 
existing capsule endoscopes.  It includes an attached balloon, which adjusts buoyancy to speed the 
colon transit; a panoramic imaging system that presents a more direct view of the mucosa with 
potentially less chance of missing features of interest due to obscuration or poor illumination; a 3D 
sensing system which allows the size of polyps to be measured; and AI-based computer aided 
detection (CADe) of colon polyps. 
 
2.2 CapsoCam® Colon (CV-3) System 
The overall system consists of the ingestible device, the capsule data access system (CDAS), the 
image-review and CADe workstation software CapsoView® (CVV), the retrieval kit (CVR), and 
CapsoCloud® (CLD), a cloud-based system allowing physicians to access and read videos online. Five 
unique design attributes of this system are: 1) it does not employ wireless communication technology 
(e.g. a radio transmitter) while in vivo and does not generate significant electromagnetic interference, 
so subjects with implanted medical devices such as pacemakers and hearing aids may safely use the 
CapsoCam®, 2) it utilizes a panoramic imaging system rather than a camera on each end of the 
capsule, with the intent to provide complete colon visualization and short video review times, 3) it 

 
 
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includes hardware and software which enable the measurement of polyp diameter, 4) it includes an 
inflatable balloon attached to the capsule to quicken transit through the colon, and 5) it includes AI-
powered software for computer assisted detection (CADe) of polyps. 
2.3 Device Description 
The CapsoCam® is an ingestible capsule, Figure 1. The video capsule contains a panoramic color 
digital video camera, two silver-oxide watch batteries, white-LED illumination sources, a laser diode 
for data download, and system-control and nonvolatile flash-memory data-storage electronics. The 
video camera capsule saves data in the on-board flash memory as it traverses the GI tract. The 
CapsoCam® is a capsule endoscope that uses non-wireless technology to capture and store images.  
The CapsoCam® is less than 12.4 x 32.6 mm in size and has four (4) lateral-facing cameras, providing 
a 360° circumferential view.  The capsule does not require placement of external sensors or a data 
recorder on the subject.  
 
 
Figure 1 Photograph of CapsoCam® Colon (CV-3) (as swallowed) 
 
 
The CapsoCam® has an in vivo feature-size measurement tool. The modified capsule has a projector 
that projects beams of light onto surrounding surfaces within the camera field of view (FOV). When an 
in vivo object is within the FOV of the camera, bright spots from these projected beams appear in the 
captured images.  As the distance between the object and CapsoCam® changes, the spot positions 
change, since the projector and the camera pupil are not coincident.  Using software to determine 
which spot comes from which beam and accounting for the distortion of the camera lens, the object 
distance is determined at every spot.  These data can be displayed as a 3-dimensional (3D) mesh 
showing the surface profile of the object.  The clinician can measure the size of polyps using the 
graphical user interface (GUI) of the CapsoView software.  
Unlike other capsule endoscopy devices, the CapsoCam® does not employ wireless communication 
technology (e.g. a radio transmitter) and does not generate significant electromagnetic interference.  
Subjects with implanted medical devices such as pacemakers and hearing aids may safely use the 
CapsoCam®.   

 
 
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The CapsoCam® consists of a capsule camera attached to a self-inflating balloon encapsulated inside a 
dissolvable outer shell. The outer shell is intended to make swallowing the device easier. The inflatable 
balloon helps to stabilize the capsule transit through the gastrointestinal tract. Inside the balloon is an 
effervescent formulation that reacts to produce CO2 gas once it contacts trace amounts of water that 
diffuse into the balloon through the balloon membrane, Figure 2.  
 
 
Figure 2 Photograph of an inflated CapsoCam® Colon, (CV-3) 
 
The CO2 inflates the balloon and the specific gravity of the device is reduced to about 1, which means 
that the capsule achieves neutral buoyancy and can more readily move through the intestines with 
flowing liquid, increasing the likelihood of a complete colon visualization. 
As the CapsoCam® passes through the GI tract, it captures and saves images and other data in the on-
board flash memory. Following retrieval of the CapsoCam®, the capsule images are downloaded using 
the Capsule Data Access System (CDAS) (Figure 3) and read by a study investigator (reader) using the 
CapsoView® Software (CVV). The software includes computer-assisted detection (CADe) of polyps 
using an artificial intelligence (AI) algorithm developed by deep learning. The software highlights 
CADe-detected polyps with a bounding box in the video frame as the reader reviews the entire video 
of the colon. 

 
 
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Figure 3 Capsule Data Access System 
2.4 Proposed Indications for Use 
The CapsoCam® Colon capsule endoscopy system is intended to provide visualization of the 
colon.  
 
It may be used for detection of colon polyps in patients after an incomplete optical colonoscopy 
with adequate preparation, and a complete evaluation of the colon was not technically possible.  
 
In addition, it is intended for detection of colon polyps in patients with major risks for 
colonoscopy or moderate sedation, who could tolerate colonoscopy and moderate sedation in the 
event a clinically significant colon abnormality was identified on capsule endoscopy. 
 
The object-size measurement tool is intended to measure the size of anatomical features, 
including polyps. 
 
The computer-assisted polyp detection software (CADe) is intended to highlight regions in the 
capsule endoscopy video which contain visualized polyps to aid endoscopists in detecting colon 
polyps.  
 
2.5 Early Clinical Investigations 
A complete Report of Prior Clinical Investigations relevant to the CapsoCam® is provided in 
Appendix A. 
2.5.1 Safety 
Interim results support a positive safety profile of the CapsoCam®. To date, there have 
been no serious or unanticipated adverse events reported. There were no capsule retentions, 
defined as subjects retaining the capsule after resuming post-procedural food ingestion. All 
capsules ingested in the studies were excreted. In all cases, the deflated balloons remained 
securely attached to the capsules upon excretion. 

 
 
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To date, there have been no device-related AEs reported. However, a small number of 
anticipated bowel preparation and booster regimen adverse events were reported: nausea, 
limited episodic vomiting, and modest abdominal discomfort (for full details see Appendix 
A). These bowel preparations-related adverse events are known to be possible whenever 
bowel preparations are administered and are well characterized in the drug manufacturers’ 
prescription information. 
2.5.2 Effectiveness 
As outlined in Appendix A, the CapsoCam® has demonstrated the ability to capture 
quality images throughout the colon, provided the subject follows the bowel preparation 
and booster regimen instructions. For recent versions of the study device, the operational 
time has been adequate for the capsule to capture images of the entire colon in most 
procedures. Recorded images were successfully downloaded using the Capsule Data Access 
System (CDAS) and were then available for physicians to review and interpret. 
 
2.6 Rationale for This Study 
Colon capsule endoscopy (CCE) has significant advantages for visualization of the colon and 
polyp detection. The procedure is less invasive than conventional optical colonoscopy (OC) and 
does not require sedation. However, significant, potentially precancerous, polyps detected by 
CCE must be subsequently removed by OC. Unlike stool or blood tests, CCE provides visual 
evidence and size measurement of pathology to assess its risk and motivate patients to get follow-
on colonoscopy when appropriate. CCE has been shown to have positive predictive value 
comparable to computed tomography colonography (CTC), another common alternative to 
conventional colonoscopy.14,15 
 
Currently, one CCE device, the PillCam COLON 2 (Medtronic) is marketed and indicated for 
visualization of the colon for patients who have had an incomplete colonoscopy or those with 
evidence of lower GI bleeding who are at major risk for colonoscopy or moderate sedation but 
who could tolerate colonoscopy and moderate sedation should CCE identify clinically significant 
abnormality. A multicenter study evaluated CCE compared to OC for agreement on the absence 
or presence of colon polyps 6 mm or larger in each subject and found 68.8% positive percent 
agreement (PPA) and 81.3% negative percent agreement (NPA).12  
 
To improve CCE’s utility, it should accurately identify those patients with potentially dangerous 
polyps who should undergo polypectomy and those at lower risk for developing colorectal cancer 
(CRC) who may not require immediate polypectomy. Since the precancerous potential of polyps 
is strongly correlated to their size, accurate size measurement would greatly assist in this 
identintification.13 Better accuracy in early polyp detection could reduce the number of 
unnecessary and costly colonoscopies and the associated risks. The CapsoCam Colon system 
includes a polyp size measurement to accurately measure polyp size, a feature the PillCam lacks.   
 
A challenge for CCE is the long video reading time and the risk that readers overlook polyps in 
the video, especially those captured in only a few frames. The PillCam produces two disjoint 
videos—one by the front- and one by the back-facing camera—increasing the reading time 
relative to a single-camera system. The CapsoCam Colon has four cameras, but their images are 

 
 
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stitched into a single coherent panoramic video, potentially reducing the reading time relative to 
the PillCam.  
 
To both reduce reading time and improve polyp-detection accuracy, the CapsoCam is the first 
CCE system to utilize artificial intelligence (AI), implemented as a convolutional neural network 
(CNN), for computer assisted detection (CADe) of polyps. The PillCam COLON 2 system 
(K123666) has a software feature dubbed “Top 100” which shows “the 100 most clinically 
relevant images in a PillCam COLON capsule study, focused on frames containing lesions, 
bleeding, and polyps.” (Quick Reference Guide, Reading a PillCam COLON 2 capsule study in 
PillCam software v9, US1600035(1) © 2019 Medtronic). However, its polyp-detection accuracy 
has not been published, and the device does not have an FDA-cleared indication for this feature. 
 
This study is designed to show that readers relying heavily on CADe (not reading the entire 
video) will achieve positive-percent agreement (PPA) and negative percent agreement (NPA) 
with a colonoscopy that exceed performance goals and, when compared to the same readers not 
using CADe (reading the entire video), superior PPA and noninferior NPA. Since readers can 
reject false-positive CADe detections, the negative percent agreement (NPA) is not expected to 
decrease significantly when CADe is used, but the study will assess this risk. 
 
2.7 Purpose and Objectives of the Investigation 
The purpose of this pivotal study is to establish the safety and effectiveness of the study device in 
the visualization of the colon and in the detection and size measurement of colonic polyps and to 
show the benefit of the CADe. The capsule video for each subject will be read by the same reader 
twice, separated by a washout period: once with and once without access to the CADe polyp 
detections. When performing the CADe read, the reader will review all the frames with CADe 
polyp detections segregated from the full video, only referring to the full video as much as 
necessary to identify landmarks, rate the colon cleanliness, review the CADe findings in the 
context of nearby frames, localize the polyps by bowel segment, and measure the polyps’ sizes. 
The study will compare the readers’ polyp detection with and without CADe. 
 
Cancerous lesions in the colon, often called tumors or cancerous polyps, will be referred to as 
cancerous polyps in this protocol. Some of the polyps detected by the CapsoCam® may be 
cancerous polyps, and, although the CapsoCam® cannot provide a diagnosis of cancer, detection 
of a polyp which is cancerous is considered a positive finding for detection of a cancerous polyp. 
The primary objective of this study is to compare the study device with CADe polyp detection to 
optical colonoscopy (OC) for agreement on the presence or absence of colon polyps ≥ 6 mm.  
 
Secondary objectives of this study are to compare the study device both with and without CADe 
to OC for agreement on the presence or absence of the colon of lesions of various types and sizes. 
Additional secondary objectives are to compare the video reading times with and without CADe 
and to show that CADe, when used in a clinically realistic manner with random readers, 
improves the polyp detection accuracy. 
 

 
 
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2.8 Study Endpoints 
2.8.1 Coprimary Endpoints 
• Positive Percent Agreement (PPA) of the device with CADe for detecting the 
presence in a subject of the largest polyp detected by optical colonoscopy (OC) if 
that polyp is ≥ 6 mm, where a match is considered to have occurred if a polyp 
detected by the device is assessed as having a size within plus or minus 50% of the 
size of the polyp detected by OC and as having a location within the same or an 
adjacent colon segment. 
• Negative percent agreement (NPA) of the device with CADe for not detecting any 
polyp ≥ 6 mm in a subject for whom OC did not detect any polyp ≥ 6 mm. 
 
