Gastroenterology Artificial INtelligence System for Detecting Colorectal Polyps (The GAIN Study)
Phase: NA
Conditions: Colon Adenoma, Colon Polyp, Colon Lesion
Sponsor: Verily Life Sciences LLC

Cover Page
Study Title
Gastroenterology Artificial INtelligence System for
Detecting Colorectal Polyps (The GAIN Study)
Rev/Date
Rev C / 29Jul2022
Sponsor Name
Verily Life Sciences
NCT #
NCT05275556

CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
colorectal polyps (The GAIN Study)
Document Number: 103820 Rev C
DCO Number: DCO-04256
Study Title
Gastroenterology Artificial INtelligence System for Detecting Colorectal Polyps
(The GAIN Study)
Protocol Number
103820
Version
Rev C
Sponsor Name
Verily Life Sciences
Sponsor Address
269 E. Grand Ave, South San Francisco, CA 94080
Sponsor Contacts
Leera Choi
Clinical Trial Manager
leerac@verily.com
(650) 253-0000
269 East Grand Avenue
South San Francisco, CA 94080
Simon Schlachter, PhD
Clinical Scientist
schlachter@verily.com
(650) 253-0000
269 East Grand Avenue
South San Francisco, CA 94080
Scooter Plowman, MD
Physician Lead
splowman@verily.com
(650) 253-0000
269 East Grand Avenue
South San Francisco, CA 94080
Regulatory Identifiers
IDE number: Not Applicable
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CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
colorectal polyps (The GAIN Study)
Document Number: 103820 Rev C
DCO Number: DCO-04256
Protocol
Investigator’s Agreement Signature Page
I, Principal Investigator, agree to conduct this study in accordance with the International
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals
for Human Use (ICH) guideline for Good Clinical Practice (GCP), applicable legal and
regulatory requirements, and in compliance with the provisions of this Protocol.
I am responsible for ensuring that the investigation is conducted according to this protocol
and for protecting the rights, safety, and welfare of the research subjects. All personnel
involved in the conduct of this study will complete Human Subject Protection training.
I agree to ensure that all staff members involved in the conduct of this study are informed
about their obligations in meeting the above commitments.
Principal Investigator
Signature
Date
Confidentiality Statement
The information in the following document is provided to you as an investigator, potential investigator, or
consultant, for review by you, your staff, and applicable Institutional Review Board, and is considered confidential.
It is understood that the information will not be disclosed to others without written authorization from Verily Life
Sciences LLC, except to the extent necessary to obtain informed consent from those persons to whom the
product may be administered.
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CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
colorectal polyps (The GAIN Study)
Document Number: 103820 Rev C
DCO Number: DCO-04256
Table of Contents
Protocol Summary
5
Version History
8
Prior Experience
8
Study Background and Rationale
9
Study Design
10
Overview
10
Study Objectives and Endpoints
10
Primary Endpoint(s)
11
Secondary Endpoints
11
Exploratory Endpoints
13
Comparator or Control Groups
13
Study Population
13
Sample Size and Number of Participating Sites
13
Inclusion Criteria
13
Exclusion Criteria
14
Discontinued/Withdrawal of Study Subjects
14
Study Assessment Plan and Methods
15
Schedule of Study Procedures Table
15
Study Conduct and Procedures
15
Screening/Screen Failures
15
Enrollment
16
Randomization/Blinding/Masking
16
Subject Compensation
16
Visit Schedule
16
User Experience
19
Investigational Product
19
Adverse Events
19
Protocol Deviations
19
Test Procedures
19
Laboratory parameters
19
Special Methodologies and Evaluations
19
Risk Analysis
20
Risk Analysis
20
Benefits
20
Risks
20
Adverse Events (AE), Serious Adverse Events (SAE), and Unanticipated Problems
21
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CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
colorectal polyps (The GAIN Study)
Document Number: 103820 Rev C
DCO Number: DCO-04256
Adverse Events
21
Serious Adverse Events
21
Unanticipated Adverse Device Effects (UADE)
21
Device Deficiencies
22
Investigational Product(s)/Medical Device
22
Investigational Product(s)/Device Description
22
Control Product/Device Description
24
Investigational Device Labeling & Accountability
25
Regulatory, Ethical and Study Oversight Considerations
25
Regulatory and Ethical Considerations
25
Financial Disclosure
26
Informed Consent Process
26
Data Protection
26
Interim Analysis Structure
26
Data Quality Assurance
27
Source Documents
27
Study and Site Closure
28
Publication Policy
28
Statistical Considerations
28
Appendices
29
References
29
Glossary
31
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CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
colorectal polyps (The GAIN Study)
Document Number: 103820 Rev C
DCO Number: DCO-04256
1.
Protocol Summary
Study Sponsor
Verily Life Sciences
Study Description
This is a prospective, multicenter, randomized controlled study to evaluate the effect of the
Endoscopy
Video
Assistant
for
Colonoscopy
(EVA-C)
System
on
Adenomas
Per
Colonoscopy and Positive Percent Agreement for routine colonoscopies. The control arm is
colonoscopy performed with High Definition White Light Endoscopy (HD-WLE) per standard
of care. The intervention arm is colonoscopy performed with HD-WLE per standard of care
plus the EVA-C System.
Study Objectives
Primary Objective
●
To evaluate the effect of High Definition White Light Endoscopy with the EVA-C
System on Adenomas Per Colonoscopy and Positive Percent Agreement relative to
standard High Definition White Light Endoscopy alone.
Secondary Objectives
●
To evaluate the effect of High Definition White Light Endoscopy using the EVA-C
System on Adenoma Detection Rate, False Alert Rate, Mean Withdrawal Time, and
other endpoints related to polyp location, size, morphology, and histopathology.
Study Endpoints
Co-Primary Endpoints
●
Difference in Adenomas Per Colonoscopy (APC) between the control and
intervention arm, evaluated for superiority on the Intent To Treat (ITT) population
●
Difference in Positive Percent Agreement (PPA) between the control and
intervention arm, evaluated for non-inferiority on the Intent To Treat (ITT)
population
Secondary Endpoints
●
Adenoma Detection Rate (ADR) evaluated on the ITT population
●
APC, ADR and PPA endpoints evaluated on the Per-Protocol (PP) population
●
APC, ADR and PPA endpoints evaluated on a modified Intent-to-Treat (mITT)
population
●
APC, ADR and PPA in subgroups defined by age group, sex, risk-group, race,
ethnicity, colonoscopist, site, and country
●
False Alert Rate (FAR)
●
Mean Withdrawal (inspection) Time (MWT)
●
Polyp Detection Rate (PDR)
●
Proximal Adenoma Detection Rate (pADR)
●
Flat Adenoma Detection Rate (fADR)
●
Serrated Lesions per Colonoscopy (SLPC)
●
Serrated Lesions Detection Rate (SLDR)
●
Adenoma Detection Rate including Carcinoma (ADR*)
●
Small Adenoma Detection Rate (sADR)
●
Polyps per colonoscopy (PPC)
●
Advanced Adenoma Detection Rate (aADR)
●
False Positive Rate (FPR)
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CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
colorectal polyps (The GAIN Study)
Document Number: 103820 Rev C
DCO Number: DCO-04256
Exploratory Endpoints
●
User fatigue
●
Changes to Colorectal Cancer (CRC) surveillance intervals
Study Phase
Not applicable
Study Type
This is a prospective multicenter, randomized controlled study.
Regulatory
Status/Trial
Classification
Non-significant risk
Study Population
A minimum of 1,200 subjects will be enrolled at a minimum of 3 sites, with a possibility of a
sample size increase up to 2,400. At least 51% of the study population will be enrolled
within the United States.
User population
Colonoscopists having performed at least 1,000 colonoscopies with a self-reported
Adenoma Detection Rate between 25% and 40%. No single colonoscopist will enroll more
than 15% of the total patient population.
