Validation of a Lab-free Low-cost Screening Test for Prevention of Cervical Cancer: Automated Visual Evaluation
Phase: NA
Conditions: Human Papillomavirus (HPV), Cervical Intraepithelial Neoplasia, Uterine Cervical Neoplasms, Cervical Cancers
Sponsor: DL Analytics

 
 
Cover Page: Clinicaltrials.gov Protocol 
 
Sponsor name: 
National Institutes of Health 
NCT number 
Not yet assigned 
Sponsor trial ID 
4R44CA247137 
Official title of study 
Validation of a lab-free low-cost screening 
test for prevention of cervical cancer: 
automated visual evaluation  
Document date 
8 October 2024 
 
 
 
 
 
 
 
 
 
 

Research Protocol​
Trial ID: 4R44CA247137 
Date: 8 October 2025  
Version: Final  
Page 1 
 
 
PROJECT TITLE 
Validation of a lab-free low-cost screening test for prevention of cervical cancer: automated 
visual evaluation  
 
SPONSOR 
National Institutes of Health 4R44CA247137 
 
PERSONNEL 
 
Principal Investigator 
Dr. David Levitz, DL Analytics, LLC, Los Angeles, California, USA 
 
Local Principal Investigator 
Dr. Karla Alfaro, Basic Health International, San Salvador, El Salvador 
 
Co-Investigators 
 
DL Analytics 
Kelwin Fernandes, Head of Data, DL Analytics, LLC, Los Angeles, California, USA 
Cathy Sebag, Head of Product, DL Analytics, LLC, Los Angeles, California, USA 
Reuven Weiser, Head of Software, DL Analytics, LLC, Los Angeles, California, USA 
 
El Salvador Ministry of Health 
Dra. Andrea Chacon, Cancer Unit, Ministry of Health, San Salvador, El Salvador 
Dr. Jose Miguel Belis, Cancer Unit, Ministry of Health, San Salvador, El Salvador 
 
Basic Health International 
Dr. Juan Carlos Rauda, Basic Health International, San Salvador, El Salvador 
Dra. Leticia López, Basic Health International, San Salvador, El Salvador 
Dr. Gabriel Conzuelo Rodriguez, Basic Health International, Pittsburgh, PA, USA 
 
Cleveland Clinic 
Dr. Miriam Cremer, Ob/Gyn Institute, Cleveland Clinic, Cleveland, OH, USA 
Dr. Montserrat Soler, Ob/Gyn Institute, Cleveland Clinic, Cleveland, OH, USA 
 
University of North Carolina  
Dr. Jennifer Smith, Gillings School of Public Health, University of North Carolina, NC, USA 
 
Medical College of Wisconsin 
 
 

Research Protocol​
Trial ID: 4R44CA247137 
Date: 8 October 2025  
Version: Final  
Page 2 
 
Dr. Juan C. Felix, Department of Pathology, Medical College of Wisconsin, WI, USA 
 
University of Southern California  
Dr. Todd Alonzo, Keck School of Medicine, University of Southern California, CA, USA 
 
Table of Contents 
1. BACKGROUND AND SIGNIFICANCE​
3 
1.1 Existing Screening and Triage tests​
3 
1.2 Innovations in Screening and Triage​
4 
1.3 Automated Visual Evaluation (AVE)​
4 
2. STUDY DESCRIPTION​
5 
2.1 Study Aims​
5 
2.2 Study Design​
5 
2.3 Study Population​
5 
2.4 Study General Description​
6 
2.5 Provider Training​
6 
2.6 Enrollment​
7 
2.7 Speculum exam and screening (first visit)​
7 
2.8 Colposcopy and biopsy (second visit)​
8 
2.9 Biopsy results and patient management​
9 
2.10 Laboratory analysis and histopathology​
9 
2.11 Pathology quality assurance​
10 
3. POWER CALCULATIONS AND DATA ANALYSIS​
10 
3.1 Aim 1: Validate AVE as a primary screening test compared to visual inspection with 
acetic acid (VIA) for the detection of high-grade cervical pre- cancer (CIN2+).​
10 
3.2 Aim 2. To compare AVE as a triage test compared to VIA for detecting CIN2+ among 
HPV-positive women.​
10 
4. DATA COLLECTION AND MANAGEMENT​
11 
4.1 Data collection​
11 
4.2 Data Management​
11 
4.3 Non-participant documentation​
11 
5. DATA SAFETY AND CONFIDENTIALITY​
11 
5.1. Dissemination of findings​
12 
6. OTHER RISKS AND SAFETY CONSIDERATIONS​
12 
6.1 Clinical risks​
12 
 