2.8.2 Secondary Endpoints  
• Study-device PPA with a random reader relying on CADe versus not using CADe for 
detecting the presence in a subject of the largest polyp detected by optical 
colonoscopy (OC) if that polyp is ≥ 6 mm, where a match is considered to have 
occurred if a polyp detected by the device is assessed as having a size within plus or 
minus 50% of the size of the polyp detected by OC and as having a location within 
the same or an adjacent colon segment. 
• Study-device NPA with a random reader relying on CADe versus not using CADe for 
not detecting any polyp ≥ 6 mm in a subject for whom OC did not detect any polyp ≥ 
6 mm. 
• Sensitivity of the study device with CADe for detecting in a subject an advanced 
neoplasia (AN) detected by OC and histopathology, defined as an adenoma ≥ 10 mm, 
or containing villous growth or high-grade dysplasia, or cancer, where a lesion in the 
subject detected by the device is assessed to be at least 6 mm in size. 
• Specificity of the study device with CADe for not detecting any lesion ≥ 6 mm in a 
subject for whom OC detected no polyps ≥ 6 mm and no AN of any size. 
• Specificity of the study device with CADe for not detecting any lesion ≥ 6 mm in a 
subject for whom OC detected no polyps. 
• PPA of the device with CADe for detecting the presence in a subject of the largest 
polyp detected by optical colonoscopy (OC) if that polyp is ≥ 10 mm, where a match 
is considered to have occurred if a polyp detected by the device is assessed as having 
a size within plus or minus 50% of the size of the polyp detected by OC and as having 
a location within the same or an adjacent colon segment. 
• NPA of the device with CADe for not detecting any polyp ≥ 10 mm in a subject for 
whom OC did not detect any polyp ≥ 10 mm. 
• PPA of the device with CADe for detecting the presence in a subject of the largest 
polyp detected by optical colonoscopy (OC) if that polyp is ≥ 6 mm and < 10 mm, 
where a match is considered to have occurred if a polyp detected by the device is 

 
 
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assessed as having a size within plus or minus 50% of the size of the polyp detected 
by OC and as having a location within the same or an adjacent colon segment. 
• Sensitivity of the device with CADe for detecting the presence of a polyp ≥ 6 mm in a 
subject with OC as the reference (without regard to polyp matching). 
• Sensitivity of the device with CADe for detecting the presence in a subject of a polyp 
≥ 10 mm with OC as the reference (without regard to polyp matching).  
• PPA of the device with CADe for detecting the presence in a subject of the largest 
sessile serrated polyp (SSP) detected by OC if that polyp is ≥ 6 mm, where a match is 
considered to have occurred if the size of a polyp detected by the device is assessed as 
having a size within plus or minus 50% of the size of the polyp assessed by OC and 
as having a location within the same or an adjacent colon segment. 
• Sensitivity of the study device with CADe for detecting in a subject a SSP detected 
by OC and histopathology, where a polyp in the subject detected by the device is 
assessed to be at least 6 mm in size. 
• PPA of the device with CADe for detecting the presence in a subject of a cancerous 
polyp biopsied by OC and diagnosed by histopathology, where a match is considered 
to have occurred if the size of a polyp detected by the device is assessed as having a 
size within plus or minus 50% of the size of the cancerous polyp assessed by OC and 
as having a location within the same or an adjacent colon segment. 
• Sensitivity of the study device with CADe for detecting in a subject a cancer detected 
by OC and histopathology, where a lesion in the subject detected by the device is 
assessed to be at least 6 mm in size. 
• The above secondary endpoints will also be assessed for the device without CADe. 
• The paired within-subject difference in video reading time with and without CADe 
(time with CADe – time without CADe). 
2.8.3 Safety Assessment 
All adverse events (AEs) including serious adverse events (SAEs) and unanticipated 
adverse device effects (UADEs) will be assessed and reported at all visits.  Side effects 
from bowel preparation, prokinetic medications, boosters and colonoscopy will be recorded 
as “Anticipated Observations” on the Adverse Event Form.  Incidence of all AEs for the 
discreet interval of capsule ingestion through excretion, will be recorded and analyzed for 
seriousness, severity, and relatedness to the device.  
2.8.4 Exploratory Endpoints 
• Sensitivity for AN and specificity for AN and polyps ≥ 6 mm as a function of the 
polyp size cutoff for capsule positivity. 
• Accuracy of the detected polyp morphology assessed by the device. 
2.9 Study Design 
This is a prospective, open-label, non-significant risk, multicenter study designed to determine 
the PPA and NPA of the investigational CapsoCam® capsule endoscope, using colonoscopy as 

 
 
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the reference in detecting colonic polyps. Subjects who meet the entry criteria will ingest 
CapsoCam®, and undergo a colonoscopy procedure.  The capsule videos are read both with and 
without CADe in a crossover design, where each video is read by one reader in each mode,  
separated by a washout period. When reading with CADe, the readers will rely on the CADe and 
not read the entire video. The performance with and without CADe will be compared in a multi-
reader multi-case (MRMC) analysis with a case-nested-within-reader split plot structure,18, 19 
using sufficient readers to generalize the results to a population of random readers. 
2.10 Duration and Extent of Investigation 
Enrollment will be competitive and subjects will be screened by up to 30 clinical trial sites until a 
minimum of 700 evaluable subjects, of whom at least 192 have at least one ≥ 6 mm polyp and 
432 have none. It is anticipated that the enrollment period will last 12-18 months. Subject trial 
participation may be for a duration of up to 8 weeks (−2 weeks prior to capsule ingestion to 6 
weeks following capsule ingestion for colonoscopy).  
All subjects will remain enrolled in the study until 6 months after the initial colonoscopy or when 
the Sponsor informs the site that the subject can be exited from the study following review of the 
second capsule report as defined in section 3.11.1, whichever comes first.   
3. 
CLINICAL PROTOCOL 
3.1 Site Selection 
Up to thirty (30) investigational sites will participate in the study. Sites will be selected based on 
the availability of the subject pool, the Investigator’s experience and familiarity with colonic 
polyp detection and diagnosis and the staff’s availability. 
3.2 Number of Subjects 
This study will continue to enroll subjects until there are at least 700 evaluable subjects, of whom 
at least 192 subjects have at least one polyp ≥ 6 mm and 432 have none.  
3.3 Subject Population 
The target population for this study are patients who have been referred for a colonoscopy. The 
eligibility criteria aim to exclude subjects for whom capsule endoscopy is contraindicated. 
Potential study subjects will be identified by the study site Investigator or Sub-Investigator with 
assistance from qualified research staff. 
3.4 Inclusion/Exclusion Criteria: 
Inclusion Criteria:  
1. 
45-75 years of age  
2. 
Committed to undergo a colonoscopy. 
3. 
Choose to participate and must have signed the IRB-approved informed consent document 
and agreed to release colonoscopy images and results report to Sponsor. 
Exclusion Criteria: 
1. 
Colonoscopy or CT-colonography within the past 5 years that demonstrated no polyps. 
2. 
Has contraindication for capsule endoscopy or colonoscopy. 

 
 
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3. 
Subject is suspected or diagnosed with familial adenomatous polyposis, hereditary non-
polyposis colon cancer, or any high-risk genetic syndrome. 
4. 
Subject is suspected or diagnosed with inflammatory bowel disease such as ulcerative 
colitis or Crohn’s disease. 
5. 
History of incomplete colonoscopy. 
6. 
Type I or uncontrolled type II Diabetes (Uncontrolled defined as HbA1C >6.4 within the 
past 3 months and/or with history of constipation or gastroparesis). 
7. 
Impaired cardiac function assessed as greater than NYHA Class II. 
8. 
History of small- or large-bowel obstructive condition. 
9. 
Known history of swallowing disorder, and/or ischemic bowel disease neuropathies and/or 
radiation enteritis.  
10. Known history of NSAID enteropathy and stricture resulting from taking NSAIDs on a 
regular basis that, in the opinion of the Investigator, would put the subject at greater risk for 
capsule endoscope retention. 
11. Known allergy to ingredients used in bowel preparation and boosters. 
12. Daily and/or regular narcotics use. 
13. Decompensated cirrhosis. 
14. Prior abdominal radiation therapy. 
15. Diagnosis of anorexia or bulimia. 
16. History of or suspicion for: strictures, volvulus or intestinal obstruction; internal hernias or 
abdominal surgeries that the Investigator considers as an exclusion. 
17. Known or suspected megacolon. 
18. Scheduled to undergo MRI examination within 7 days after ingestion of the capsule.  
19. Has known slow gastric-emptying time or confirmed diagnosis of gastroparesis. 
20. Pregnant or nursing or is of child-bearing potential and does not practice medically 
acceptable methods of contraception. WOCBP must have a negative urine pregnancy test at 
screening. 
21. Unable to follow or tolerate fasting, bowel preparation, and other study procedures. 
22. Any documented medical or psychological condition or significant concurrent illness 
which, in the Investigator’s opinion, would make it unsafe for the subject to participate in 
this research study. 
23. Are currently enrolled in an interventional clinical study or currently enrolled in or within 
the last 30 days, a pharmaceutical clinical study. 
Chronic constipation as defined by < 3 bowel movements per week, or the use of routine 
laxatives (other than fiber) to attain regular bowel movements.  
 
3.5 Study Procedures 
3.5.1 Subject Consent 
Potential study subjects will be provided with the IRB approved consent detailing the study 
device, participation requirements, risks and benefits and subject’s rights. Written 
documentation, following Good Clinical Practice (GCP) must be obtained prior to initiating 
any study activities. 

 
 
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3.5.2 Screening/Baseline (Day -14 to -3) 
• Informed consent completion and verification of eligibility 
• Medical history including medications and assessment of GI health 
• Review of colon preparation requirements and administration of prep 
• Pregnancy test when applicable 
• Dispense: 
o Bowel Prep Regimen and instructions on use 
o Instructions on diet requirements and restrictions 
o Schedule return date and time for CapsoCam® swallow 
 
3.5.3 Pre-procedure Prep (Day -2 to 0) 
• Two days prior to capsule ingestion through the day of ingestion, participant will 
begin prescribed bowel prep regimen and adhere to dietary requirements 
3.5.4 Day of Procedure – Capsule Ingestion (Day 0) 
• Confirm completion of prep 
• Assess bowel prep with Bowel Prep Visual Aid 
o If subject does not confirm bowel cleanliness with image 1 or 2 on the Visual 
Aid, the subject will be considered a screen failure or will be permitted to re-
attempt bowel preparation as follows: 
 If the subject has been scheduled for Day 1 colonoscopy, and does not 
indicate adequate bowel preparation per image selection, this subject 
will be considered a screen failure 
 If the subject has been scheduled for Day 21-42 colonoscopy, they may 
be permitted to perform another bowel preparation and capsule swallow 
attempt so long as at least 2 weeks elapse between bowel preparations 
such as:  
• Initial attempt2 weeksbowel preparation for 
capsulecapsule swallow2 weeksbowel prep for 
colonoscopy 
• Initial attempt21-41 daysbowel preparation for 
capsulecapsule swallowDay 1 colonoscopy  
• Administer prokinetic medication 30-60 minutes prior to capsule ingestion 
• Anticipated Observation review/reporting 
• Capsule ingestion (30-60 minutes after prokinetic) 
• Dispense/review (can be done while subjects wait to ingest capsule after prokinetic 
medication consumed): 
o Booster/suppository (if needed) regimen following capsule ingestion 
Instructions on clear liquid diet 
o Subject diary to record booster use 
o CapsoRetrieve® Kit 
o Instruct return of CapsoCam® to CapsoVision 
• Discharge from clinic  
 

 
 
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3.5.5 Follow-Up Phone Call (Day 3 ± 2 days)—can be completed in office if subject has 
opted for Day 1 Colonoscopy  
• Verify capsule excretion and retrieval  
• AE review 
• Confirm return of CapsoCam® to CapsoVision 
 
3.5.6 Colonoscopy (Day 1 or Day 21-42) 
• Perform colonoscopy 
• Capture images of polyps with and without Napoleon measuring tool in frame 
• Record colonoscopy 
• Unmask capsule results (if available) 
o Immediate 2nd look colonoscopy if potentially significant polyps are noted on 
the CapsoCam report that were not seen during colonoscopy and if it’s in the 
best interest of the subject 
• Boston Bowel Prep Scale score recorded for all colon sections 
• Anticipated Observation capture 
• Upload images and video to secure server 
 
3.5.7 2nd-look Colonoscopy (when warranted as described in section 2.10) 
• Perform colonoscopy to seek potentially missed polyp 
• Capture video images of polyp with and without measurement tool, as was completed 
for initial colonoscopy 
• Boston Bowel Prep Scale score 
• Anticipated Observations 
• Complete colonoscopy  
• Enter data from newly discovered polyps, if applicable, into EDC.  
 