Description of
Study Intervention
Subjects in the intervention arm will undergo a routine clinically-indicated colonoscopy
using HD-WLE in conjunction with the EVA-C System. The control group will also undergo a
routine clinically-indicated colonoscopy using HD-WLE not aided by the EVA-C System.
The EVA-C System is designed to detect polyp-like morphologies. It does not differentiate
between adenomatous and hyperplastic polyps. It is up to the colonoscopist’s discretion,
based on all available information, to decide whether to resect a given polyp, irrespective of
the presence of an EVA-C System bounding box. The EVA-C System is not intended to
change the colonoscopist’s management of an identified lesion.
Subject Duration
The subject duration is approximately 1-2 hours, including informed consent process and
colonoscopy procedure. There is no follow-up required.
Procedure
Colonoscopy procedure
●
High Definition White Light Endoscopy will be used, per standard of care.
●
Dye-based or virtual chromoendoscopy may be used for characterizing individual
polyps at the colonoscopist's discretion, but may not be used for overall inspection
of the colon.
●
Bowel preparation will be evaluated after cleaning and will be scored using the
Boston Bowel Preparation Scale (BBPS) separately in each of the three regions of
the colon: the right colon (including the cecum and ascending colon), the
transverse colon (including the hepatic and splenic flexures), and the left colon
(including the descending colon, sigmoid colon, and rectum).1 Subjects with a
BBPS score of 0 or 1 in any of the three colonic regions of the colon will be
excluded from the Per Protocol analysis.
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CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
colorectal polyps (The GAIN Study)
Document Number: 103820 Rev C
DCO Number: DCO-04256
●
In the right, transverse, and left colon, lesions are to be removed, at the
colonoscopist’s discretion, per standard of care. Notably, in the left colon, only
those lesions that appear adenomatous are to be removed, per standard of care.
In the intervention arm only:
●
The EVA-C System does not differentiate between adenomatous and hyperplastic
polyps. It is designed to identify polyp-like morphologies. It is up to the
colonoscopists’ discretion, based on all available information, to decide whether to
resect a given polyp or lesion, irrespective of the presence of the EVA-C System
bounding box. The EVA-C System is not intended to change the colonoscopist’s
management of an identified polyp or lesion.
●
The colonoscopist is expected to interrogate any region of interest highlighted by
the EVA-C System bounding box.
●
In the right, transverse, and left colon, lesions are to be removed, at the
colonoscopist’s discretion, and irrespective of the EVA-C System bounding box, per
standard of care. Notably, in the left colon, only those lesions that appear
adenomatous are to be removed, per standard of care.
●
For bounding boxes that persist on the screen for at least 2-3 seconds (per
colonoscopist’s discretion)
but do not contain a polyp, the colonoscopist will
verbally confirm a ‘false alert’ to the study personnel.
Polyp resection and pathology processing:
●
Endoscopic images of each polyp will be acquired before polyp removal.
●
Study personnel will record the polyp size (≤5 mm, 6-9 mm, ≥10 mm), location
(cecum,
ascending,
hepatic flexure, transverse, splenic flexure, descending,
sigmoid, rectum), and morphology (Pedunculated 0-Ip, Sessile 0-Is, Flat 0-IIa, or
Depressed 0-IIc in accordance with Paris classification²), as reported by the
colonoscopist.
●
Study personnel will record the time-of-day at the moment the colonoscopist says
‘snare closed’ (or as the snare is closed) and each polyp will be assigned a number
or letter in the sequential order in which it is removed (eg. 1, 2, 3,… or A, B, C, …) per
standard of care.
●
If the polyp is not able to be retrieved, the study personnel will note ‘not retrieved’ in
the source documentation.
●
Each polyp will be placed into an individually labeled specimen jar with only one
polyp per specimen jar. If a polyp trap is used on the endoscope, the polyp trap
needs to be advanced/rotated for each new resected polyp.
●
The specimen jar will be labeled with the sequential number or letter correlating to
the order in which the polyp was removed (eg. 1, 2, 3,… or A, B, C,...) per standard
practice.
●
The pathology report will note each sequential polyp number or letter and location
per standard practice.
Inclusion Criteria
●
Scheduled
to
undergo
routine
screening
(including,
but
not
limited
to,
FIT/Cologuard positive), routine surveillance (≥3 years as scheduled since last
colonoscopy), or diagnostic (symptomatic) colonoscopy with High Definition White
Light Endoscopy.
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CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
colorectal polyps (The GAIN Study)
Document Number: 103820 Rev C
DCO Number: DCO-04256
●
Between the ages of 45 and 80 years, inclusive
●
Able and willing to provide written informed consent
Exclusion Criteria
●
Self-reported pregnancy
●
Known diagnosis of Colorectal Cancer
●
History of, or referral for, Inflammatory Bowel Disease
●
Previous surgery involving the colon or rectum
●
Referral for known polyp or assessment of post-polypectomy site (i.e. less than 3
years since last colonoscopy).
●
High suspicion or diagnosis of genetic polyposis syndromes, including familial
adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC),
or any other high-risk family history meeting Bethesda guidelines.3
●
Referral for overt, symptomatic gastrointestinal bleeding
2.
Version History
Version
Date
Rev A
05-Nov-2021
Rev B
29-Nov-2021
Rev C
29-Jul-2022
3.
Prior Experience
3.1.
Existing published benchtop and clinical results
The development and testing of the neural networks used for polyp detection in the Endoscopy
Video Assistant for Colonoscopy (EVA-C) System has recently been published in Gastrointestinal
Endoscopy4, a peer-reviewed journal. This publication describes how the neural networks were
trained to detect polyps in High Definition White Light Endoscopy videos, and reports out the
subsequent retrospective and prospective clinical testing that was performed.
To train the neural networks that underlie the EVA-C System, 3,611 colonoscopy videos, drawn
from 2,487 unique patients were labeled by three board-certified gastroenterologists, who placed
bounding boxes around any polyps that were found. This labeled dataset allowed parameters of
the neural networks to be optimized such that the networks detected polyp-like tissue structures
in High Definition White Light Endoscopy videos with high sensitivity.
To test the performance of the trained networks, a separate and independent validation set of
1,393 videos from 1,181 patients was used. The system demonstrated a sensitivity of 97.1% for
detecting polyps in the validation dataset. This was combined with a per-frame false alarm rate of
0.23%, which corresponds to an average of 4.6 false ‘alerts’ per procedure.
Finally, a prospective 100-patient pilot study was conducted at Shaare Zedek Medical Center in
Jerusalem using the system (clinicaltrial.gov ID:NCT04693078). This study demonstrated that the
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CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
colorectal polyps (The GAIN Study)
Document Number: 103820 Rev C
DCO Number: DCO-04256
system detected an additional 0.89 polyps per procedure that were not detected by the
colonoscopist. There were 3.87 false ‘alerts’ per procedure on average, and no adverse events
were recorded.
3.2.
Summary
In summary, the EVA-C System has positive safety and efficacy data from existing benchtop and
clinical studies. The details of EVA-C testing to ensure conformance with the standards and
guidance documents are noted in the Investigator’s Brochure.
4.
Study Background and Rationale
4.1.