 

Research Protocol​
Trial ID: 4R44CA247137 
Date: 8 October 2025  
Version: Final  
Page 3 
 
6.2 Monitoring and adverse events​
13 
6.3 Data Safety and Monitoring Board​
13 
6.4 Ethics Committees​
13 
7. TIMELINE AND MILESTONES​
13 
8. REFERENCES​
15 
 
 
 

4 
1. BACKGROUND AND SIGNIFICANCE 
 
Effective prevention measures have lowered cervical cancer rates in high-income countries, but 
the disease remains a leading cause of death in in low- and middle-income countries (LMICs) 
where up to 80% of the disease burden and 90% of global deaths occur.1 The World Health 
Organization (WHO) launched a call to action in May of 2018 for the global elimination of 
cervical cancer by 2030 through a combination of vaccination, screening, and treatment.2 
Screening women a single time in their lifetimes at the age of 35 can reduce the risk of 
developing cervical cancer by up to 36%, while two screening visits per lifetime reduces the risk 
by a further 40%3 However, the traditional multi-step screening strategy of cytology (Pap 
smear), colposcopy and treatment of women diagnosed with high-grade cervical abnormalities 
is not always feasible in LMICs due to limited resources and patient barriers to access and 
follow-up.4,5 Thus, there is an urgent need for a true low-cost point of care test to detect 
high-grade cervical precancer so women can be treated immediately. The purpose of this study 
is to validate Automated Visual Evaluation (AVE), a point-of-care screening and triage 
diagnostic tool based on the assessment of digital images through artificial intelligence. AVE 
has been in development since 2021. The current study will consist of a clinical trial to compare 
the sensitivity of AVE with traditional screening and triage tests.  
 
1.1 Existing Screening and Triage tests  
 
The most widely used cervical cancer screening and triage tests used around the world are 
unaided visual inspection with acetic acid (VIA), cytology (the Pap smear or test), and human 
papillomavirus (HPV) testing. However, each of these methods has significant drawbacks.  
VIA uses 3% to 5% acetic acid applied to the cervix, which turns cervical abnormalities white 
(“acetowhite”), so the provider is able to identify them with the naked eye. While simple and 
low-cost, there is a large variation of sensitivity and quality control is difficult.6,7 Although VIA 
programs are widely utilized in LMICs, the method has not made the impact that advocates had 
hoped for in reducing cervical disease burden. Cytology programs have been highly effective in 
high resource settings but have not led to a decrease in mortality from cervical cancer in 
LMICs.8,9 In some regions, adherence to screening programs is as low as 6%, and loss to 
follow-up is higher in limited-resource settings.10,11 HPV testing has higher sensitivity and lower 
specificity than VIA or cytology.12,13 However, the high cost and complex processing of currently 
available HPV assays have been barriers for their widespread use.14,15 In addition, programs that 
rely on HPV testing to determine patient management result in high degrees of overtreatment. 
In El Salvador, where about 12% of screen-eligible women are HPV positive, only about 2% have 
biopsy-confirmed high-grade cervical precancer (cervical intraepithelial neoplasia or CIN2+).16,17 
The use of accurate triage methods for HPV-positive women could notably decrease the amount 
of overtreatment. 
 
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1.2 Innovations in Screening and Triage 
 
In recent years, there have been significant advances in the development of new cervical cancer 
prevention technologies. Digital cervicography (DC) is an alternative to VIA that involves 
obtaining a digital image of the cervix to allow for magnified visualization by the provider. DC 
adds very little to the cost of cervical visualization and produces a permanent image for 
documentation, quality control and remote consultation. Images for 
DC can be taken with a colposcope but also with easily accessible 
tools such as a smartphone. The Enhanced Visual Assessment (EVA) 
System (Fig. 1) developed by MobileODT (Tel Aviv, Israel) is a 
portable colposcope that utilizes a smartphone which can be used 
to capture cervical images for DC (Fig. 3). The EVA System has been 
utilized in several large clinical trials, including two led by members 
of our group (NCT03084081 and NCT 03429582).  
 