3.5.8 Capsule retrieval and return 
The subject collects the capsule after it is excreted using the retrieval system and then 
returns it to the Sponsor-affiliated download center in the provided vial from the 
CapsoRetrieve® Kit, where the video will be processed into video format for distribution to 
be read by an independent reader. The processing includes application of the polyp CADe 
to the image data, so that the detection area coordinates are encoded into the video 
metadata. If the capsule is retrieved during colonoscopy, the site will return the capsule to 
the download center for this processing. 
 
 

 
 
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Table 1.1: Schedule of Assessments 
Study Visit 
Screening 
Baseline 
Pre-
Procedure 
Pre-
Procedure 
Day of 
Procedure 
Follow up 
Phone Call 
Colonoscopy* 
Colonoscopy* 
Study Day 
-14 to -3 
-2  
-1 
0 
+1 to +3 
+1 
+21 to 42 
Informed Consent 
X 
 
 
 
 
 
 
CapsoCam®/Colonoscopy 
Instruction 
X 
 
 
 
 
 
 
Demographic 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Medication Use 
X 
 
 
X 
 
 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
Prep Regimen/Prokinetic 
Drugs 
 
X 
X 
X 
 
 
 
Capsule Ingestion 
 
 
 
X 
 
 
 
After Capsule Swallow; 
Booster 
Regimen/Suppository as 
needed 
 
 
 
X 
 
 
 
Clear Liquids 
 
 
 
X 
 
 
 
First Full Meal (if having 
day 1 colonoscopy) 
 
 
 
 
 
X 
 
Follow up  
 
 
 
 
X 
 
 
Anticipated Observation/ 
Adverse Event Assessment 
 
 
 
X 
X** 
X 
X** 
Colonoscopy 
 
 
 
 
 
O* 
O* 
*0=Day 1 or Day 21-42 option: if it is in the best interest of the subject, as determined by the investigator, a study subject may have 
colonoscopy the day after CapsoCam® ingestion. For all others, colonoscopy will be performed from 21-42 days following CapsoCam® 
ingestion. 
**Anticipated observations: Events captured prior to capsule ingestion (bowel prep related to capsule ingestion) and after excretion (bowel 
prep related to colonoscopy, colonoscopy related events) 

 
 
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3.6 Moment of Enrollment 
Subjects will be considered enrolled in the study when they have successfully ingested the 
capsule without regurgitating it. Subjects who attempt swallow but are not successful will be 
withdrawn from the study but remain in the safety analysis population. Subjects that screen fail 
as a result of poor bowel prep who are not given another opportunity to complete bowel 
preparation, will be considered screen failures and will not be included in any analysis. 
3.7 CapsoCam® Video Reading 
CapsoVision will download image data from the capsules, and each subject will be assigned 
without bias to one independent video reader from a pool. Two versions of the video will have 
been created at the download center, one for the CADe read and one the non-CADe read. The 
reader will be blinded to the correspondence between video and subject and will be randomly 
assigned to read either the non-CADe version first (sequence A) or the CADe version first 
(sequence B), with the second reading following a washout period of at least three (3) weeks. The 
two crossover sequences are summarized below. 
Sequence A: 
1. 
The reader first reviews the entire video without exposure to the CADe output 
and annotates all polyps detected, including measured size and location (colon 
segment). Anatomical landmark frames and bowel cleanliness ratings are 
recorded. 
2. 
Following a washout period of at least three weeks, the same reader reviews a 
secondary video that only includes frames with CADe polyp detections that are 
highlighted with a bounding box around the detection area. The reader can 
switch from the secondary video to the main video to view nearby frames. For 
CADe detections assessed to be a true polyp, and for any additional polyps 
detected in the main video, the reader annotates the polyp, including measured 
size and location (colon segment). Anatomical landmark frames and bowel 
cleanliness ratings are recorded. The reader is instructed to review the main 
video only to the extent necessary to make these assessments and not to read it 
in its entirety. 
Sequence B: 
1. 
The reader first reviews a secondary video that only includes frames with CADe 
polyp detections that are highlighted with a bounding box around the detection 
area. The reader can switch from the secondary video to the main video to view 
nearby frames. For CADe detections assessed to be a true polyp, and for any 
additional polyps detected in the main video, the reader annotates the polyp, 
including measured size and location (colon segment). Anatomical landmark 
frames and bowel cleanliness ratings are recorded. The reader is instructed to 
review the main video only to the extent necessary to make these assessments 
and not to read it in its entirety. 
2. 
Following a washout period of at least three weeks, the same reader reviews the 
entire video without exposure to the CADe output and annotates all polyps 

 
 
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detected, including measured size and location (colon segment). Anatomical 
landmark frames and bowel cleanliness ratings are recorded. 
 
For each read, the reader will rate the bowel cleanliness in the left colon (cecum and ascending), 
transverse colon, and right colon (descending/sigmoid, and rectum) using the CC-CLEAR 
method and the overall colon cleanliness will be determined adequate or inadequate from these 
ratings using a standardized validated method.18 For each identified polyp, at least one annotated 
frame number (time stamp) will be documented on the report. The size of the polyp will be 
measured using the size measurement tool. When necessary, readers will have the option to use 
the software measurement function of combining measurements, for polyps that are too large to 
be captured in a single frame, or using the output of the size-measurement tool to inform an 
estimated final value, for example by averaging multiple measurements or by measuring a 
fraction of a polyp and scaling the value by the inverse of the fraction. In other instances, the size 
measurement tool may not be able to make a measurement for reasons such as excessive bubbles 
or turbidity and the reader shall make a best estimate of the size and select the final image(s) that 
support the final measurement for each polyp. The polyp size will be recorded in millimeters to 
one decimal place (e.g. 11.2 mm or 8.0 mm).  
Only those findings which the reader records, not the CADe output, are included in the CCE 
subject clinical dataset for comparison to the OC reference. There will be at least 9 and up to 16 
central readers trained by CapsoVision to read the capsule videos. Each central reader is a board-
certified gastroenterologist in good standing and experienced with capsule endoscopy and 
colonoscopy. The readers are independent reviewers that will have been trained on the reading of 
video captured by the study device using the CapsoView® software. Financial disclosures will be 
collected on all readers in accordance to 21 CFR Part 54. To the extent practical, the readers will 
all review an approximately equal number of subject videos. 
3.8 Colonoscopy and Biopsy (follow these procedures for initial and/or repeat 
colonoscopy) 
The Sponsor will identify, train, and qualify physicians with reported adenoma-detection rates 
(ADRs) of at least 25% for both male and female. The colonoscopy and biopsy will be performed 
according to the clinic’s standard of care by trained Study Investigators. Instructions on polyp 
measurement and photography requirements will be provided by the Sponsor. Study Investigators 
must agree to video record the entire colonoscope withdrawal for every study subject. Each OC 
performed on study subjects must have a withdrawal procedure time of at least 6 minutes. Polyps 
will be resected per the site’s standard of care.  
The Boston Bowel Preparation Scale (BBPS) will be used to rate bowel cleanliness of three colon 
sections (right, transverse, and left) during the colonoscopy on the standard scale of 0 to 3. The 
overall colon cleanness will be rated inadequate if the BBPS score for any of the three colon 
sections is 0 or the total BBPS score (scale of 0 to 9) is less than 5. 
Colonoscopy will be performed during the period starting 3 weeks after capsule ingestion and 
ending 6 weeks (+2 weeks window) post-ingestion, or, if it is in the best interest of the subject, as 
determined by the Investigator, a study subject may instead have colonoscopy the day after 
CapsoCam ingestion, but must be scheduled more than 26 hours post-capsule-ingestion to allow 
the capsule to finish recording if it has not been excreted. In the event the capsule is seen during 

 
 
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the colonoscopy, it is recommended that the physician retrieve the capsule and return it to the 
Sponsor. If the capsule is retrieved in the cecum, there is no need for the physician to perform 
steps 3, 5 and 6 listed below and the capsule video will not need to be read by the independent 
reader. 
Subjects will be prepared for colonoscopy according to Investigator instructions.  
The following procedures are specified for significant polyps, where significant polyps are 
defined as those estimated to be ≥ 4 mm. In addition, all suspected advanced neoplasia, including 
cancers, will be considered significant polyps. 
1. 
The entire colonoscope withdrawal will be video recorded.  
2. 
The colonoscopist will estimate the size of detected polyps. 
3. 
A measurement reference tool will be imaged with the polyps and used as a reference 
for a later final polyp size determination by independent readers. 
4. 
The colonoscopist will capture at least one photograph showing an unobstructed view of 
each significant polyp. 
5. 
The colonoscopist will capture at least one photograph of each significant polyp with 
the measurement tool in frame. If the entire polyp cannot be captured in a single image, 
multiple images of the polyp with the measurement tool should be captured. These 
photographs will be analyzed to determine the ground-truth polyp size.  
6. 
Each resected significant polyp will be placed in a separate vial for biopsy labeled to 
match the polyp to the subject and to the polyp diagnosis, including the polyp 
photographs, size estimate, and the colon-segment location. 
7. 
The location of each significant polyp is recorded by segment: cecum, ascending colon, 
transverse colon, descending/sigmoid colon, or rectum. 
 
The histopathology report is referred to to determine if a subject has CRC or an advanced 
precancerous lesion, defined as an adenoma with at least one of the following characteristics: 
• Size  ≥ 10mm 
• Villous growth (a tubulovillous or villous adenoma) 
• High-grade dysplasia (HGD).  
 
Sessile serrated polyps (SSPs) are counted as adenomas. Advanced neoplasia is considered either 
cancer or an advanced precancerous lesion. 
Immediately after the colonoscope pull-back is complete, the first CapsoCam® read results, if 
available, will be unmasked. The results list the size, morphology, and colon segment of all 
polyps detected, and include at least one capsule image of each. If the Investigator suspects that a 
significant CapsoCam® polyp was missed by OC, but especially if the CapsoCam® results 
include a polyp ≥ 6 mm or suspected cancer and no OC polyp of size estimation ≥ 4 mm was 
detected in the same or adjacent colon segment, the colonoscopist should repeat the colonoscopy 
at least in the indicated colon segments and those adjacent to it, if it is in the best interest of the 
subject. The prior photography procedures should be repeated for each new significant polyp 
found and the record should indicate which OC polyps were found after unmasking.  

 
 
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3.9 Second-colonoscopy determination and subject exit from study 
If, based on either the CADe or no-CADe capsule report, it is determined that a significant 
finding, including a polyp assessed at 6mm or larger, may have been missed during OC (and 
confirmed by a member of the CEC as defined in section 3.11.1), this determination will be 
conveyed to the PI. If a second colonoscopy is decided to be in the best interest of the subject and 
is performed within 6 months of the original colonoscopy, any additional significant polyps will 
be added to the Polyp Measurement Log case report form for analysis and marked as found 
during 2nd colonoscopy. The subject can be exited from the study at this point.  
For subjects that complete next-day “Day 1” colonoscopy, capsule results will not be available 
the day of the colonoscopy. In these cases, once a capsule report (either with or without CADe) is 
available and reviewed, if it is determined that a polyp assessed at 6mm or larger may have been 
missed during OC (and confirmed by a member of the CEC as defined in section 3.11.1), this 
determination will be conveyed to the PI. The physician and subject may choose to repeat the 
colonoscopy. If repeat colonoscopy is decided to be in the best interest of the subject and is 
performed within 6 months of the original colonoscopy, any additional significant polyps will be 
added to the Polyp Measurement Log case report form for analysis and marked as found during 
2nd colonoscopy.  
In both colonoscopy scenarios, subjects completing a second colonoscopy will be exited from the 
study following the second colonoscopy or within 6 months after colonoscopy, whichever occurs 
first. Sites will be informed of negative CapsoCam results after both the CADe and non-CADe 
reports are reviewed and may then exit the subject from the study.   
For subjects that were exited from the study prior to the introduction of CADe, they will not be 
considered for reconsenting.  However, both their capsule reports will be reviewed as defined in 
section 3.11.1. Any positive findings will not be collected for analysis.  
3.10 Reference Polyp Size Determination 
The video record of the colonoscopy and photographs taken during the OC procedure, showing 
the measurement tool proximal to the polyps, will be collected from the clinical sites and 
distributed to two independent physicians to determine the polyp sizes. Provided that the 
measurements of both readers are within 1 mm, the measurements will be averaged and treated as 
ground truth for a particular polyp. When the discrepancy between the two size measurements 
exceeds the greater of either 1 mm or 10% of the larger measurement and the largest 
measurement is > 6 mm, a third reader will evaluate and measure the polyp in question. In cases 
where one reader selects the CRF option “< 6 mm” and the other reader provides a numerical 
measurement > 6 mm, a third measurer will also be asked to measure the polyp. For polyps with 
three measurements, the median will be used as the final measurement.  
The physician measures the polyps in the photographs using a measurement software application, 
which may include a graphical user interface (GUI) which allows the user to draw one line across 
the measurement tool and another line across the long axis of the polyp. The software calculates 
the polyp size from the length of these lines and the known size of the measurement tool. The 
polyp size will be recorded in millimeters to one decimal place (e.g. 11.2 mm or 8.0 mm). 
If a single photograph is deemed inadequate to make a measurement, either because the entire 
polyp or a sufficient portion of measurement tool is not visible, then the reader should refer to all 