Background
Reductions in the incidence of colorectal cancer (CRC) and age-related mortality have long been
demonstrated through population-based screening programs.5,6 Of these, regular cadence
colonoscopy exams are the preferred cancer prevention screening test, for concurrent detection
and removal of suspicious neoplasms.7,8
However, approximately 25% of adenomas and serrated polyps (primarily those ≤10mm) are
missed during screening colonoscopies.9,10
The primary quality indicator relied upon by colonoscopists performing colonoscopies is
adenoma detection rate (ADR)11,12, defined as the percentage of patients undergoing screening
colonoscopy who have one or more conventional adenomas detected and removed. Another
important quality metric, particularly applicable to CADe technologies, is Adenomas Per
Colonoscopy (APC), which is defined as the average number of histologically confirmed
adenomas resected per colonoscopy. Polyp recognition or the failure to optimally recognize
polyps is a major factor contributing to ADR and APC.13,14
Computer-aided polyp detection (CADe) systems show the ability to enhance polyp detection and
recognition, thereby positively impacting ADR and APC.15,16 Estimates report that every 1%
increase in ADR lowers the risk of interval colorectal cancers by 3%-6%.17 As such there is great
importance in studying and developing CADe systems to enhance the diagnostic performance of
screening colonoscopy, particularly as the recommended screening age in the United States has
been reduced from 50 to 458, increasing the overall screening population.
There are multiple factors preceding missed polyps. Operator related factors including skill level,
fatigue, and distraction, are known and reported previously.18 Patient related factors include age,
gender, and quality of bowel preparation. Algorithmic CADe solutions represent an attractive
option to proactively mitigate some of these factors, and have the potential to improve polyp and
adenoma detection in real-time.
4.2.
Rationale
The clinical performance of the EVA-C System was previously tested in a prospective 100 patient
pilot study where the use of the device was determined to increase the polyp detection rate in a
colonoscopy practice outside of the United States.4 The present global multicenter, randomized,
controlled study is designed to determine the clinical performance of the EVA-C System
compared
to
standard-of-care
colonoscopy
in
patients
undergoing
clinically
indicated
colonoscopy. The co-primary outcomes of the study are to measure the difference in APC and
PPA between routine colonoscopy procedures and those assisted by the EVA-C System. The
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CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
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Document Number: 103820 Rev C
DCO Number: DCO-04256
results of this study will provide further insight into the clinical impact of the use of the EVA-C
System during colonoscopy.
5.
Study Design
5.1.
Overview
This is a prospective, multi-center, randomized controlled study.
5.2.
Study Objectives and Endpoints
This study will evaluate the effect of the EVA-C System on Adenomas Per Colonoscopy and
Positive Percent Agreement for routine colonoscopies. The control arm is colonoscopy with High
Definition White Light Endoscopy (HD-WLE) per standard of care. The intervention arm is
colonoscopy with HD-WLE per standard of care plus the EVA-C System.
Adenomas Per Colonoscopy (APC) is defined as the average number of histologically confirmed
adenomas resected per colonoscopy.
The following findings are considered positive for the definition of APC, ADR, and other
adenoma-related secondary endpoints (where specified):
●
Adenoma
●
Tubular adenoma
●
Tubulovillous
●
Villous
●
High Grade Dysplasia
The following pathology findings are not considered positive for the definition of APC and ADR,
and other adenoma-related secondary endpoints (where specified):
●
Serrated-class lesions:
○
Hyperplastic polyps (HPs)
○
Sessile serrated lesions (with or without dysplasia) (SSLs)
○
Traditional serrated adenomas (TSAs)
●
Inflammatory, lymphoid aggregate, normal mucosa
Positive Percent Agreement (PPA) is defined as the total number of histologically confirmed
Clinically Significant Excised Lesions, divided by the total number of excisions.
For calculating PPA, Clinically Significant Excised Lesions are defined as follows:
●
Neoplastic lesions (Adenoma, Tubular adenoma, Tubulovillous, Villous, High Grade
Dysplasia, Intramucosal carcinoma, Adenocarcinoma);
●
Serrated-class
lesions
classified
according
to
the
WHO
serrated-class
lesion
classification below;
●
Hyperplastic polyps of the proximal colon (caecum, ascending colon, hepatic flexure,
transverse colon)
According to the World Health Organization (WHO), serrated-class lesions are currently classified
into three main categories as follows:
●
Hyperplastic polyps
●
Sessile serrated lesions (with or without dysplasia), and
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CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
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Document Number: 103820 Rev C
DCO Number: DCO-04256
●
Traditional serrated adenomas
5.3.
Primary Endpoint(s)
●
Both co-primary endpoints are evaluated on the Intent to Treat (ITT) population.
●
Adenomas Per Colonoscopy Co-Primary Endpoint
Difference in Adenomas Per Colonoscopy (APC) between the control and intervention
arm, evaluated for superiority.
The APC co-primary endpoint is a test of superiority. The null and alternative hypotheses
for establishing superiority are as follows, where APC(I) and APC(C) are Intervention and
Control arms APCs respectively:
Ho: APC(I) < APC(C)
Ha: APC(I) > APC(C)
A statistical test of this hypothesis will be conducted.
●
Positive Percent Agreement (PPA) Co-Primary Endpoint
Difference in Positive Percent Agreement (PPA) between the control and intervention
arm, evaluated for non-inferiority.
The PPA co-primary endpoint is a non-inferiority comparison based on the difference in
PPA across arms. For non-inferiority, the goal of the study is to show that the effect of
Intervention (I) is not inferior to the effect of Control (C) by a pre-specified amount, i.e.,
the NI margin (M). The null and alternative hypotheses are as follows:
Ho: PPA(I) – PPA(C)
M (I is inferior to C)
≤
Ha: PPA(I) – PPA(C)
M (I is not inferior to C)
>
A statistical test of Ho will compare the lower bound of the two sided 95% confidence
interval for PPA(I)–PPA(C) with M, which is pre-specified as -10%. If the lower bound lies
above M, non-inferiority of I relative to C will be established.
●
As co-primary endpoints, there are no issues related to multiple testing as both tests
must successfully reject H0 in order to declare overall endpoint success.
5.4.
Secondary Endpoints
●
Adenoma Detection Rate (ADR)
The Adenoma Detection Rate is defined as the number of patients with at least one
histologically confirmed adenoma (the pathology findings that count as positive for
adenoma are defined in Section 5.2) divided by the total number of patients enrolled per
study arm.
●
Evaluation of ADR on the ITT population
●
Evaluation of the APC, ADR and PPA endpoints on the Per-Protocol (PP) population
●
Evaluation of the APC, ADR and PPA endpoints on a modified Intent-to-Treat (mITT)
population that includes only patients in the Screening and Surveillance risk groups
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CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
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Document Number: 103820 Rev C
DCO Number: DCO-04256
●
Subgroup analysis of APC, ADR and PPA in groups defined by age group, sex, risk-group,
site, race, ethnicity, colonoscopist, site, and country
●
False Alert Rate (FAR)
A false alert is defined as a bounding box that persists on the screen (approximately 2-3
seconds per the judgment of the colonoscopist) that is then determined by the
colonoscopist not to contain a polyp. The false alert rate is calculated as the number of
false alerts per procedure conducted in the intervention arm of the study.
●
Mean Withdrawal and Inspection Time (MWT)
The withdrawal time is defined as the time measured from the moment the withdrawal
phase of the procedure begins (with the scope in the cecum) to the moment the scope is
withdrawn from the patient. The mean Inspection time measurement (also called net
withdrawal time) will exclude resection time, and other peri-resection activity not deemed
to be colonic inspection. Inspection times for both the control arm and intervention arm
will be calculated retrospectively upon review of the video recordings.
●
Polyp Detection Rate (PDR)
Polyp detection rate is defined as the proportion of patients with at least one
histologically-confirmed polyp detected.
●
Proximal Adenoma Detection Rate (pADR)
pADR is defined as the proportion of patients with at least one histologically-confirmed
adenoma (the pathology findings that count as positive for adenoma are defined in
Section 5.2) detected in proximal colon (caecum, ascending colon, hepatic flexure,
transverse colon).