1.3 Automated Visual Evaluation (AVE) 
 
We will expand the functionality of the existing EVA System by adding Automated Visual 
Evaluation (AVE), a software with artificial intelligence (AI) capabilities. AVE consists of an image 
classifier that has “learned” to differentiate precancerous lesions from normal tissue. In other 
words, AVE software can evaluate a digital image to determine if a cervix is normal or presents 
high-grade pre-cancer. There are multiple teams around the world developing and testing 
different versions of AVE. Preliminary data suggest that AVE technology has a higher detection 
rate for disease in comparison to other methods, both as a screening test in the general 
population and as a triage test in an HPV positive population. One study using natural history 
data from an earlier Costa Rica trial revealed that AVE was able to predict abnormal pathology 
years before cytology or the HPV tests that were available at that time.18 Another analysis on 
global images using human annotations to define positives showed similar results.19 A recent 
study in Zambia using HPV screening and AVE triage was able to identify stratified risk groups 
when combining HPV genotyping and AVE data.20 Data collection is also ongoing for a much 
larger study using a version of AVE as an HPV-triage tool in 9 countries, including El Salvador.21 
 
The version of AVE that we are validating in this study was developed in a previous phase of the 
project (NCI R44CA247137) and includes three main components: 1) a diagnostic classifier that 
indicates the possibility of CIN2+ (“CINFinder”) and which is the main component of AVE, 2) a 
quality assurance module (“CerVisibility”) that evaluates the quality of images, provides a score 
depending on how clear and free of obstructions the cervix appears, and provides live feedback 
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on what corrective steps can be taken to capture clear images that are adequate for diagnosis, 
and 3) a patient management module to input and save patient information (“CervManager”).  
To generate a result, CINFinder uses an ensemble of three best-performing neural networks or 
AI models (i.e., EfficientNet, DenseNet Multiple Instance Learning and MobileNetv2 
Fine-Tuned) selected based on results from the initial phase. To mitigate overfitting, 
these models are combined using a weighted average of 50%-25%-25% in favor of 
EfficientNet. The result is a numeric value ranging from 0 to 1, which is interpreted as 
the probability of CIN2+. The optimal threshold to classify participants as positive or 
negative is .45, as data from the development phase shows it maximizes sensitivity 
(84%) while maintaining good specificity (72%). Our AVE software (including CINFinder, 
CerVisibility, and CervManager modules), will be installed as user-friendly features that can be 
easily accessed by authorized users on the screen interface of the EVA System device. 
 
If confirmed to be valid for cervical precancer detection, AVE has the potential to dramatically 
change screening in LMICs because it is low-cost and does not require laboratory facilities. 
Instead, AVE needs to be installed on a device that can both capture images and which has 
computational abilities to run AI classifiers, such as certain types of smartphones. The EVA 
System, which is commercially available in over 50 countries, offers an optimal platform to 
install and use AVE because it is built around an Android smartphone. While our version of AVE 
will be able to run on any mobile Android device (e.g., phone, tablet), the colposcope 
component of the EVA System allows the user to capture high-quality images. However, we are 
also refining our AVE technology to run on a smartphone with minimal hardware 
requirements. This would make AVE a uniquely affordable and accessible solution for 
global cervical cancer screening and triage. 
 
2. STUDY DESCRIPTION 
2.1 Study Aims 
 
Aim 1. Validate AVE as a primary screening test compared to VIA for the detection of high-grade 
cervical pre-cancer (cervical intraepithelial neoplasia grade 2 or higher, or CIN2+). 
 
Aim 2. To compare AVE as a triage test compared to VIA for detecting CIN2+ among 
HPV-positive women.  
 
2.2 Study Design 
 
Non-randomized prospective study to test the difference in sensitivities between AVE and VIA to 
detect CIN2+ as a primary screening method. 
 