 
 
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photographs of the polyp, the colonoscopist’s polyp-size estimation, and the video record of the 
colonoscopy and make a size determination, adjudicating discrepant size values. If the reader 
cannot confidently estimate the polyp size but can confidently classify it as < 6 mm, then this 
classification should be recorded. Otherwise, the size should be recorded as indeterminate, and, if 
no other polyp is found in the subject ≥ 6 mm to serve as the reference polyp, then the subject 
should be excluded from the endpoint analyses due to “missing size measurement data.” 
3.11 Adverse Events (AEs) 
An adverse event (AE) is defined as any untoward medical occurrence, independent of its 
association with the study device.     
Adverse events that start on the day of capsule ingestion (Procedure) through excretion will be 
recorded on the appropriate CRF. All side effects from bowel preparation, pro-kinetic medication, 
boosters or anything related to colonoscopy (e.g., anesthesia) will be recorded as anticipated 
observations on the adverse event CRF. Subjects discontinuing prematurely from the study due to 
an AE that has not yet been stabilized will be managed by their treating physician. 
Adverse events that occur during the study will be recorded on the Adverse Event CRF.  Data to 
be collected will include the description of the adverse event, onset and resolution date (or 
whether the adverse event is ongoing), severity, management/treatment, outcome, and 
determination of the relationship to the study device and/or procedure (i.e., Prep, Pro-kinetics, or 
Booster).  In general, AEs should be reported and classified by the Investigator using a diagnosis 
rather than symptoms.     
The relationship of the AE will be coded as follows: 
• Not related: The AE is due to an underlying or concurrent illness or effect of another device, 
drug or intervention and is not related to the study device or device procedure. 
• Possibly related: The causal and/or temporal relationship to the study device or device procedure 
is equally or less likely than other plausible explanations. 
• Probably related: The causal and/or temporal relationship to the study device or device 
procedure is likely or significantly more likely than other plausible explanations. 
• Definitely related: A clinical event that can only be attributed to the study device or device 
procedure. 
Severity will be coded as to the degree of severity as follows: 
Mild:  The AE is transient and easily tolerated by the subject, even if it causes discomfort 
Moderate:  The AE causes the subject discomfort and interrupts the subject’s usual activities. 
Severe:  The AE causes considerable interference with the subject’s usual activities; may be 
incapacitating and may require hospitalization. 
All adverse events that occur in the study population (including Serious Adverse Events and 
Unanticipated Adverse Device Effects) will be tabulated and summarized.  In addition, the 
incidence of all types of adverse events will be reviewed during the course of the study for any 
indications that use of study device confers any unanticipated significant risk.  An unanticipated 

 
 
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adverse device effect (UADE) is defined by the FDA as “any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application (including a supplementary plan or application), or any 
other unanticipated serious problem with a device that relates to the rights, safety, or welfare of 
subjects.”  Should any unanticipated adverse device effects occur during the course of the study, 
the Investigator is required to report the events to the Sponsor as soon as possible after learning 
of the event but no later than 10 working days after learning of the event. The Investigator must 
report to the governing IRB per IRB reporting requirements.  The Sponsor, will conduct an 
evaluation of such effects.  In addition, the study Sponsor will report the UADE to FDA and 
participating Investigators within 10 working days after the Sponsor first receives notice of the 
effect.  Following the evaluation, if the Sponsor determines that an unanticipated adverse effect 
presents an unreasonable risk to subjects, the investigation will be terminated as soon as possible.  
Termination shall occur no later than five working days after the Sponsor makes the 
determination and no later than 15 working days after the Sponsor receives notice of the 
unanticipated adverse device effect.  FDA and IRB approval will be obtained prior to resuming a 
terminated investigation.  
A serious adverse event (SAE) is any AE that: 
• 
led to a death, 
• 
led to a serious deterioration in the health of the subject that: 
• 
resulted in a life-threatening illness or injury, 
• 
resulted in a permanent impairment of a body structure or a body function, 
• 
required in-patient hospitalization or prolongation of existing hospitalization, 
• 
resulted in medical or surgical intervention to prevent permanent impairment to body 
structure or a body function 
• 
or led to fetal distress, fetal death or a congenital abnormality or birth defect. 
Note that an elective or pre-planned hospitalization for a condition that did not worsen during the 
study is not an AE. 
ALL SAEs and UADEs should be reported to the Sponsor within 24 hours of the knowledge of 
the event and reported to the respective IRB per their requirements.  In the event of subject death, 
a copy of death records, medical records pertaining to the events leading up to the death, and an 
autopsy report (if performed) should be sent to the Sponsor as soon as possible.   All subject 
identifiers other than the subject number should be removed from the documents submitted to the 
Sponsor.  
3.11.1 Clinical Events Committee (CEC) 
The CEC will consist of one to three independent physicians. The CEC will adjudicate all 
reported SAEs.  The CEC will be responsible for review, adjudication, and validation of all 

 
 
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reported SAEs that occur over the course of the study and subsequent classification of these 
complications as related to the study device, procedure, or other.  If the CEC’s classification 
differs from the Investigator, Investigator will be notified of the determination.  The CEC’s 
adjudication is final for all SAEs.  In addition, the CEC will review all deviations that may affect 
the study endpoints.  The CEC will meet as needed based on the rate of reported events. 
Members will be provided data summaries from the clinical study.  
The CEC will also review both capsule report results with the colonoscopy reports for subjects 
that have colonoscopy on Day 1 as described in section 3.8. The CEC will be provided with all 
images/video and report documentation from the capsule report and the colonoscopy report when 
a polyp >4 mm is identified on the capsule report that is not reflected in the colonoscopy report. 
The committee will review the documentation independently and submit their recommendation 
regarding repeat colonoscopy. When the committee is in agreement, the site will be notified of 
the final recommendation. If a repeat colonoscopy is recommended, the final decision to repeat 
the exam will be the responsibility of the Principal Investigator and subject.  In the event of a 
disagreement between the committee members, a live meeting will be held to discuss the case. If 
a unanimous agreement cannot be reached, the site will be notified of the conclusion from all 
members of the committee to better inform their decision regarding repeat colonoscopy. 
3.12 Device Malfunction 
Throughout the study, the Investigator and study staff will report and document all study device 
deficiencies and malfunctions related to the identity, quality, durability, reliability, safety or 
performance of the study device.   
This includes reporting of study device deficiencies/malfunctions that did not lead to an AE but 
could have if:  
1) suitable action or intervention had not been taken, or  
2) if intervention had not been made or 
3) circumstances had been less fortunate.   
If possible, the Investigator should return study devices suspected of deficiency or malfunction to 
the Sponsor for analysis. 
All malfunctions of the study device observed during capsule administration or at the download 
center must be documented on the Device Malfunction/Performance Case Report Form within 24 
hours of the knowledge of the event.  If possible, study devices should be returned to the Sponsor 
for analysis.  All performance issues and malfunctions will be reported in the final report.  
Instructions for returning the study device are included in the Instructions for Use. 
3.13 Subject Withdrawal 
Subjects will be advised that they may voluntarily withdraw from the study at any time and will 
be instructed to notify the Investigator immediately if they choose to withdraw.  Subjects may 
choose to withdraw for any reason and are not obligated to reveal their reason(s) for withdrawal.  
Should subjects withdraw prior to the Final Visit, the site will communicate with the subject and 
exit them from the study.  In addition, subjects may be involuntarily withdrawn by the 
Investigator if the Investigator believes it is in the best interest of the subject (e.g., adverse event) 

 
 
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or if the subject needs re-intervention. AEs that are study device related (onset after ingestion and 
prior to excretion) and ongoing at study exit will be followed for 30 days or until resolved, 
whichever comes first. 
3.14 Data Collection and Reporting 
Electronic Case Report Forms (eCRFs) will be used to capture patient data in the clinical trial. 
The Principal Investigator consents to visits by the staff of the Sponsor and its authorized 
representatives and the U.S. Food and Drug Administration or any other governmental body to 
review the study subjects’ medical records including any test or laboratory data. 
3.14.1 Reporting of Protocol Deviations:  
A Protocol Deviation Form must be completed for each study protocol deviation (e.g., failure to 
obtain informed consent, enrolling a subject who does not meet inclusion/exclusion criteria, not 
performing required testing, subject not following the prep regimen, missed follow-up window, 
etc.).  Deviations involving subjects’ rights, safety or welfare should be reported to the Sponsor 
as soon as the Investigator or other study staff are made aware. IRB’s may require the reporting 
of protocol deviations. The site Investigator and study staff are responsible for knowing and 
adhering to their IRB requirements. 
Deviations will be reviewed regularly by the Sponsor and corrective actions may be implemented 
if required to assure data integrity and the protection of study subjects. 
3.14.2 Confidentiality of Data:  
All information and data sent to the Sponsor, Contract Research Organizations, or the CEC 
concerning subjects or their participation in this study will be considered confidential.  All data 
used in the analysis and reporting of this evaluation will be used in a manner without identifiable 
reference to the subject.   
3.14.3 Lost to Follow Up 
If a subject is lost to follow up, the End of Study eCRF will be completed.  If a subject fails to 
comply with the follow up evaluations, the study site will attempt to contact the subject at least 
three times, and retain documentation of contact attempts.  
In order to minimize loss to follow-up, at the baseline evaluation visit, the Study Coordinator will 
ensure accuracy of contact information for the study subjects.  It is recommended that the 
research site obtain contact information for at least one individual to serve as an alternate contact 
for the participant. The contacts will be utilized in the event that the subject relocates or cannot 
be reached by mail or telephone.  This information will be treated as confidential and for use by 
the investigative site only. 
3.14.4 Quality Assurance of the Data 
Subject case report forms will be reviewed for completeness and accuracy as well as for any 
evidence suggesting subject risk.  Where any discrepancies are noted, they will be resolved with 
the Investigator and/or an individual designated by the Investigator.  Where the data are 
incomplete, attempts will be made to obtain the missing data.   
3.15 Study Termination 
If new information is discovered during the study that indicates that the study device provides an 

 
 
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unreasonable risk to subjects, study enrollment will be suspended or discontinued.  Enrollment 
will only be resumed once the risk has been appropriately mitigated and authorization to resume 
is obtained from FDA and the IRB.  
Regardless of ability to resume the study, all subjects may undergo the planned colonoscopy. 
4. 
STATISTICAL CONSIDERATIONS 
4.1 Analysis Population 
Evaluable population. This population will consist of all subjects who have both an evaluable 
colonoscopy and an evaluable CapsoCam®. This population will be used for all effectiveness 
analyses.  
The following circumstances contribute to procedures that are not evaluable and therefore such 
subjects will be excluded from all effectiveness analyses: 
1. Subjects who fail to undergo either the capsule or OC procedure. 
2. Subjects for whom the capsule did not leave the cecum in 24 hours post-ingestion. 
3. Subjects for whom the capsule did not reach the colon within 24 hours post-ingestion. 
4. Subjects with incomplete colonoscopies. 
5. Subjects whose bowel cleanness was rated as inadequate for either the colonoscopy or 
capsule procedures.  
6. Subjects with capsule malfunction resulting in more than approximately 5 minutes of video 
data in the colon missing or unevaluable, within the first 24 hours of capsule operation. 
7. Subjects with missing colon image data due to filling of available data memory within 12 
hours of operation and prior to excretion. 
8. Subjects who undergo colonoscopy on Day 1 and the colonoscope reaches the capsule while 
it is still in the colon and recording video, as determined from review of the capsule video, 
prior to a timestamp of 24 hours.  
9. Inability to measure polyps in structured light setting in CapsoView 
 
The bowel cleanliness will be rated adequate or inadequate for each subject using the CC-CLEAR 
method.18 The colon is divided into three segments: right (cecum and ascending colon), transverse, 
and left (descending/sigmoid and rectum). In each read, the reader assigns points for each segment 
based on the fraction of the mucosa visualized (Table 1). If only a portion of a segment is 
visualized because the capsule stopped recording, the score for the segment is based on the 
percentage of mucosa visualized in the portion visualized. In [18] the overall score for a read is 
considered adequate if all segment scores are at least 2. However, for this study, the cleanliness is 
considered adequate if all segment scores are at least 1. Otherwise, it is inadequate. Segments not 
included in the video because the camera stopped recording are not counted in the adequacy 
determination.  
 