●
Flat Adenoma Detection Rate (fADR)
fADR is defined as the proportion of patients with at least one histologically-confirmed
non-polypoid adenoma (the pathology findings that count as positive for adenoma are
defined in Section 5.2) detected;
●
Serrated Lesions per Colonoscopy (SLPC)
SLPC is defined as the number of histologically confirmed serrated lesions detected,
divided by the total number of colonoscopies
●
Serrated Lesions Detection Rate (SLDR)
SLDR is defined as the proportion of patients with at least one histologically confirmed
serrated lesion detected
●
Adenoma Detection Rate including Carcinoma (ADR*)
ADR* is defined as ADR (see above), but also includes histologically-confirmed
intramucosal carcinoma and adenocarcinoma.
●
Small Adenoma Detection Rate (sADR)
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sADR is defined as proportion of patients with at least one adenoma 5mm or smaller
detected (the pathology findings that count as positive for adenoma are defined in
Section 5.2);
●
Polyps per Colonoscopy (PPC)
PPC is defined as the total number of histologically-confirmed polyps found divided by
the total number of colonoscopies performed, per study arm.
●
Advanced Adenoma Detection Rate (aADR)
aADR is defined as the proportion of patients with at least one adenoma (the pathology
findings that count as positive for adenoma are defined in Section 5.2) ≥10 mm, or any
adenoma < 10 mm, which was either of high-grade dysplasia (HGD) or villous or
tubulovillous;
●
False Positive Rate (FPR)
Defined as the proportion of colorectal lesions resected or biopsied and subsequently not
histologically-confirmed to be clinically relevant colorectal polyps (e.g. a pathology
finding of normal mucosa, inflammatory tissue, stool or debris, lymphoid aggregates)
5.5.
Exploratory Endpoints
●
User Fatigue
We will assess (a) whether there is detectable drop in user performance with time of day
or other fatigue measure, and (b) whether use of the EVA-C System mitigates
fatigue-associated declines in performance, as measured by PPC, APC, or other
measures.
●
Changes to Colorectal Cancer (CRC) surveillance intervals
We will assess whether the device resulted in a change to the CRC surveillance intervals.
5.6.
Comparator or Control Groups
Patients randomized to the control arm of the study will undergo a standard-of-care colonoscopy
procedure (using High Definition White Light Endoscopy) without the EVA-C System turned on.
6.
Study Population
6.1.
Sample Size and Number of Participating Sites
A minimum of 1,200 subjects will be enrolled at a minimum of 3 sites, with a possibility of a
sample size increase up to 2,400. At least 51% of the study population will be enrolled within the
United States.
6.2.
Inclusion Criteria
Prospective subjects must meet all of the following criteria to be eligible for participation in the
study:
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1.
Scheduled to undergo routine screening (including, but not limited to, FIT/Cologuard
positive), routine surveillance (≥3 years as scheduled since last colonoscopy), or
diagnostic (symptomatic) colonoscopy with High Definition White Light Endoscopy
2.
Between the ages of 45 and 80 years, inclusive
3.
Able and willing to provide written informed consent
6.3.
Exclusion Criteria
Prospective subjects must be excluded from participation in this study if any of the following
criteria are met:
1.
Self-reported pregnancy
2.
Known diagnosis of Colorectal Cancer
3.
History of, or referral for, Inflammatory Bowel Disease
4.
Previous surgery involving the colon or rectum
5.
Referral for known polyp or assessment of post-polypectomy site (i.e. less than 3 years
since last colonoscopy).
6.
High
suspicion
or
diagnosis of genetic polyposis syndromes, including familial
adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), or
any other high-risk family history meeting Bethesda guidelines
7.
Referral for overt, symptomatic, gastrointestinal bleeding
6.4.
Discontinued/Withdrawal of Study Subjects
Participation in this research study is voluntary and subjects may withdraw at any time. In the
event the subject chooses to withdraw, he/she will be instructed to contact the Investigator
immediately and may be asked the reason for their withdrawal from the study. The subject may
also be terminated from the research study at any time if the Investigator considers it to be in
his/her best medical interest. The Investigator may withdraw the subject any time due to the
non-compliance with respect to the provisions of the protocol. If a subject withdraws prior to
study completion, no new health information identifying him/her will be gathered after that date.
Information that has already been gathered may still be used and given to others. Subjects will be
informed of any new significant information regarding new findings related to the study device
that may develop during the course of the study that may be related to his/her willingness to
continue participation as a research subject.
Subjects will either satisfactorily complete all requirements set forth in the Clinical Investigation
Plan or their participation in the clinical study will be prematurely terminated. The completion of a
subject’s participation in the study or early departure from the study, including reasons for early
discontinuation, will be fully documented on the appropriate case report form.
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CPR, Protocol, Gastroenterology Artificial INtelligence System for detecting
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Document Number: 103820 Rev C
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7.
Study Assessment Plan and Methods
7.1.
Schedule of Study Procedures Table
Proceduresa
Screening
Enrollment
Control
(Colonoscopy)
Intervention
(Colonoscopy +
EVA-C System)
Informed Consent
✔
Inclusion/Exclusion Criteria
✔
Medical History
✔
Demographics
✔
Current Medications
✔
Randomization
✔
✔
Colonoscopy
✔
✔
Colonoscopy Recording
✔
✔
Device Accountability
✔
Histology
✔
✔
Adverse Event Evaluation
✔
✔
Protocol Deviation Evaluation
✔
✔
Device Deficiency Evaluation
✔
a Case Report Forms not limited to the below listed data
7.2.
Study Conduct and Procedures
The study is conducted in accordance with this clinical investigational plan and ethical principles
consistent with GCP and applicable regulatory requirements to protect the rights, safety, and
well-being of the study subjects.
Prior to any study-related procedures, informed consent must be obtained (Section 12.3).
7.2.1.
Screening/Screen Failures
The following will be conducted during the Screening Visit:
1.
Both the subject and the investigator (or designee) will sign the Informed Consent
Form (ICF).
2.
The Investigator (or designee) will complete an assessment to determine that the
subject still meets eligibility criteria.
3.
The Investigator (or designee) will review the subjects’ current medication, medical
history, and collect demographics.
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4.
If the subject does not meet all eligible criteria, the subject will be exited from the
study.
Screen failures are defined as subjects who consent to participate in the clinical trial but
are not randomized into the study intervention or entered in the study. A minimal set of
screen failure information is required to ensure transparent reporting of screen failure
subjects, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing
requirements and to respond to queries from regulatory authorities. Minimal information
includes demography, screen failure details, eligibility criteria, and any serious adverse
event (SAE).
This data will be documented on the appropriate case report form.
7.2.2.
Enrollment
Subjects will be considered enrolled in the study when they have signed the IRB/EC
approved ICF and have met all eligibility criteria.
7.2.3.
Randomization/Blinding/Masking
Enrolled subjects will be randomized into control or intervention arms in a 1:1 allocation
using block randomization within subjects strata defined by age-group, sex, and
risk-group. Subjects will be assigned to control or intervention arms within each
colonoscopist based on a predetermined randomization schedule.
Subjects, investigators, study site personnel, and pathologists will not be blinded to
treatment assignments. All Verily personnel involved in the statistical analysis of this
study will be blinded to treatment assignment. For the interim analysis, unblinded
analysis will be performed by an independent statistician, the results of which will be
communicated to a select group of Verily personnel not involved in the study
management.
7.2.4.
Subject Compensation
Subjects may be compensated for their participation in the study. The details of
compensation will be provided to the subjects in the informed consent form.
7.2.5.
Visit Schedule
After confirmation that the ICF has been signed by both the investigator (or designee)
and the subject and eligibility has been confirmed, the following assessments will be
performed.
●
Subjects will be randomized using the randomization system within the EDC
system provided by Sponsor.
●
If a subject is assigned to the intervention group, the EVA-C System will be turned
on prior to scope insertion and will remain on for the duration of the colonoscopy.
●
If a subject is assigned to the control group, the EVA-C System will not be used
and will remain turned off during the colonoscopy.