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2.3 Study Population 
 
A total of 10,000 women participating in El Salvador’s national HPV screening program will be 
recruited for the study (see Section 3 below for power calculation estimates). The non-profit 
organization Basic Health International (BHI), which has a long-standing collaboration with the 
Ministry of Health (MoH) will be the coordinating organization. Women will be approached at 
MoH municipal health units in the Metropolitan region. Clinical procedures, including capture of 
cervical images using the EVA System, will be performed by trained study staff in coordination 
with MoH healthcare workers at the clinics. Eligibility criteria will follow those of the national 
HPV screening program, including: 
 
Inclusion 
●​ Women aged 30-59 years at the time of screening 
 
Exclusion  
●​ Pregnancy at time of colposcopy/biopsy 
●​ Hysterectomy with surgically absent cervix 
●​ HPV testing in the past five years  
●​ Prior diagnosis or treatment of invasive cervical cancer  
 
2.4 Study General Description 
 
Women will be recruited at MoH local clinics (“health units”) where HPV screening takes place 
as part of the national cervical cancer control program. Informed consent procedures and data 
collection will be performed by BHI nurse research assistants with extensive experience in 
previous studies. During the screening visit, participants will undergo routine HPV sample 
collection, VIA, AVE with the EVA System, and cervical image capture with an Android 
smartphone. Women with a positive screening result on any of the three screening tests (HPV, 
VIA, or AVE with the EVA System) will be referred to a second study visit to undergo HPV testing 
with a genotyping test, VIA and AVE with the EVA System for the second time, and colposcopy 
with biopsy. In addition, 5% of screen-negative women will undergo the same procedures. 
Women will be referred to treatment within the public health system as necessary according to 
biopsy results. Results from VIA and AVE with the EVA System during the first and the second 
visit will be compared to determine AVE performance as a screening and triage test, 
respectively. Histopathology findings will serve as the reference to establish the true diagnosis 
of each case.  
 
2.5 Provider Training 
 
All clinical procedures will be conducted by study personnel in coordination with MoH clinic 
staff. General physicians will conduct screening and image capture during the first visit, while 
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colposcopists will conduct second visit procedures. Study providers will receive training in the 
use of the EVA System device, the installed AVE software, and image capture using a mobile 
telephone prior to study start-up. Training will be provided by BHI staff familiar with the EVA 
System and AVE, including an experienced colposcopist who has used these technologies in 
several previous projects.  
 
2.6 Enrollment 
 
Given our previous experience it will be feasible to enroll 10,000 women in 18 months (78 
weeks). An estimate of approximately 556 women per month (129 per week) results in a total of 
10,008 women in the study period (556 X 18 = 10,008). As per routine practice, MoH 
community health promoters will engage in community outreach and schedule screening 
appointments for eligible women at participating health units. Research assistants will visit 
health units on screening days and invite eligible women to participate in the study. Those who 
agree will complete informed consent procedures and will be assigned an alphanumeric 
identification code to preserve confidentiality (“study ID”). They will also complete a brief intake 
questionnaire before proceeding to the speculum exam and screening. 
 