Table 1 CC-CLEAR Bowel cleanliness rating per segment 
Points per segment 
Percentage of mucosa visualized 
0 
Less than 50% 
1 
Between 50% and 74% 
2 
Between 75% and 89%  

 
 
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3 
At least 90% 
 
 
For the exclusion criteria numbered 2, 3, 5, 6, 7, 8, or 9, the subject is excluded from the evaluable 
population if the criterion is met based on either read. For calculating capsule transit for each 
subject, the first cecal time and excretion time will be the average of the two reads and the last 
cecal timestamp is the larger of the two. 
 
Safety Population. This population will consist of all subjects who attempted to ingest the 
capsule, whether successful or not.  
 
4.2 Study Endpoint Analyses 
All polyps identified and resected during colonoscopy will be confirmed as polyps on the 
histopathology report to be considered polyps in the analysis. If a histopathology report is not 
available, those findings classified as polyps by the colonoscopist will be considered polyps in 
the analysis. Details of the endpoint analyses will be described in the Statistical Analysis Plan. 
Coprimary Effectiveness Endpoints. The coprimary effectiveness endpoints involve the PPA 
and NPA for detecting polyps ≥ 6 mm.  
 
PPA will be defined, based on all patients for whom OC’s largest (reference) polyp ≥ 6 mm, as 
follows:  
– True Positive (TP) if a polyp identified by CapsoCam is in same or adjacent colon 
segment and matches in size, per matching rules in section 4.3. 
 
– False Negative (FN) if not 
 
Then PPA =  
TP
TP + FN
 
 
NPA will be defined, based on all patients for whom OC’s largest polyp < 6 mm, as follows: 
 
– False Positive (FP) if CapsoCam identifies a polyp ≥ 6 mm 
 
– True Negative (TN) if not 
 
Then NPA =  
TN
TN + FP
 
 

 
 
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Point estimates and 95% confidence intervals for PPA and NPA using exact Clopper-Pearson 
methodology will be computed.17 The null and alternative hypotheses to be tested are defined in 
Section 4.6.  
Secondary effectiveness endpoints involving polyp matching. All the secondary endpoints 
involving polyp matching will be analyzed in a manner analogous to the corresponding primary 
effectiveness endpoint, with endpoint-specific definitions of TP, FN, TN, and FP.  
Multi-reader multi-case analysis. A multi-reader multi-case (MRMC) analysis will be applied 
to the secondary endpoints comparing the PPA and NPA with and without CADe. The MRMC is 
a case-nested-within-reader split-plot structure with one reader per case,18, 19 using sufficient 
readers to generalize the results to a population of random readers. The possibly unequal number 
of positive and negative cases for each reader will be considered when calculating the cross-
reader variances. 
Sensitivity for advanced neoplasia. Advanced neoplasia comprises cancer or an advanced 
precancerous lesion, where an advanced precancerous lesion has at least one of the following 
characteristics: 
• Adenoma of size ≥ 10mm 
• Villous growth (tubulovillous or villous adenoma). 
• High-grade dysplasia (HGD). 
 
The histopathology report determines if a polyp is an adenoma, where SSPs are considered 
adenomas, and if it has villous growth or HGD.  
 
Additional Analyses. In addition, we will cross-tabulate the size of the largest polyp detected 
with OC by the size of the largest polyp detected with CapsoCam® using the categories of 0 mm, 
> 0 to < 6 mm, 6 to <10 mm, and > 10 mm. 
4.3 Polyp Matching Rules 
Many of the study endpoints involve polyp matching. This section defines the rules for such 
matching. The matching rules are applied to polyp sizes and polyp-size thresholds expressed in 
millimeters to one decimal place. So, for example, a polyp measured to be 5.8 mm in 
colonoscopy or by the capsule is not rounded to 6 mm before comparison to the 6.0 mm 
threshold and is thus not included in the ≥ 6 mm category.  
For each subject with at least one polyp ≥ 6 mm detected by OC, the largest polyp will be the 
reference (index) polyp to which CapsoCam® detected polyps will be compared. The colon 
segment location of the polyp will be recorded as the cecum, ascending colon, transverse colon, 
descending/sigmoid colon, or rectum. If two or more OC polyps ≥ 6 mm in different colon 
segments are of equivalent size (all within 1.0 mm of the largest) and they are the largest in their 
segment, each will be a reference polyp for a separate CapsoCam® to-OC-polyp matching 
analysis, and the final matching result for this subject will be the one signifying the best 
CapsoCam® accuracy.  
 

 
 
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A polyp detected by CapsoCam® will be a match to the reference polyp if (1) its size is within ± 
50% of the reference polyp, and (2) its location is in the same segment as the reference polyp or 
it is in an adjacent colon segment. The calculated upper and lower limits of the size matching 
range are rounded to one decimal place before determining if a capsule polyp is in the range. 
Very large polyps (≥ 20 mm) typically are not completely visualized by CapsoCam® in a single 
or even two frames, making accurate measurement difficult. Accurate measurement of very large 
polyps can be difficult in colonoscopy as well. Thus, for purposes of size matching, both study 
device and reference polyps measured larger than 20mm will be considered 20 mm for size 
matching. While polyp matching on size will primarily be based on the ±50% rule just described, 
sensitivity analyses will also be conducted in which the size matching will be based on a rule of –
50% or larger. 
4.4 Safety Assessment 
Safety will be assessed based on analysis of adverse events (AEs). The frequency and capsule 
relatedness of AEs will be reported and reviewed with CEC and tabulated for reporting purposes. 
4.5 Sample Sizes  
Assumptions for sample size calculations: 
• True PPA for detecting polyps ≥ 6 mm without CADe is 69% 
• True PPA for detecting polyps ≥ 6 mm with CADe is 80% 
• True NPA for detecting polyps ≥ 6 mm without CADe is 90% 
• True NPA for detecting polyps ≥ 6 mm with CADe is 86% 
• True sensitivity for detecting advanced neoplasia is 85% 
• One-sided alpha = 0.025 
• Non-inferiority margin of 0.1 
• Within-reader between-test correlation of accuracy measurement errors, r1 = 0.6 
• Error variances assume a binomial distribution 
• PPA test-by-reader variance = 0.00033. 
• NPA test-by-reader variance = 0.00015. 
• Number of readers = 9.  
• Readers read an equal number of positive cases and an equal number of negative cases. 
• More readers increase the study power for demonstrating superior PPA and noninferior 
NPA with random readers. The number of readers is likely to exceed the conservatively 
assumed value of 9. On the other hand, the number of cases read by each reader may not 
be exactly equal, reducing the effective number of readers. For the sample size 
calculations, these affects are considered counteracting and thus ignored. 
 
Calculated sample sizes for each statistically-powered endpoint: 
• Observed PPA for detecting polyps ≥ 6 mm with CADe ≥ 65%, with 99% probability of 
success: 40 evaluable positive subjects. 
• Observed NPA for detecting polyps ≥ 6 mm with CADe ≥ 75%, with 99% probability of 
success: 56 evaluable negative subjects. 

 
 
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• The PPA for detecting polyps ≥ 6 mm with CADe is superior to that without CADe with 
power 90%: 162 evaluable positive subjects. 
• The NPA for detecting polyps ≥ 6 mm with CADe is non-inferior to that without CADe 
with power 90%: 432 evaluable negative subjects. 
• The sensitivity for detecting advanced neoplasia is at least 65%: 52 evaluable positive 
subjects. 
Enrollment Plan 
It is desired to have at least as many cases with polyps ≥ 6 mm as were obtained in the pivotal 
study for the predicate device (PillCam)12 and to have at least as many evaluable subjects. The 
PillCam study had 700 evaluable subjects and 192 subjects with at least one polyp ≥ 6 mm, 
which exceeds the calculated positive sample size of 40. Thus, this CapsoCam study will enroll 
subjects until there are at least 192 subjects with at least one polyp ≥ 6 mm and 432 without, with 
the total equaling at least 700.  
4.6 Hypotheses 
1. 
Secondary Endpoint #1 – The null hypothesis is that “true” difference in PPA 
for detecting polyps ≥ 6 mm with CADe versus without CADe (PPA with CADe 
– PPA without CADe) is ≤ 0. The alternative hypothesis is that this difference is 
> 0.  
2. 
Secondary Endpoint #2 – The null hypothesis is that “true” difference in NPA 
for detecting polyps ≥ 6 mm with CADe versus without CADe (NPA with 
CADe – NPA without CADe) is ≤ -10%. The alternative hypothesis is that this 
difference is > -10%.  
3. 
Secondary Endpoint #3 – The null hypothesis is that the sensitivity for detecting 
advanced neoplasia with CADe is < 65%. The alternative hypothesis is that it is 
≥ 65%. 
4.7 Multiple Comparisons 
A hierarchical testing procedure will be utilized to control the overall study-wise type I error rate 
at the pre-specified one-sided alpha=0.025 level. Hypothesis testing will be conducted in the 
order listed. Formal hypothesis testing will stop following the first non-statistically significant 
result (p-value ≥0.05), and nominal p-values will be displayed for subsequent endpoints.  
Full details of this approach will be described in the SAP.   
4.8 Masking Procedures 
The study design and clinical practice for this study prohibit the use of strict blinding 
methodology during the conduct of the study. However, the colonoscopist will not have access to 
the results of the CapsoCam results until after the colonoscopy has been completed.  
 
5. 
PERSONNEL RESPONSIBILITIES 
5.1 Principal Investigator Responsibilities 
• 
Permit monitor inspection of facilities and records. 

 
 
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• 
Permit FDA and other government health authority’s inspection of facilities and 
records. 
• 
Submit protocol and informed consent to IRB and receive approval prior to enrolling 
first subject. 
• 
Submit proposed amendments to protocol and informed consent to IRB and await 
approval, unless the change reduces the risk to subjects. 
• 
Obtain informed consent of subjects. 
• 
Implement study in accordance with protocol. 
• 
Complete case report forms.  
• 
Record and explain deviations from protocol and report to monitor. 
• 
Submit annual progress reports, final reports, and adverse effect reports to IRB and 
Sponsor. 
• 
Record the receipt, disposition, and return of study devices. 
• 
Refrain from promoting study or study articles in such a way that the potential 
participant will be biased in his/her responses. 
• 
Maintain medical histories of subjects. 
• 
Retain records for two years following FDA approval of marketing application. 
 
5.2 Sponsor Responsibilities 
• 
Assure IRB approval of protocol and informed consent is obtained prior to enrollment 
of study subjects. 
• 
Select and train monitors. 
• 
Select Investigators. 
• 
Train Investigators in study device use. 
• 
Obtain Agreement Letter and curriculum vitae and proof of appropriate licensure of 
Investigator and other study staff. 
• 
Control shipment of study devices. 
• 
Conduct day-to-day administration of study. 
• 
Investigate unanticipated, device related adverse effects. 
• 
Document protocol deviations and violations. 
• 
Obtain statement of financial disclosure. 
 