●
In both the control and intervention groups, the colonoscopy video feed will be
recorded from scope-in to scope-out, while the scope is inside the subject. Any
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protected health information (PHI) in the colonoscopy video feed will be masked
prior to recording or removed after recording, but prior to sending to Sponsor.
Colonoscopy procedure
●
High Definition White Light Endoscopy will be used, per standard of care.
●
Dye-based or virtual chromoendoscopy may be used for characterizing individual
polyps at the colonoscopist's discretion, but may not be used for overall
inspection of the colon.
●
Bowel preparation will be evaluated after cleaning and will be scored using the
Boston Bowel Preparation Scale (BBPS) separately in each of the three regions of
the colon: the right colon (including the cecum and ascending colon), the
transverse colon (including the hepatic and splenic flexures), and the left colon
(including the descending colon, sigmoid colon, and rectum).1 Subjects with a
BBPS score of 0 or 1 in any of the three colonic regions of the colon will be
excluded from the Per Protocol analysis.
●
In the right, transverse, and left colon, lesions are to be removed, at the
colonoscopist’s discretion, per standard of care. Notably, in the left colon, only
those lesions that appear adenomatous are to be removed, per standard of care.
In the intervention arm only:
The EVA-C System does not differentiate between adenomatous and hyperplastic polyps.
It is designed to identify polyp-like morphologies. It is up to the colonoscopists’
discretion, based on all available information, to decide whether to resect a given polyp or
lesion, irrespective of the presence of the EVA-C System bounding box. The EVA-C
System is not intended to change the colonoscopist’s management of an identified polyp
or lesion.
●
The colonoscopist is expected to interrogate any region of interest highlighted by
the EVA-C System bounding box.
●
In the right, transverse, and left colon, lesions are to be removed, at the
colonoscopist’s discretion, and irrespective of the EVA-C System bounding box,
per standard of care. Notably, in the left colon, only those lesions that appear
adenomatous are to be removed, per standard of care.
●
For bounding boxes that persist on the screen for at least 2-3 seconds (per
colonoscopist’s discretion) but do not contain a polyp, the colonoscopist will
verbally confirm a ‘false alert’ to the study personnel.
Polyp resection and pathology processing:
●
Endoscopic images of each polyp will be acquired before polyp removal.
●
Study personnel will record the polyp size (≤5 mm, 6-9 mm, ≥10 mm), location
(cecum, ascending, hepatic flexure, transverse, splenic flexure, descending,
sigmoid, rectum), and morphology (Pedunculated 0-Ip, Sessile 0-Is, Flat 0-IIa, or
Depressed 0-IIc in accordance with Paris classification²), as reported by the
colonoscopist.
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●
Study personnel will record the time-of-day at the moment the colonoscopist
says ‘snare closed’ (or as the snare is closed) and each polyp will be assigned a
number or letter in the sequential order in which it is removed (eg. 1, 2, 3,… or A,
B, C, …) per standard of care.
●
If the polyp is not able to be retrieved, the study personnel will note ‘not retrieved’
in the source documentation.
●
Each polyp will be placed into an individually labeled specimen jar with only one
polyp per specimen jar. If a polyp trap is used on the endoscope, the polyp trap
needs to be advanced/rotated for each new resected polyp.
●
The specimen jar will be labeled with the sequential number or letter correlating
to the order in which the polyp was removed (eg. 1, 2, 3,… or A, B, C,...) per
standard practice.
●
The pathology report will note each sequential polyp number or letter and
location per standard practice.
Pathology processing guidelines:
●
Histopathology will be performed per standard of care with the following
recommended guidelines. As assessed by pathologists:
○
For polyp sizes of 1 cm and greater:
Recommend allowing at least 24 hours in formalin for fixation prior to
sectioning. Serial section (through stalk, if present) into a maximum of 3
mm blocks.
For each block, recommend at least 2 sections will be
acquired.
○
For polyp sizes greater than 6mm and less than 1cm:
Bisect or serial section (through stalk, if present) into a maximum of 3
mm blocks. For each block, recommend at least two sections will be
acquired.
○
For polyp sizes between 3mm and 6mm, inclusive:
Recommend at least two slides with 8 ribbon sections per slide. For ‘no
significant abnormality’ findings, at least 3 serial sequential deeper levels
will be performed. Exhaust the block on Pathologist’s discretion.
○
For polyp sizes less than 3mm:
Recommend to ribbon section block entirely (‘exhaust the block’ – at
least 3 slides)
○
Histopathology sections shall be stained and imaged as per standard of
care.
Review of Adverse Event, Protocol Deviation, and Device Deficiencies will be completed
from time of consent to study exit.
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7.2.6.
User Experience
Colonoscopists using the EVA-C System as a part of this study may be asked to provide
their written or electronic feedback about their experiences with using this system
throughout the course of the study.
7.2.7.
Investigational Product
The study device will be used on the day of the study visit.
The investigator is
responsible for accountability at the study site as indicated in Section 11.3, and the study
devices will be stored in a locked cabinet and/or in a locked office at the site.
7.2.8.
Adverse Events
Adverse events related to study device and study procedures, all serious adverse events,
and all unanticipated adverse device effects will be reported on the appropriate CRF in a
timely manner as indicated in Section 9. They will be collected from time of consent to
study exit and will be reviewed by the Sponsor. The investigator will provide further
information regarding adverse events as requested by the Sponsor.
7.2.9.
Protocol Deviations
A protocol deviation is when the procedures that are outlined in the Protocol are not
followed. There are two types of protocol deviations in this study: major deviations and
minor deviations.
A major deviation is defined as an event that resulted in an increased risk to a subject or
others; affecting the rights, safety and/or welfare of the subject; or affecting the integrity
of the clinical study. Major deviations include (but are not limited to): failure to obtain
Informed Consent prior to enrollment, enrolled subject who participated in the study
session does not meet inclusion/exclusion criteria or unauthorized use of study device
on a subject not enrolled in the study; AEs that are not reported by the Investigator during
the protocol-specified timeframe.
A minor protocol deviation is defined as deviating from the protocol and include (but are
not limited to): protocol-required testing and/or study visit were not completed.
All deviations will be reported on the appropriate CRF.
7.3.
Test Procedures
7.3.1.
Laboratory parameters
This section is not applicable for this study.
7.3.2.
Special Methodologies and Evaluations
7.3.2.1.
Retrospective Review of Colonoscopy Video Recording
Inspection time, defined as time when not resecting, washing, or preparing for
resection, will be calculated retrospectively from colonoscopy video recording
(subtracting out the non-inspection time).
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8.
Risk Analysis
This study is a non-significant risk device study and subjects in this study will not be exposed to
significant risk. The risks of participation in this study are not expected to be different from
patients’ routinely scheduled colonoscopy visit.
8.1.
Risk Analysis
Verily Life Sciences has conducted an analysis of the benefits and risks of the EVA-C System.
Verily Life Sciences has determined that this clinical investigation is justified, as the overall
potential benefit to the population outweighs its risks.
8.2.
Benefits
There is no direct benefit to the participating subjects for this study, but the information obtained
will be used in scientific research and may be helpful to others in the future.
8.3.
Risks
This study is a non-significant risk device study, and this study exposes subjects to minimal risks
not expected to be significantly different from patients’ routinely scheduled colonoscopy visit.
Possible risk, in addition to risks associated with the clinical colonoscopy, may include:
●
Algorithm malfunction or misinterpretation leading to:
○
False positive detection potentially resulting in procedural delays due to
prolonged interrogation/examination. However, the software is not designed to
replace clinical decision making.
○
False
negative missed detection, potentially resulting in delayed patient
treatment. However, this delay would have occurred regardless of device use.
Additionally, it is possible physicians could develop an overreliance on the
device.