2.7 Speculum exam and screening (first visit)  
 
After intake procedures are completed, women will proceed to an exam room. A study provider 
will place a speculum and conduct the procedures explained below. All procedures, including 
VIA and AVE results, will be recorded on paper forms by a nurse research assistant. In addition, 
the provider will input clinical information on the CervManager application installed on the EVA 
System. 
●​ HPV sampling: The provider will obtain a cervical sample for HPV testing with careHPV 
(Qiagen, Gaithersburg, MD). HPV samples will be placed in a tube linked to the 
participant’s study ID.  
●​ VIA: Following HPV sampling, the provider will clear the cervix of any mucus or blood 
and place a 5% acetic acid solution on the cervix. The provider will wait one full minute 
for any acetowhite lesions to appear and then record the unaided VIA impression 
(observed with the naked eye) on CervManager. The nurse research assistant will also 
record the VIA impression on paper forms.  VIA will be recorded as “satisfactory” or 
“unsatisfactory”, and if satisfactory, either “positive” (signs of cervical disease) or 
“negative” (normal cervix). If VIA is unsatisfactory, the reason will be indicated. 
●​ AVE with the EVA System: The provider will re-apply acetic acid and wait another full 
minute before capturing cervical images using the EVA System. During this time, while 
the device’s lens is pointed at the cervix, the CerVisibility module will sharpen the image 
using auto-focus and will assess the present or absence of 6 common obstructions (i.e., 
blur, blood, mucus, collapsed vaginal walls, squamocolumnar junction [SCJ] inside the 
os, incorrect orientation of the cervix). A notification will appear on the screen to notify 
the provider if corrective actions need to be taken to ensure the image is free of 
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obstructions (for example, the provider may need to re-position the speculum or clean 
the cervix). If no obstructions are detected, a notification will also indicate that the 
image is ready and adequate for analysis by CINFinder, the diagnostic component of 
AVE. The provider will then capture at least two cervical images that are adequate for 
analysis. All information (images, obstructions, diagnostic score, etc.) will be 
automatically stored in each patient’s CervManager profile and uploaded to the 
CervManager cloud server. Images are analyzed by CINFinder when the 
image-capturing device (in this case the EVA System) is connected to the server. 
AVE results will display as a score from 0 to 1 and scores at or above a threshold of .45 
will be considered positive for CIN2+, as explained in section 1.3. To avoid introducing 
bias, the software will calculate results in the background but the device will not display 
them until after the provider’s VIA impression has been inputted into the CervManager 
database. The result will also be recorded on paper forms. 
●​ Image Capture with Mobile Phone: Immediately after image capture for AVE, a final set 
of at least two images will be captured using an Android smartphone. The CervManager 
app will be installed on the phone so that images can be captured, stored, and merged 
with all additional patient information. To ensure image quality, the provider will utilize 
a previously arranged external light source. This will be done to compare performance 
of AVE installed on a mobile phone vs. on the EVA System colposcope as a secondary 
analysis, but will not guide patient management in any way. 
 
2.8 Colposcopy and biopsy (second visit) 
 
In El Salvador, women must return after 30 days to receive their HPV test results in-person. 
Women who test positive are usually contacted during that time by community health 
promoters to ensure they return for results, counseling, and ablation treatment if eligible. A 
team of research assistants will coordinate efforts with community health promoters to ensure 
that women with any positive screening result (HPV test, VIA, or AVE) schedule an appointment 
at a designated clinic. In addition, 5% of screen-negative women will also be invited to the 
second visit to undergo the same procedures to estimate the proportion of false negative 
screening results. At this visit, speculum exams will be conducted by study colposcopists in 
coordination with MoH staff. Procedures will include: 
●​ Urine pregnancy test: Women with a positive pregnancy test will be excluded from the 
study and referred to routine care in the public health system. 
●​ HPV Genotyping test: During the speculum exam, providers will first collect a cervical 
sample for testing with the ScreenFire HPV genotyping assay (Atila BioSystems, 
Mountain View, CA). This test identifies four groups of HPV types by oncogenic risk: 
highest risk (16), high risk (18/45), moderate risk (33/31/52/58/35) and low risk 
(39/51/59/56/68). Tests will be processed at the BHI laboratory facilities as is currently 
being done for another clinical trial (NCT05431699). 
●​ VIA: Following HPV sampling, the provider will clear any mucus or blood and apply a 5% 
acetic acid solution on the cervix to conduct VIA in the same way as described in Section 
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2.7. The VIA impression will again be recorded on the CervManager application and on 
paper forms. 
●​ AVE: AVE image capture will be performed and the result will be recorded following the 
same steps as described previously (section 2.7). Secondary analysis may be performed 
utilizing different AVE thresholds and different neural network models but none of these 
will impact patient management.   
●​ Assessment of ablation eligibility: Treatment will not be offered during this visit as it will 
depend on biopsy findings, but providers will inspect the cervix for contraindications for 
ablation treatment, including: lesion that cover over 75% of the cervix, lesion that 
extends into the endocervical canal, a SCJ that is not fully visible, atrophied or disfigured 
cervix, hard to reach cervix, or suspicion of cancer. If a woman is found to be ineligible 
for ablation, she will be referred to appropriate care once her results are available. 
●​ Colposcopy and biopsy: The EVA System digital colposcope will be used to check for 
lesions under cervical magnification and the colposcopic impression will be recorded. If 
cervical lesions are noted, the physician will take directed biopsies of each lesion 
(between two and four biopsies) as well as perform an endocervical curettage (ECC). If 
no cervical lesions are observed, the physician will take two random biopsies from the 
10 and 2 o’clock areas in the squamocolumnar junction and also perform an ECC.22 This 
two-biopsy protocol results in a better sensitivity for CIN2+ detection than taking a 
single random cervical biopsy.23 Some women will have inadequate colposcopy and 
biopsies will not be able to be taken. These women will be referred for Loop Electro 
Excision Procedure (LEEP). 
 