6. 
RISK/BENEFIT ANALYSIS 
The investigational study was designed to assure that the benefits and knowledge gained about 
the use of the CapsoCam® outweigh the potential risks to the study subjects. CapsoVision has 
submitted a previous version of this study protocol to the U.S. Food and Drug Administration 
(FDA). After review of the submission, FDA issued a decision letter on June 25, 2018 stating that 
the study would be a non-significant risk (NSR) device study. 
6.1 Potential Risks to Study Subjects 
The following are the possible risks associated with the Capsule Endoscope; some may be rarer 
than others: 
• 
Abdominal discomfort while the capsule is passing through the subject’s gastrointestinal 
tract 

 
 
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• 
Injury of the mucosa  
• 
Bleeding of the mucosa  
• 
Retention of the capsule (rarely) possibly resulting in obstruction; if this happens, the 
subject may need a procedure or surgery to remove the capsule. Often the capsule will 
pass with time or after administration of medication.  
• 
Aspiration 
 
Capsule endoscope retention poses the greatest potential risk. However, all subjects being 
enrolled in the study will meet all the eligibility criteria and therefore this study has been 
designed to minimize this risk to the study subject. 
Retention of the capsule is highly unlikely, but has been reported in subjects with unknown and 
undiagnosed abdominal strictures. Exclusion criteria have been developed to minimize the 
possibility of a subject being enrolled in the study who has signs and symptoms of 
gastrointestinal strictures. In the event that a subject experiences retention of the capsule, the 
capsule may subsequently be excreted by itself over time or medical therapy may be 
administered to encourage capsule excretion. In some cases of capsule retention, endoscopic 
retrieval or other surgical intervention might be needed.  
In the event that a subject fails to successfully retrieve and return a capsule within 7-14 days 
following ingestion of the study device, or it is suspected by the Principal Investigator that the 
capsule may be retained in the subject’s gastrointestinal system, an abdominal x-ray will be 
performed to determine the location of the capsule. If the x-ray is negative, it will be assumed 
that the subject failed to notice the passage of the capsule during defecation, and that it was 
successfully excreted. If retention of the capsule is determined, appropriate treatment will be 
decided and provided by the Principal Investigator. Depending on the location of the retention, 
the subject’s medical status and potential risks to the subject, removal may be done via 
endoscopic retrieval or via other surgical methods at the discretion of the Principal Investigator. 
Additional Risks 
The additional risks to study subjects are the risks posed from using the bowel preparation and 
post-capsule ingestion drugs in this study: NuLYTELY (or generic version), SuPrep, bisacodyl, 
simethicone and prucalopride (Motegrity). This increased risk has been mitigated by excluding 
subjects from the study who might be at increased risk by using these drugs. Risks of consuming 
NuLYTELY and SuPrep and similar sulfate-based prep as capsule boosters are low and are 
expected to be limited to subject discomfort and mild side effects which are listed below. The 
risk associated with prucalopride is low and is expected to be limited to subject discomfort and 
mild side effects which are listed below.  
NuLYTELY is an osmotic laxative indicated for cleansing of the colon as a preparation for 
colonoscopy in adults 18 years of age or older. 
NuLYTELY is provided for use in this study. (contains polyethylene glycol 3350, sodium 
chloride, sodium bicarbonate, and potassium chloride) is a prescription medicine used by adults 
to clean the colon before a colonoscopy or barium enema X-ray examination. NuLYTELY and 
other osmotic bowel preparations can cause serious side effects, including: Serious loss of body 

 
 
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fluid (dehydration) and changes in blood salts (electrolytes) in your blood. These changes can 
cause: abnormal heartbeats that can cause death, seizures (can happen even if you have never had 
a seizure), or kidney problems. Your chance of having fluid loss and changes in body salts with 
NuLYTELY is higher if you: have heart problems, kidney problems, or take water pills or non-
steroidal anti-inflammatory drugs (NSAIDS). The most common side effects of NuLYTELY 
include nausea, stomach (abdominal) fullness, bloating, stomach (abdominal) cramps, vomiting, 
and anal irritation. 
The use of commercially available, oral solution SUPREP as a booster used in this study. 
SUPREP (sodium sulfate, potassium sulfate and magnesium sulfate) is an osmotic laxative 
indicated for cleansing of the colon as a preparation for colonoscopy in adults. Nausea, vomiting 
abdominal discomfort/cramping and bloating are the most common side effects reported 
(occurring in up to 54% of subjects). Serious but rare side effects include fluid and electrolyte 
abnormalities, seizures, cardiac arrhythmias, renal impairment, and mucosal aphthous 
ulcerations.    
The use of commercially available prucalopride, which is indicated for the treatment of chronic 
idiopathic constipation (CIC) in adults is also used in this study. Prucalopride induces a 
stimulation of contractile activity in the proximal colon and has been shown to stimulate and 
amplify giant migratory contraction, which is the high-amplitude type of contraction that initiates 
the urge to defecate. Thus, prucalopride not only accelerates the colonic transit but also 
accelerates gastric emptying and small bowel transit. In clinical trials, prucalopride was shown to 
significantly increase the spontaneous bowel movements when compared with the placebo 
group. In these studies, as well, it was observed a numerical improvement in mean colonic transit 
time and a significant increase in spontaneous complete bowel movement without marked 
changes in the anorectal function. For purposes of this study, a 2 mg dose is given prior to 
capsule ingestion.  Common adverse reactions reported in clinical trials are headache, abdominal 
pain, nausea, diarrhea, abdominal distension, dizziness, vomiting, flatulence and fatigue, while 
less common adverse reactions occurring in < 2% of subjects receiving prucalopride 2 mg once 
daily include: abnormal gastrointestinal sounds, decreased appetite, migraine, and pollakiuria.  
Adverse reactions of special interest were evaluated in a pool of 28 completed clinical trials (19 
double-blind and 9 open-label) for prucalopride at doses including 0.5 mg, 1 mg, 2 mg, or 4 mg 
per day in adult subjects with CIC (the recommended dosage of prucalopride for CIC is 2 mg 
once daily). The total exposure in the double-blind trials was 565 subject-years in the 
prucalopride group, 384 subject-years in the placebo group, and 2769 subject-years in the double-
blind and open-label clinical trials. 
In an evaluation of prucalopride by an independent adjudication committee of all potential major 
adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial 
infarction, and nonfatal stroke, the standardized incidence rate (IR) per 1000 subject-years for 
MACE for prucalopride was compared with the IR for placebo. In the double-blind trials, the IR 
for MACE was 3.5 (2 subjects out of 3366; 1 subject on 2 mg and 1 subject on 4 mg) in the 
prucalopride group and 5.2 (2 subjects out of 2019) in the placebo group.  
In the double-blind trials, the IR for MACE was 3.5 (2 subjects out of 3366; 1 subject on 2 mg 
and 1 subject on 4 mg) in the prucalopride group and 5.2 (2 subjects out of 2019) in the placebo 
group. When combining the double-blind and open-label trials, the IR for MACE was 3.3 (9 
subjects out of 4472, doses ranging between 0.5 to 4 mg) for prucalopride.  

 
 
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In population with CIC the recommended oral dose regimen for adults is 2 mg once daily, and for 
subjects with severe renal impairment 1 mg once daily (creatinine clearance (CrCL) less than 30 
mL/min) common adverse reactions to prucalopride (2 mg Once Daily; N=1,279) and placebo 
(N=1251):  Headache 19% vs.  9%, Abdominal pain 16% vs. 11%, Nausea 14% vs. 7%, Diarrhea 
13% vs. 5%, Abdominal distension 5% vs. 4%, Dizziness 4% vs. 2%, Vomiting 3% vs. 2% 
Flatulence 3% vs. 2%, Fatigue 2% vs. 1%.  
Additional side effects or adverse events are also possible as a result of the subject taking 
bisacodyl (10 mg/daily). However, side effects caused by bisacodyl when used infrequently and 
at this limited dose are fairly minor and serious effects are rare. 
Bisacodyl is used to relieve occasional constipation and to clean out the intestines before bowel 
examinations. Bisacodyl belongs to a class of drugs known as stimulant laxatives. It works by 
increasing the amount of fluids that enter the bowels, causing bowel movements within 6 to 12 
hours. Short-term usage of bisacodyl at normally- prescribed dosages may result in abdominal 
pain or cramps and rarely nausea or vomiting can occur. Rare side effects and adverse events 
usually associated with higher doses or longer-term use include: rectal bleeding, persistent 
diarrhea, dizziness, decreased urination, muscle cramps and/or weakness, or irregular heart 
rhythms. A very serious allergic reaction to this drug is rare, but possible. Subjects should be 
instructed to seek immediate medical attention if they notice any symptoms of a serious allergic 
reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, 
or trouble breathing, or any of the unusual side effects noted above. 
Simethicone is an over-the-counter medication used to reduce bloating, discomfort or pain caused 
by excessive gas. There are no reports of side effects of this medication and allergic reaction is 
very rare. For this study, simethicone is used the night before and the morning of capsule 
ingestion at 80 mg/dose.  
Subjects may experience identification of otherwise unnoticed abnormality(ies) in the colon by 
swallowing the CapsoCam® prior to having a colonoscopy. It is also possible that subjects may 
not experience a clinical benefit from study participation, however there may be a beneficial 
addition to the body of knowledge for this type of diagnostic tool. 
7. 
MONITORING PROCEDURES 
CapsoVision, Inc. is the Sponsor of this clinical study.  Study monitoring will be performed in 
accordance with CapsoVision, Inc. procedures, or those approved by CapsoVision, Inc.  
CapsoVision, Inc. will have overall management responsibility for this study.  In addition, 
CapsoVision, Inc. will direct regional monitoring staff who may serve as clinical study monitors, 
study administrators, and/or have oversight responsibility for data review and data integrity.   
7.1 Clinical Study Monitors 
CapsoVision Inc. will engage the services of one or more qualified organizations or individuals 
to perform monitoring functions, and provide participating sites with relevant contact 
information, as necessary.  Study monitors may change periodically over the course of this study.  
All monitors will be qualified to perform their assigned responsibilities, and participating 
Investigators/site personnel will be notified of any changes as they occur. 
Due to COVID-19 pandemic, monitoring will occur remotely until limitations of travel and 
mandates for mask use have been lifted at all participating sites.  Monitoring will be frequent 

 
 
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enough to assure continued acceptability of the data by assessing site compliance with the study 
protocol, adherence to data collection procedures, and maintenance of study records.  Scheduled 
monitoring visits will include, but are not limited to, the following:  
• Site initiation visit: prior to enrolling subjects, an initiation visit will be conducted by 
clinical study personnel to review this study protocol and associated study operational 
procedures.   
• Interim monitoring site visit: monitoring visits will be conducted at all sites to assess the 
progress of the study and identify any concerns that result from review of the study 
records, study management documents, or subject informed consent documents.  To 
assure the integrity of the data, a representative number of individual subject records and 
other supporting documents will be compared to CRFs completed at the site to determine 
that: 
o The study protocol is being followed, and only eligible subjects are being enrolled; 
variances, if they occur, are recorded and reported as appropriate. 
o Informed consent is properly documented.  
o Adverse events are being reported appropriately. 
o Information recorded on CRFs is complete, accurate and legible. 
o Subjects failing to complete the clinical study and the reason for failure are 
properly recorded. 
• Final monitoring/Close-out site visit: a close-out visit to participating sites may be made 
by the study monitor, if necessary. Any ongoing responsibilities will be discussed with the 
Investigator and/or site personnel as appropriate.  At the close of the study at an 
investigational site, appropriately trained personnel appointed by the Sponsor will perform 
a close-out process remotely or on-site.  The purpose of this visit is to collect all 
outstanding study data documents, ensure that the Investigator's files are accurate and 
complete, review record retention requirements, ensure final accounting of all study 
devices shipped to the Investigator, provide for appropriate disposition of any remaining 
supplies, and ensure that all applicable requirements are met for the study.  The 
observations and actions made during the visit will be documented and communicated to 
the Investigator 
 
 
 

 
 