●
Failure to identify lesions, potentially resulting in delayed patient treatment, because of
software or hardware malfunction. Such malfunctions might include:
○
Incompatibility with hardware and/or data source
○
Inadequate mapping of software architecture
○
Degradation of image quality
○
Prolonged delay of real-time endoscopic video
In all cases of device malfunction, the device may be turned off or unplugged by the
colonoscopist or the study team at any time, to avoid further procedural risk, and the procedure
would continue as planned without the use of the EVA-C System.
Another risk of this study includes breach of privacy and confidentiality of protected health
information (PHI).
The following measures will be implemented to help minimize risks to subjects during the study:
●
All PHI will be stored in a secure locked office on a password protected computer. The
informed consent forms will be stored in a locked cabinet in a locked office at the site.
Measures to ensure complete de-identification prior to data transfer and analysis will be
taken.
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9.
Adverse Events (AE), Serious Adverse Events (SAE), and Unanticipated Problems
During and following a subject's participation in the study, the investigator/institution should ensure that
adequate medical care is provided to a subject for any adverse events, including clinically significant
laboratory values, related to the trial. The investigator/institution should inform a subject when medical
care is needed for intercurrent illness(es) of which the investigator becomes aware.
In the event medical care to a subject is required, the medical care given to, and medical decisions made
on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of
a qualified dentist.
9.1.
Adverse Events
An Adverse Event (AE) is defined as any untoward medical occurrence, unintended disease or
injury in subjects, users or other persons, that is considered a change from baseline or pre-study
status, whether or not related to the investigational medical device.
Any pre-existing medical condition or symptoms present in a subject will not be considered an
AE in this study, unless it worsens as a result of this study.
For this study, AEs related to the study device and study procedures will be reported on an AE
Case Report Form and will include the following: Date/time of onset, date the site first becomes
aware of the event, description of the event, the duration of the event, the severity of the event,
assessment of the relation of the event to the study device and study procedure, description of
action taken, if any, and the event outcome.
In the event medical care to a subject is required, the medical care given to, and medical
decisions made on behalf of, subjects should always be the responsibility of a qualified physician.
9.2.
Serious Adverse Events
A Serious Adverse Event (SAE) is defined as an adverse event that is anticipated or unanticipated
and which reasonably suggests that one of the manufacturers’ devices has or may have caused
or contributed to a death or serious injury.
A Serious Adverse Event is an Adverse Event that led to: (a) death, (b) serious deterioration in the
health of the subject that either resulted in a (i) life-threatening illness or injury or (ii) permanent
impairment of a body structure or a body function, or (iii) in-patient or prolonged hospitalization or
(iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent
impairment to a body structure or a body function or (c) fetal distress, fetal death or a congenital
abnormality or birth defect.
These events are typically reportable to health authorities. For this study, all serious Adverse
Events will be reported to the Sponsor within 24 hours of knowledge of the event.
9.3.
Unanticipated Adverse Device Effects (UADE)
An Unanticipated Adverse Device Effect (UADE) is a serious adverse effect on health or safety or
any life-threatening problem or death caused by, or associated with, a device, if that effect or
problem 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 associated with a device that relates to the rights, safety, or
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welfare of subjects. Anticipated potential adverse device effects have been identified in the
Sponsor Risk Management files.
The Principal Investigator will assure that all unanticipated adverse device effects (UADE)
involving risk to subjects or others will be reported to the Sponsor within 24 hours of knowledge
of the event. All UADE’s will be evaluated and the results of such evaluation will be reported to the
IRB within ten (10) working days after the event is reported by the study subjects. The Sponsor
will report all SAE’s and UADE’s to the appropriate regulatory authority. All Serious and
Unanticipated Adverse Effects will be reviewed by a Medical Monitor.
10.
Device Deficiencies
A device deficiency is an observed or detected inadequacy of an investigational medical device with
respect to its identity, quality, durability, reliability, safety or performance/efficacy. Device deficiencies will
be collected on the Device Deficiency CRF. Any adverse events resulting from a device deficiency will be
collected on the Adverse Event CRF as appropriate.
If the EVA-C System breaks or malfunctions, the device will be returned to the Sponsor and may be
replaced with a new device.
Verily will manage the EVA-C System troubleshooting with sites and as well as logistics of device returns
and replacement if necessary.
11.
Investigational Product(s)/Medical Device
11.1.
Investigational Product(s)/Device Description
The EVA-C System is a computer-aided detection (CADe) system that uses artificial intelligence
to aid in identifying colorectal polyps during High Definition White Light Endoscopy (HD-WLE)
based colonoscopies. This device connects the Gastroenterologist’s colonoscopy video output
source to the main monitor and highlights the regions of interest where the device detects a
potential lesion. The EVA-C System overlays graphical markers onto video from the endoscope
camera and does not perform further processing to the endoscope video signal. This device is
not intended to replace clinical decision making.
The EVA-C System consists of both hardware and software. The device hardware connects the
endoscope video output system to the main endoscope display monitor (Figure 1). The software
employs artificial intelligence algorithm (neural network) techniques to detect and localize
regions of interest. Identified areas of interest are highlighted using a bounding box (see Figure
2).
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Figure 1: The EVA-C System is connected between the endoscopy light source and video
processor unit and the main endoscopic display monitor.
Figure 2: Gastroenterologist’s view of polyp detection feature on main monitor
Two configurations of the EVA-C System hardware may be deployed into the clinical study, the
EVA-C Base System (Figure 3) and the EVA-C Plus System (Figure 4), as shown below.
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Figure 3: EVA-C Base System
Figure 4: EVA-C Plus System
The AI polyp detection algorithm deployed to both devices will be identical. Hardware used for
video and image processing is also identical across both devices. The primary differences
between devices are as follows:
●
EVA-C Plus System will have a touch-screen that will allow physicians to both adjust
volume and turn the polyp-detection boxes on and off
●
EVA-C Base System will not have a touch-screen.
Volume will be adjustable during
installation only, and polyp detection boxes will default to being always on.
The differences listed above are principally the results of human factors and user research
testing and there is not an expectation that the differences between these two devices will have a
significant impact on our primary or secondary endpoints.
11.2.
Control Product/Device Description
This section is not applicable for this study.
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11.3.
Investigational Device Labeling & Accountability
The Investigator is responsible for accountability at the study site. The Investigator should take
adequate precautions, including storage of the investigational study devices to prevent diversion
of the products into unauthorized channels of distribution. All unused products will be returned to
the Sponsor.
The EVA-C System is an investigational device and will be packaged with a label with the name
and place of business of the manufacturer and distributor. The device will also be labeled with the
following: “CAUTION: Investigational device. Limited by Federal (or United States) law to
investigational use.” Devices used outside the United States will be labeled with the following:
“CAUTION: Investigational device. For use in clinical studies only.”
The investigational device label information will be transcribed to the appropriate case report
form as well as for device accountability and traceability.
Only sites/Investigators participating in the clinical study will be eligible to receive the EVA-C
System after Verily has declared the site ready to start the clinical study.
At the end of the study, all investigational devices must be returned to the Sponsor. To return the
devices to Verily, a Return Material Authorization (RMA) number is required. The site will contact
Verily to issue an RMA number, and Verily will provide the site with appropriate device return
packaging and shipment materials. The Sponsor-issued RMA number will be captured within the
appropriate shipping and/or device accountability documentation.
12.
Regulatory, Ethical and Study Oversight Considerations
12.1.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
●
Consensus
ethical
principles
derived
from international guidelines including the
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines
●
Applicable ICH Good Clinical Practice (GCP) Guidelines
●
Applicable laws and regulations
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, advertisements)
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC
before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of changes
made to the study design, except for changes necessary to eliminate an immediate hazard to
study subjects.
The investigator will be responsible for the following:
●
Providing written summaries of the status of the study to the IRB/IEC annually or more
frequently in accordance with the requirements, policies, and procedures established by
the IRB/IEC
●
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC
procedures; and
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●
Providing oversight of the conduct of the study at the site and adherence to requirements
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies
(if applicable), and all other applicable local regulations
12.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial
information as requested to allow the sponsor to submit complete and accurate financial
certification or disclosure statements to the appropriate regulatory authorities. Investigators are
responsible for providing information on financial interests during the course of the study and for
1 year after completion of the study.
12.3.
Informed Consent Process
Subjects must be given ample time and opportunity to inquire about details of the study and to
decide whether or not to participate in the study before informed consent is obtained and per
sites’ local and IRB guidelines. The investigator or his/her representative will explain the nature of
the study to the subject and answer all questions regarding the study.
Subjects must be informed that their participation is voluntary. Subjects will be required to sign a
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where
applicable, and the IRB/IEC or study center.
There must be a source document that includes a statement that written informed consent was
obtained before the subject was enrolled in the study and the date the written consent was
obtained. The authorized person obtaining the informed consent must also sign the ICF.
Subjects must be re-consented to the most current version of the ICF(s) during their participation
in the study.
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized
representative.
12.4.
Data Protection
Subjects will be assigned a unique identifier by the sponsor. Any subject records or datasets that
are transferred to the sponsor will contain the identifier only; subject names or any information
which would make the subject identifiable will not be transferred.
The subject must be informed that his/her personal study-related data will be used by the
sponsor in accordance with local data protection laws. The level of disclosure must also be
explained to the subject. All data used in the analysis and reporting of this evaluation will be used
in a manner without identifiable reference to the study subject.
The subject must be informed that his/her medical records may be examined by Clinical Quality
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate
IRB/IEC members, and by inspectors from regulatory authorities.
12.5.
Interim Analysis Structure
An independent statistician will be utilized for the interim analysis. Within Verily and/or a
designee, data and programming for the interim analysis will be performed by an interim analysis
dedicated group who are not involved in the management of the study. This group will
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communicate with the independent statistician and will provide the unblinding codes. The
independent statistician will execute the unblinding with the set of programs prepared by the
interim analysis dedicated group and will then communicate the results to a pre-selected group
within Verily not involved in the management of the study. A detailed unblinding and a
communication plan will be provided in the statistical analysis plan.
12.6.
Data Quality Assurance
●
All subject data relating to the study will be recorded on printed or electronic CRF unless
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator
is responsible for verifying that data entries are accurate and correct by physically or
electronically signing the CRF.
●
The investigator must maintain accurate documentation (source data) that supports the
information entered in the CRF.
●
The investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections and provide direct access to source data documents.
●
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring),
methods, responsibilities and requirements, including handling of noncompliance issues
and monitoring techniques (central, remote, or on-site monitoring) are provided in the
Monitoring Plan.
●
The sponsor or designee is responsible for the data management of this study including
quality checking of the data.
●
The sponsor assumes accountability for actions delegated to other individuals (eg,
Contract Research Organizations).
●
Study monitors will perform ongoing source data verification to confirm that data entered
into the CRF by authorized site personnel are accurate, complete, and verifiable from source
documents; that the safety and rights of subjects are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.
●
Records and documents, including signed ICFs, pertaining to the conduct of this study
must be retained by the investigator for 2 years after study completion unless local
regulations or institutional policies require a longer retention period. No records may be
destroyed during the retention period without the written approval of the sponsor. No
records may be transferred to another location or party without written notification to the
sponsor.
12.7.
Source Documents
●
Source documents provide evidence for the existence of the subject and substantiate the
integrity of the data collected. Source documents are filed at the investigator’s site.
●
Data reported on the CRF or entered in the eCRF that are transcribed from source
documents must be consistent with the source documents or the discrepancies must be
explained. The investigator may need to request previous medical records or transfer
records, depending on the study. Also, current medical records must be available.
●
If study data is recorded directly on the CRFs (i.e., no prior written or electronic record of
data), it is considered to be source data.
●
Definition of what constitutes source data can be found in CRF completion guidelines.
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12.8.
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any time
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study
completion. A study site is considered closed when all required documents and study supplies
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are
not limited to:
●
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or
local health authorities, the sponsor's procedures, or GCP guidelines
●
Inadequate recruitment of subjects by the investigator
●
Discontinuation of further study intervention development
12.9.
Publication Policy
●
The results of this study may be published or presented at scientific meetings. If this is
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor
before submission. This allows the sponsor to protect proprietary information and to
provide comments.
●
The sponsor will comply with the requirements for publication of study results. In
accordance with standard editorial and ethical practice, the sponsor will generally support
publication of multisite studies only in their entirety and not as individual site data. In this
case, a coordinating investigator will be designated by mutual agreement.
●
Authorship will be determined by mutual agreement and in line with International
Committee of Medical Journal Editors authorship requirements.
13.
Statistical Considerations
Based on previous feasibility data, a sample size of 600 patients per arm (1:1 allocation, 1,200 total in
both arms) would provide >99% Power to detect superiority for APC assuming a data loss of 15%. This
same number of patients would also provide 90% Power to detect superiority for ADR, based on the
expected ADR of 35% in the control arm, and 45% for the intervention arm.. Based on the assumption that
PPA will be at least 70% in both arms, Power for the PPA non-inferiority comparison will be > 90%.
The co-primary endpoint of PPA will be tested for non-inferiority using a non-inferiority margin of 10%.
PPA will be calculated for each arm as the number of positive biopsies of total removed lesions. A
resampling distribution of the difference in PPA will be used to calculate a two-sided 95% confidence
interval for the difference: PPA(intervention)-PPA(control). Non-inferiority will be concluded if the lower
confidence limit of the 95% two-sided confidence interval is above -10%. For APC, superiority will be
assessed based on a one-sided test of the difference in mean rates at a 0.025 level of significance. For
ADR, superiority will be assessed using a stratified CMH test at a one-sided 0.025 level of significance.
Interim analysis: When approximately 600 subjects have completed the trial, an interim analysis will be
conducted, and a conditional power analysis will be performed. The conditional power will assess the
probability (power) that the study will meet its objectives on the superiority endpoint of APC and ADR, and
on the non-inferiority of the PPA endpoint. If the conditional power is below 90% for either one of the
co-primary endpoints or for ADR, an increase in the sample size from 1200 up to 2400 will be considered.
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The increase in the sample size will be based on the probability of achieving success on both co-primary
endpoints (APC and PPA) and success on the ADR endpoint. If the increase in sample size leads to an
increase in the power for these endpoints to approximately 90%, then the study will enroll the additional
subjects to allow the increase in power. Otherwise, the study may continue to the originally planned
sample size of 1200 or stopped for futility. Due to a possible increase in the sample size, the final analysis
will be done using a simple combination test, by transforming the test statistics of the interim patients,
and the test statistic of the post-interim patients to standard normal (Z) statistics. Using prespecified
weights of w1 = 1/2 and w2 = 1/2, the final Z = √w1 * interim Z + √w2 * post-interim Z. The interim
analysis will be conducted by an independent statistician. Recommendations will be communicated
confidentially to a select committee within Verily not directly involved in the study. Communication
processes will be laid out in the interim analysis section of the statistical analysis plan.
The co-primary endpoints of APC and PPA will be analyzed using the ITT population. Sensitivity analyses
will be conducted to assess the effect of missing complete or partial data by considering various
imputation methods and will be described in the Statistical Analysis Plan. Subgroup analysis will include
assessments of APC, ADR and PPA in groups defined by age-group, sex, race, ethnicity, site,
colonoscopist and country
Of the subjects receiving intervention, a subset of subjects may receive an iteration of the device that
incorporates varying hardware and software configurations (see Section 11.1). The predicted result of
these variations is not expected to significantly impact primary or secondary endpoints.
The Intent to Treat (ITT), modified Intent to Treat (mITT) and Per Protocol (PP) populations will be further
defined within the Statistical Analysis Plan.