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8. 
REFERENCES 
1. 
World J Gastroenterol. 2014 Dec 7;20(45):16948-55. Colon capsule endoscopy: What we 
know and what we would like to know. Spada C, Barbaro F, Andrisani G, Minelli Grazioli 
L, Hassan C, Costamagna I, Campanale M, Costamagna G.  
2. 
Colorectal Dis. 2015 Jan;17 Suppl 1:31-5. Colorectal polyp diagnosis: results with the 
second-generation colon capsule (CCE-2). Rondonotti E, Pennazio M. 
3. 
World J Gastrointest Endosc. 2013 Nov 16;5(11):559-67. PillCam COLON 2 capsule in 
patients unable or unwilling to undergo colonoscopy. Negreanu L, Babiuc R, Bengus A, 
Sadagurschi R. 
4. 
World J Gastroenterol. 2014 Nov 28;20(44):16596-602. Colon capsule endoscopy: current 
status and future directions. Tal AO, Vermehren J, Albert J. 
5. 
Endoscopy. 2014 Jun;46(6):485-92. Epub 2014 Apr 28. Second-generation colon capsule 
endoscopy vs. colonoscopy in pediatric ulcerative colitis: a pilot study.Oliva S, Di Nardo G, 
Hassan C, Spada C, Aloi M, Ferrari F, Redler A, Costamagna G, Cucchiara S. 
6. 
World J Gastrointest Endosc. 2012 Dec 16;4(12):575-8. First PillCam COLON 2 capsule 
images of Whipple's disease: Case report and review of the literature. Mateescu BR, Bengus 
A, Marinescu M, Staniceanu F, Micu G, Negreanu L. 
7. 
Gastrointest Endosc. 2012 Dec;76(6):1170-4. Epub 2012 Sep 29. Accuracy of automatic 
detection of small-bowel mucosa by second-generation colon capsule endoscopy. Adler S, 
Hassan C, Metzger Y, Sompolinsky Y, Spada C. 
8. 
J Clin Gastroenterol. 2012 Sep;46(8):691-5. A survey of potential adherence to capsule 
colonoscopy in patients who have accepted or declined conventional colonoscopy. Rex DK, 
Lieberman DA. 
9. 
United European Gastroenterol. J 2017, Aug: 5(5): 677-686 Capsule retention related to 
small bowel capsule endoscopy: a large European single-center 10-year clinical experience, 
Nemeth A., Johnasson G. W., Nielsen J., Thorlacius H. Toth E. 
10. J Int Med Res. 2016 Aug; 44(4): 968-975 Retention during capsule endoscopy: Is it a 
problem in routine practice? Ormeci A. C. et. al. 
11. Inflamm Bowel Dis 2019 May; (e-publication) Capsule retention in Crohn’s disease: A 
meta-analysis. Pasha S. F. et. al. 
12. De Novo Classification Request for PillCam COLON 2 Capsule Endoscopy System,  
https://www.accessdata.fda.gov/cdrh_docs/reviews/K123666.pdf. 
13. Hassan C, Pickhardt PJ, Kim DH, Di Giulio E, Zullo A, Laghi A, Repici A, Iafrate F, 
Osborn J, Annibale B Systematic review: distribution of advanced neoplasia according to 
polyp size at screening colonoscopy. Aliment Pharmacol Ther. 2010 Jan15; 31(2):210-7; 
Vleugels JLA, Dekker E, Does polyp size matter? 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546901. 2017 Aug; 5(8): E746–E748 
14. Clin Gastroenterol Hepatol. 2014 Aug; 12(8):1303-10. Epub 2014 Jan 5. Accuracy of 
capsule colonoscopy and computed tomographic colonography in individuals with positive 
results from the fecal occult blood test. Rondonotti E, Borghi C, Mandelli G, Radaelli F, 
Paggi S, Amato A, Imperiali G, Terreni N, Lenoci N, Terruzzi V, Baccarin A, Martegani A, 
Spinzi G. 
15. Gut. 2015 Feb;64(2):272-81. Epub 2014 Jun 24. Colon capsule versus CT colonography in 
patients with incomplete colonoscopy: a prospective, comparative trial. Spada C, Hassan C, 
Barbaro B, Iafrate F, Cesaro P, Petruzziello L, Minelli Grazioli L, Senore C, Brizi G, 

 
 
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Costamagna I, Alvaro G, Iannitti M, Salsano M, Ciolina M, Laghi A, Bonomo L, 
Costamagna GBb 
16. Endoscopy 2011, 123-127. A grading scale to evaluate colon cleansing for the PillCam 
COLON capsule: a reliability study. Leighton J. A., Rex D. K. 
17. Clopper, C. and Pearson, S. The use of confidence or fiducial limits illustrated in the case of 
the Binomial. Biometrika 26: 404-413, 1934. 
18. Rui de Sousa Magalhães, Carolina Chálim Rebelo, Bernardo Sousa-Pinto, José Pereira, 
Pedro Boal Carvalho, Bruno Rosa, Maria J. Moreira, Maria A. Duarte & José Cotter (2022) 
CC-CLEAR (Colon Capsule Cleansing Assessment and Report): the novel scale to evaluate 
the clinical impact of bowel preparation in capsule colonoscopy – a multicentric validation 
study, Scandinavian Journal of Gastroenterology, 57:5, 625-632. 
19. N. A. Obuchowski, Multireader receiver operation characteristic studies: a comparison of 
study designs, Acad. Radiol. 1995:2:709-716.  
20. S. L. Hillis and K. M. Schartz, Mulitreader sample size program for diagnostic studies: 
demonstration and methodology, J. Med. Imag. 5(4), 045503 (2018). 
 
 

 
 
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9. 
Appendix A 
APPENDIX A 
 
Summary of Prior Clinical Investigations 
 
CapsoCam® SV-1 Capsule Endoscope Clinical Study 
 
The CapsoCam® SV-1 capsule endoscope has been evaluated in a non-significant risk clinical study in the 
United States and Canada for obtaining 510k clearance from the US FDA per protocol # SV-1. 
 
The CapsoCam® SV-1 Study was a prospective, randomized, comparative multi-center, non-significant risk 
study which enrolled 121 subjects with suspected small bowel disease who were referred for capsule endoscopy. 
All subjects signed the IRB approved informed consent prior to participation.  The study began on January 3, 
2012 and the last subject was enrolled on March 10, 2014. Of these 121 subjects, 120 (99%) subjects continued 
in the study as part of the Intent-to-Treat (ITT) cohort. One hundred fourteen (114, (94%)) subjects made up the 
Per Protocol (PP) cohort defined as subjects who: 1) were part of the ITT cohort; 2) met inclusion and exclusion 
criteria (or received a waiver that allowed enrollment); 3) ingested and retrieved both study capsules; 4) whose 
ingested capsules reached the small bowel; 5) had a primary diagnosis recorded by the video Readers for the 
study; and 6) were without major study protocol violations.  
 
The Intent-to-Treat (ITT) cohort in the study consisted of 51 (42.5%) males and 69 (57.5%) females with a 
mean age of 55.2 years (SD=15.42), median age of 56 years (range 19-85). One hundred four (104 (86.7%)) 
self-identified their race as White. The Per Protocol (PP) cohort subset in the study consisted of forty-seven (47, 
41.2%) males and sixty-seven (67, 58.8 %) females with a mean age of 55.7 years (SD=15.40), median age of 
56.3 years (range 19-85). One hundred (100, 87.7%) self-identified their race as White. 
 
Thirteen (13(11%)) of all enrolled subjects experienced fifteen (15) adverse events as reported by the clinical 
investigational site Investigators. Twelve (12) of these thirteen (13) subjects were included in the ITT analysis 
cohort. 
 
One subject was not included in the ITT analysis cohort because the subject gagged when attempting to ingest 
the capsule endoscopes and, although enrolled, did not continue in the study.  
 
Two (2) subjects reported experiencing two (2) adverse events each with the remaining ten (10) subjects only 
reported experiencing one (1) adverse event each. 
 
Two (2) of the fifteen (15) adverse events were classified as Serious Adverse Events (SAEs). In both subjects 
from the same investigational site, previously undiagnosed bowel obstructions were present. In both subjects, 
retained ingested capsules were retrieved when surgical procedures to correct the bowel obstructions were 
performed. After the surgeries, the Investigator for the site reported no further adverse sequelae for either 
subject. 
 
The remaining adverse events were largely attributed by the site clinical Investigators as due to discomfort 
associated with the administration of the small bowel prep drugs and agents 
 
FDA 510(k) clearance of the CapsoCam SV-1 capsule endoscope (K151635) in February 2016.  
 
CapsoCam® SV-2 Capsule Endoscope Clinical Validation  

 
 
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The CapsoCam® SV-2 capsule endoscope was evaluated in a clinical validation study per the protocol CVN-
CVI-005 for the purpose of validating the safety profile of the SV-2 device and its ability to capture and 
download small bowel images in a manner consistent with the predicate CapsoCam® SV-1 Capsule Endoscopy 
System. The SV-2 Clinical Validation Study was a single center non-significant risk study which enrolled 
subjects with no known or suspected gastrointestinal diseases: “Normal Healthy Volunteers”.  The SV-2 
Clinical Validation Study began on June 11, 2014 and the last subject was enrolled on July 9, 2014. Eleven (11) 
normal healthy volunteers with no known or suspected gastrointestinal disease, seven (7) and four (4) females, 
were enrolled in the study. The mean age of the enrolled subjects was 40 years (range 18 to 71). There were no 
reported adverse events (AEs) in the study.  
 
Subsequent to the clinical validation study, the CapsoCam® SV-2 capsule endoscope has been commercially 
released outside the US since August 2014. Based upon information received to date, the product has performed 
as designed with a safe product performance profile.  
 
The CapsoCam® Plus SV-3 capsule endoscope Clinical Validation  
 
The CapsoVision CapsoCam® Plus (SV-3) capsule endoscope was evaluated in a clinical validation study per 
protocol CVN-CVI-006 for the purpose of validating the safety profile of the CapsoVision CapsoCam® Plus 
(SV-3) capsule device and its ability to capture and download small bowel images in a manner consistent with 
and comparable to the predicate CapsoCam® SV-2 Capsule Endoscopy System. The SV-3 Clinical Validation 
Study was a single center non-significant risk study which enrolled subjects with no known or suspected 
gastrointestinal diseases: “Normal Healthy Volunteers”.  The SV-3 Clinical Validation Study was initiated on 
October 1, 2015 and the fourth phase of enrollment was completed on April 11, 2016. 
 
A total of 49 Subjects, twenty-eight (28) males twenty-one (21) females, were enrolled in the study.  The mean 
age of the enrolled subjects was 37 years (range 19 to 63), were enrolled (Intention to Treat (ITT) population), 
having met the inclusion/exclusion criteria and signed the Informed consent.7 patients were withdrawn from the 
study: 1 subject did not return his capsule to the Sponsor/Investigator, and was believed to have inadvertently 
flushed it down the toilet; 1 subject attempted but could not swallow the CE/gagged after attempting to do so 
over a period of 1 hour, and 5 subjects experienced prolonged gastric retention of the CE such that no small 
bowel images were captured by the CE before it was excreted after the subjects resumed eating post 
procedure.There were no reported adverse events (AEs) in the study. 
 
An analysis of the results on the remaining 47/49 (Per Protocol (PP) population) subjects was presented to the 
FDA to obtain 510(k) clearance of the CapsoCam® Plus (SV-3) capsule endoscope (K161773). Overall, the 
CapsoCam® Plus (SV-3) Validation Study CVN-CVI-006 study results demonstrated that the SV-3 Capsule 
Endoscope, as compared to the earlier generation CapsoCam® SV-1 Capsule Endoscope had comparable 
results. We have concluded from the study that the quality and clinical utility of the CapsoVision CapsoCam® 
Plus (SV-3) CE device is equivalent to that of the predicate device, SV-1 (K151635). 
 
 
Prior Clinical Validation of CapsoVision Colon Capsule 
 
Two previous early pilot studies with the objective to assess the visualization and imaging capability of the 
colon, using an earlier version of the CapsoVision Video Capsule diagnostic system, were performed by 
Professor Jacques Van Dam at Stanford (Protocol CV-001); and by Dr. Michael Draelos located in Highpoint, 
NC and Dr. John Canio located in Roseville, CA (Protocol CVI-002). 
 

 
 
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The study design used with Protocol CV-001 included two cohorts of subjects.  Cohort 1 involved cecum drop 
and Cohort 2 involved oral ingestion.  A total of 11 patients were enrolled in this study between April 1 and 
November 12, 2009.  Eight subjects were enrolled in Cohort 1 and three subjects were enrolled in Cohort 2.  
Evaluation of the capsules returned for assessment for ten subjects (one capsule was lost at Stanford receiving 
department) revealed that bowel cleanliness was not adequate to allow visualization.  Additionally, the desired 
transit time for the capsule of <12 hours was not achieved.  The inadequate bowel cleanliness and resulting 
prolonged capsule transit time were attributable to the absence of commercially available products indicated for 
this purpose in the U.S.  The study was discontinued since the effectiveness target defined as identification of 
95% of polyps with diameter ≥ 10mm, comparable to standard colonoscopy, could not be met.  No 
complications, adverse events or unanticipated adverse device effects were reported during this trial.   
 
The other study (Protocol CVI-002) was initiated to assess the capsule’s safety and visualization and imaging 
capabilities of the colon and the effectiveness of standard bowel preparation.  The study was designed to enroll 
up to 50 subjects who swallowed the capsule following bowel preparation.  A total of 21 patients were enrolled 
in Highpoint, NC between November 30, 2009 and October 14, 2010 and 22 patients were enrolled in Roseville, 
CA between January 8, 2010 and October 1, 2010.  Evaluation of the capsules returned for assessment for the 41 
subjects (two subjects lost the capsule) revealed that bowel cleanliness was not adequate to allow visualization.  
The effectiveness target defined as sufficient visualization of the colon to enable identification of 95% of polyps 
with diameter ≥ 10mm, comparable to standard colonoscopy, could not be achieved. Therefore, the study was 
discontinued for failure to generate meaningful clinical findings.  No complications, adverse events or 
unanticipated adverse device effects were reported during this trial.   
 
The CapsoCam® Colon capsule endoscope Clinical Validation  
Provided below is a summary of prior clinical performance data regarding an earlier iteration of the subject 
device - the CapsoCam® Colon (CV-3). This information is being submitted since the CapsoCam® Colon (CV-
3) is the same capsule as the CapsoCam® Colon (CV-2) version E (CV-2E), with the only exception that the 
CV-3 version also comprises the structured light size measurement technology.  
 
The clinical feasibility evaluations, which are detailed below, were performed using two different clinical 
protocols: CLN-CVI-007 and CLN-CVI-4047. The various iterations of the CapsoCam® Colon (CV-2) device 
were developed with the intention of improving the visualization ability, user friendliness, and manufacturability 
of the device. The iterations primarily consisted of altering the balloon or outer shell design, the enteric coating 
formulation, and/or varying the center of gravity of the capsule.  
 
 

 
 
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Any reproduction in part or whole without the prior written permission of CapsoVision is prohibited. 
 
 
Clinical protocol CLN-CVI-007 
A clinical study was performed based on Clinical protocol CLN-CVI-007.  The clinical study evaluated the 
performance of the CapsoVision CapsoCam® Colon capsule in 59 of 79 total enrolled subjects at one (1) 
Investigational Site. The investigational site obtained the necessary IRB approval prior to enrollment of any 
study subject. The majority of screened subjects were considered eligible for the study. After pre-procedure 
preparation, capsules were ingested and retrieved using the CapsoRetreive® system. Following retrieval of the 
CapsoCam® capsule endoscope, the capsule images were downloaded using the Capsule Data Access System 
(CDAS3) and read by the study Investigator using the CapsoView® Software (CVV). 
 
Of the 59 subjects who ingested versions A, B, C, or D of the CapsoCam® Colon Capsule during the study, 
thirty-five (35) are defined as CapsoCam® Colon Capsule Study Completers who: 1) ingested the version D of 
the CapsoCam® Colon Capsule during the study and 2) had complete and interpretable small bowel imaging 
and imaging of the colonic mucosa. Four (4) subjects not classified as Completers experienced temporary gastric 
or small bowel retention resulting in incomplete or no images of the small bowel and/or of the colonic mucosa. 
One (1) subject not classified as a Completer had uninterpretable images due to technical difficulties with image 
recording. The remaining nineteen (19) not classified as Completers ingested the version A, B, or C of the 
CapsoCam® Colon (CV- 2) Capsule.  
 
The CapsoCam® Colon Capsule Study outcomes and conclusions are based upon analysis of data from the 35 
subjects in the CapsoCam® Colon Capsule Study Completer Cohort defined as subjects who: 1) ingested the 
CV-2 version D of the CapsoCam® Colon Capsule during the study and 2) had complete and interpretable small 
bowel imaging and imaging of the colonic mucosa. The CapsoCam® Colon Capsule version D is the version of 
the capsule for which CE mark is being pursued. 
The conclusions reached through the analysis of the CapsoCam® Colon Capsule Study Completer Cohort are as 
follows:  
Based upon the results of the clinical evaluation in the CapsoCam® Colon Capsule Endoscope Completer 
Cohort (n =35 subjects), the CapsoCam® Colon Capsule Endoscope has been proven to be safe and effective.  
Safety of clinical prescription of the CapsoCam® Colon Capsule Endoscope has been demonstrated by the 
absence of Serious or Unanticipated Adverse Events. There were no capsule retentions defined as subjects 
retaining the capsule after resuming post procedural food ingestion. All capsules in this cohort, and the overall 
per protocol study cohort who ingested (swallowed) study capsules, were excreted. In all cases of capsule 
ingestions and excretions, the deflated balloons remained securely attached to the capsules.  
The subjects experienced few adverse events overall with the exception of a small number of anticipated bowel 
preparation and booster regimen adverse events, for example, nausea, limited episodic vomiting, and modest 
abdominal discomfort. These bowel-preparation related adverse events are known to be possible whenever 
bowel preparations are administered and are well characterized in their manufacturers’ prescription information. 
All bowel preparation and boosters used in the study and possible adverse events were described in the protocol 
and to the subjects during the screening and enrollment phases of the study. Virtually all research subjects found 
the bowel preparation and boosters regimens tolerable and stated that they would be willing to undergo colon 
capsule endoscopy again if prescribed by their physicians. 

 
 
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CONFIDENTIAL - All information contained in this document is confidential and is the property of CapsoVision. 
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Efficacy of the device has been demonstrated by the CapsoCam® Colon Capsule Endoscope meeting the 
objectives of the study as outlined in the protocol defined information to be gained from the study:  
The CapsoCam® Colon Capsule Endoscope captures diagnostic quality images throughout the small bowel and 
colon, provided the subject (patient) follows the bowel preparation and booster regimen instructions defined for 
optimal use of the capsule. The capsule operational time has been demonstrated to be adequate for the capsule to 
capture both small bowel and colon images during the diagnostic evaluation. And, finally, recorded images are 
successfully downloaded using the Capsule Data Access System (CDAS3) utilizing the current versions of the 
CapsoView® Software (CVV) in both Mac and PC formats and thus available for physicians to review and 
interpretation of clinical results. 
Clinical protocol CLN-CVI-4047 
The CapsoCam® Colon (CV-2) study is currently being conducted based on clinical protocol CLN-CVI-4047 at 
one (1) investigational site, with the intended use of visualizing the colon mucosa. The clinical feasibility study, 
with anticipated completion Q4-2020, evaluates the performance of the CapsoCam® Colon (CV-2) (versions D-
G). The investigational site obtained the necessary IRB approval prior to enrollment of study subjects. The 
majority of screened subjects have been eligible for study participation. After pre-procedure preparation, 
capsules were ingested and retrieved using the CapsoRetreive® system. Following retrieval of the CapsoCam® 
Colon (CV-2), the capsule images were downloaded using the Capsule Data Access System (CDAS) and read 
by the study Investigator using the CapsoView® Software (CVV).  
As of 4/23/2023, the clinical study has evaluated the performance of the CapsoCam® Colon (CV-2) in three 
hundred ninety-seven (397) subjects, defined as subjects who were initially screened and signed the study 
consent form. Of these 397 consented subjects, three hundred sixty-nine (369) subjects ingested the 
CapsoCam® Colon (CV-2) during the study. Two hundred forty-four (244) of the 369 subjects (66.1%) excreted 
within the targeted time of 24 hours and had interpretable imaging of the colonic mucosa.  
There were no capsule retentions after resuming post procedural food ingestion and all capsules were excreted 
with the balloons still securely attached. The subjects experienced few adverse events overall with the exception 
of a small number of anticipated bowel preparation and booster regimen adverse events; for example, nausea, 
limited episodic vomiting, and modest abdominal discomfort. These bowel-preparation related adverse events 
are known to be possible whenever bowel preparations are administered and are well characterized in their 
manufacturer’s prescription information. In addition, one subject had an allergic reaction to the bowel 
preparation (MoviPrep). The patient was administered Benadryl in the emergency room and withdrew from the 
study before ingesting the capsule. Virtually all other research subjects found the bowel preparation and boosters 
regimens tolerable and stated that they would be willing to undergo colon capsule endoscopy again, if 
prescribed by their physicians.  
The recorded images from all capsules were successfully downloaded using the Capsule Data Access System 
(CDAS) utilizing the current versions of the CapsoView® Software (CVV) and thus available for the 
independent readers to review and evaluate the imaging quality. Based on the independent reader reports, who 
rated each region of the colon with a segment score from 0-3 (where anything above 2 is considered adequate), 
the CapsoCam® Colon (CV-2) captures diagnostic quality images throughout the colon (and the small bowel), 
provided the study subject follows the bowel preparation and booster regimen instructions defined for optimal 
use of the capsule.  
In addition, the capsules target operational life (as outlined in the Device Description, Section 3) exceeded the 
total transit times for the one-hundred-forty-nine (149) of the 190 subjects (78.4%) in the CapsoCam® Colon 
(CV-2) Study Completer Cohort.  
Based upon the interim results of the clinical evaluation of the CapsoCam® Colon (CV-2) Completer Cohort (n 
=149 subjects), outlined above, the outcome demonstrates preliminary safety of clinical administration of the 
CapsoCam® Colon (CV-2) versions, as shown by the absence of serious or unanticipated adverse events, and 
effectiveness.  

 
 
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CONFIDENTIAL - All information contained in this document is confidential and is the property of CapsoVision. 
Any reproduction in part or whole without the prior written permission of CapsoVision is prohibited. 
 
Finally, out of the 190 subjects who ingested CapsoCam® Colon (CV-2), fifty-seven (57) subjects ingested 
CapsoCam® Colon (CV-2) version E, which as discussed above, is exactly the same capsule as CapsoCam® 
Colon (CV-3), with the only exception that the CV-3 version also comprises the structured light size 
measurement technology. The remaining one-hundred-thirty-three (133) subjects ingested one of the other 
CapsoCam® Colon (CV-2) versions (D, F, or G). 
 
Clinical protocol CLN-CVI-5248 
This pilot study was undertaken to assess the safety and performance of the CapsoCam® Colon capsule and 
inform the larger planned, Pivotal study. One hundred-twelve subjects (112) were enrolled (ingested the 
capsule) at five (5) investigational sites including locations in California, Florida, Michigan and Ohio. More site 
details are located in Table 1. One hundred-ten capsules (110) were returned after ingestion. Two (2) capsules 
were lost in the study (1 by mail courier, 1 subject failed to use the retrieval kit), two (2) subjects did not 
complete colonoscopy after capsule swallow (1 withdrawal, 1 anesthesia contraindicated arrhythmia). Two (2) 
capsule videos contained images that were too dim to be of diagnostic quality due to capsule malfunction and 
were deemed technical failures. One site failed to capture any colonoscopy images or video or provide usable 
polyp size estimates in one (1) subject leading to exclusion. Intent-to-treat analysis includes all 112 subjects, per 
protocol analysis includes 105 subjects. 
The largest polyps (which are >6 mm) on colonoscopy were compared to capsule findings according to size and 
location. A match for a subject was considered to have occurred if the largest (reference) polyp > 6 mm 
identified on colonoscopy was matched by size (+ 50%) and location (same or adjacent colon segment) with a 
polyp identified on capsule video. Positive Percent Agreement (sensitivity) and Negative Percent Agreement 
(specificity) were calculated for each reader. The overall PPA/NPA for polyps >6 mm for 105 subjects were 
84.8% and 92.7% respectively with a prevalence of 21.9%. Overall PPA/NPA for polyps >10 mm were 87.5% 
and 99.0% respectively with a prevalence of 7.6%. Detection of sessile serrated polyps > 6mm was also 
analyzed and PPA was 87.5% for both readers with a prevalence of 3.8% in the study. The 95% confidence 
interval (CI) for PPA for polyps > 6 mm was 71.1 - 98.5%.  
Complete examination was considered to have occurred when readers were able to visualize excretion. 
Complete examination was assessed for all returned capsules (110) and was shown to occur in 76% of study 
participants. In two instances the capsules were removed during next day colonoscopy, while still recording and 
thus were not considered to be complete examinations. 
Capsule safety was confirmed with no reports of device related adverse events, serious adverse events or 
unanticipated adverse device effects. All events and observations reported in the study were not related to the 
study or related to medications for bowel preparation or to the prokinetic boosters.  There were no serious 
adverse events reported for bowel preparation or booster consumption.  
Based on the results of the study, the safety profile remains the same CapsoCam Colon capsule.