14.
Appendices
●
NSR Rationale
15.
References
1.
Calderwood AH, Jacobson BC. Comprehensive validation of the boston bowel preparation
scale. Gastrointest Endosc. 2010;72(4):686-692. doi:10.1016/j.gie.2010.06.068
2.
Kaltenbach T, Anderson JC, Burke CA, et al. Endoscopic removal of colorectal
lesions-recommendations by the US multi-society task force on colorectal cancer.
Gastroenterology. 2020;158(4):1095-1129. doi:10.1053/j.gastro.2019.12.018
3.
Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary
nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer
Inst. 2004;96(4):261-268. doi:10.1093/jnci/djh034
4.
Livovsky DM, Veikherman D, Golany T, et al. Detection of elusive polyps using a large-scale
artificial intelligence system (With videos). Gastrointest Endosc. Published online June 30,
2021:S0016-5107(21)01468-1. doi:10.1016/j.gie.2021.06.021
5.
Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic
polypectomy. The national polyp study workgroup. N Engl J Med. 1993;329(27):1977-1981.
doi:10.1056/NEJM199312303292701
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6.
Nishihara R, Wu K, Lochhead P, et al. Long-term colorectal-cancer incidence and mortality
after lower endoscopy. N Engl J Med. 2013;369(12):1095-1105.
doi:10.1056/NEJMoa1301969
7.
Rex DK, Johnson DA, Anderson JC, et al. American College of Gastroenterology guidelines for
colorectal cancer screening 2009 [corrected]. Am J Gastroenterol. 2009;104(3):739-750.
doi:10.1038/ajg.2009.104
8.
US Preventive Services Task Force, Davidson KW, Barry MJ, et al. Screening for colorectal
cancer: us preventive services task force recommendation statement. JAMA.
2021;325(19):1965-1977. doi:10.1001/jama.2021.6238
9.
Zhao S, Wang S, Pan P, et al. Magnitude, risk factors, and factors associated with adenoma
miss rate of tandem colonoscopy: a systematic review and meta-analysis. Gastroenterology.
2019;156(6):1661-1674.e11. doi:10.1053/j.gastro.2019.01.260
10. van Rijn JC, Reitsma JB, Stoker J, Bossuyt PM, van Deventer SJ, Dekker E. Polyp miss rate
determined by tandem colonoscopy: a systematic review. Am J Gastroenterol.
2006;101(2):343-350. doi:10.1111/j.1572-0241.2006.00390.x
11. Corley DA, Jensen CD, Marks AR, et al. Adenoma detection rate and risk of colorectal cancer
and death. N Engl J Med. 2014;370(14):1298-1306. doi:10.1056/NEJMoa1309086
12. Kaminski MF, Regula J, Kraszewska E, et al. Quality indicators for colonoscopy and the risk of
interval cancer. N Engl J Med. 2010;362(19):1795-1803. doi:10.1056/NEJMoa0907667
13. Buchner AM, Gomez V, Heckman MG, et al. The learning curve of in vivo probe-based confocal
laser endomicroscopy for prediction of colorectal neoplasia. Gastrointest Endosc.
2011;73(3):556-560. doi:10.1016/j.gie.2011.01.002
14. Misawa M, Kudo SE, Mori Y, et al. Artificial intelligence-assisted polyp detection for
colonoscopy: initial experience. Gastroenterology. 2018;154(8):2027-2029.e3.
doi:10.1053/j.gastro.2018.04.003
15. Repici A, Badalamenti M, Maselli R, et al. Efficacy of real-time computer-aided detection of
colorectal neoplasia in a randomized trial. Gastroenterology. 2020;159(2):512-520.e7.
doi:10.1053/j.gastro.2020.04.062
16. Hassan C, Wallace MB, Sharma P, et al. New artificial intelligence system: first validation
study versus experienced endoscopists for colorectal polyp detection. Gut.
2020;69(5):799-800. doi:10.1136/gutjnl-2019-319914
17. Urban G, Tripathi P, Alkayali T, et al. Deep learning localizes and identifies polyps in real time
with 96% accuracy in screening colonoscopy. Gastroenterology. 2018;155(4):1069-1078.e8.
doi:10.1053/j.gastro.2018.06.037
18. Forbes N, Boyne DJ, Mazurek MS, et al. Association between endoscopist annual procedure
volume and colonoscopy quality: systematic review and meta-analysis. Clin Gastroenterol
Hepatol. 2020;18(10):2192-2208.e12. doi:10.1016/j.cgh.2020.03.046
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16.
Glossary
Term
Abbr.
Definition
Adverse Event
AE
Any untoward medical occurrence, unintended disease or injury in
subjects, users or other persons, that is considered a change from
baseline or pre-study status, whether or not related to the investigational
medical device.
Case Report Form
CRF
A set of documents, designed for complete recording of all relevant
subject and device related data, as required by the clinical investigation
plan.
Trial Master File
TMF
Contains essential documents for a clinical trial that may be subject to
regulatory agency oversight.
Clinical
Investigation
N/A
Any controlled systematic study in human subjects, undertaken to verify
the safety and performance of a specific medical device, under normal
conditions of use. This is also known as a Clinical Study or Clinical Trial.
Clinical Research
Associate
CRA
A person appointed by the sponsor and responsible for monitoring and
reporting on the progress of the clinical investigation. This is also known
as a Monitor.
Contract
Research
Organization
CRO
Contract research organizations are independent contractors who
assume, by contract, some or all of the regulatory responsibilities of a
sponsor and/or monitor.
Informed Consent
IC
A process by which a subject voluntarily confirms his or her willingness to
participate in a particular trial, after having been informed of all aspects
that are relevant to the subject's decision, including potential risks and
benefits to participate. Informed consent is documented by means of a
written, signed, and dated informed consent form. Informed consent
continues throughout the trial.
Intent to treat
ITT
All randomized subjects.
Investigational
Device
N/A
Any medical device intended for use by an appropriately qualified
practitioner when conducting clinical investigations in an adequate
clinical environment.
Modified Intent to
treat
mITT
The subset of ITT subjects, including only those indicated for Screening
or Surveillance
Per Protocol
PP
The subset of ITT subjects, excluding those whose procedure could not
be completed per protocol (e.g. poor bowel prep).
Principal
Investigator
PI
The investigator responsible for the conduct of a clinical investigation
and who takes the clinical responsibility for the well being of the subjects
involved.
Serious Adverse
Event
SAE
A Serious Adverse Event (also referred to as Adverse Incident) is defined
as an adverse event that is anticipated or unanticipated and that
reasonably suggests that one of the manufacturers devices has or may
have caused or contributed to a death or serious injury. A Serious Adverse
Event is an Adverse Event that led to: (a) death, (b) serious deterioration
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in the health of the subject that either resulted in a (i) life-threatening
illness or injury or (ii) permanent impairment of a body structure or a body
function, or (iii) in-patient or prolonged hospitalization or (iv) medical or
surgical intervention to prevent life-threatening illness or injury or
permanent impairment to a body structure or a body function or (c) fetal
distress, fetal death or a congenital abnormality or birth defect. These
events are typically reportable to health authorities.
Sponsor
N/A
An individual or an organization which takes responsibility for the
initiation and/or implementation of a clinical investigation.
Sub-Investigator
Sub-I
A member of the clinical study team with appropriate credentials and is
supervised by the Principal Investigator at a site and allowed to perform
critical trial-related procedures and/or to make key trial-related decisions.
Subject/ Research
Subject
N/A
A human being, either a patient or a non-patient volunteer, participating in
a clinical investigation.
Unanticipated
Adverse Device
Effect
UADE
Serious adverse effect on health or safety or any life-threatening problem
or death caused by, or associated with, a device, if that effect or problem
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 associated with
a device that relates to the rights, safety, or welfare of subjects.
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