2.9 Biopsy results and patient management 
 
Patient management will depend on local histopathology findings of biopsied specimens. All 
women will be contacted to receive their biopsy results. At least three attempts via phone call 
will be made to contact each participant, although additional phone calls, texts, or home visits 
to invite women to a result delivery appointment may also be made. We will keep a record of 
women who are lost to follow-up and the reasons why. 
 
Participants with histologically confirmed CIN2+ will be referred to treatment by ablation, if 
eligible. Based on previous studies, we anticipate that approximately 10% of women will be 
ineligible for ablation; these women will be offered LEEP. Participants with suspected invasive 
cancer will be referred to the public health system for follow-up care. Data on treatment and/or 
referral, including histopathology findings from any LEEP specimens, will also be collected. 
Study staff will track referred patients to maximize adherence to further care. 
 
2.10 Laboratory analysis and histopathology  
 
HPV samples taken with careHPV will be analyzed at MoH laboratories as they are part of the 
standard of care. Results will be obtained in coordination with MoH laboratory personnel. 
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ScreenFire HPV test results will be analyzed and stored at BHI facilities. Cervical biopsy 
specimens obtained during the colposcopy visit will be processed and evaluated by a local study 
pathologist. These results will be communicated to study coordinators to contact women who 
will need treatment or further care. Local pathology results will be used for referral to 
treatment per standard-of-care guidelines.  
 
2.11 Pathology quality assurance 
 
An expert gynecologic pathologist will evaluate slides with CIN2+ diagnoses and those of the 5% 
screen-negative sample on a regular basis for confirmation of underlying diagnosis. Local 
pathology will guide patient management, but primary analysis will be based on the results of 
the review by the expert pathologist. This expert evaluation may be done in person or remotely 
using a slide scanner. If the expert pathologist upgrades the local diagnosis, the MoH and 
patient will be informed and offered treatment as appropriate. It will also be important to 
differentiate CIN2 from CIN3 diagnoses, given recent epidemiological evidence that CIN3 is 
more likely to progress to invasive cervical cancer.24  
 
3. POWER CALCULATIONS AND DATA ANALYSIS  
 
3.1 Aim 1: Validate AVE as a primary screening test compared to visual inspection with acetic 
acid (VIA) for the detection of high-grade cervical pre- cancer (CIN2+). 
 
A study with 10,000 women will be able to detect a minimum difference of 10% between VIA 
and AVE with 80% power and a Type I error rate of 5%, assuming a minimum sensitivity of VIA 
of 65% and a correlation coefficient of the tests in the diseased population (Rho) of at least 
50%. Based on the study design, all participants who test positive on any test will be referred to 
colposcopy with biopsy (i.e., proportion of verification = 1), as opposed to only 5% of those who 
are double negative being referred (i.e., proportion of verification = 0.05). Finally, based on our 
previous experience working in El Salvador, we estimate the prevalence (lambda) of CIN2+ in 
the general screening population at 2%.  
 
3.2 Aim 2. To compare AVE as a triage test compared to VIA for detecting CIN2+ among 
HPV-positive women.   
 
3.2.2 Data analysis 
Since all women who test positive with careHPV, VIA or AVE will undergo colposcopy with 
biopsy, the positive predictive value (PPV) for CIN2+ will be estimated directly using the women 
who test positive with a particular screening test. An unbiased estimate of NPV will be obtained 
by using only results for the 5% of women who are negative for the three screening tests who 
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are randomly selected to receive colposcopy and a minimum of two biopsies. Methods that 
account for verification-biased sampling will be used to obtain unbiased estimates of sensitivity 
and specificity for CIN2+ detection.25 A method developed by Leisenring et.al. 26 will be used to 
test for significant differences in PPV and NPV.  
 
4. DATA COLLECTION AND MANAGEMENT 
  
4.1 Data collection 
 
All data will be recorded in real time on paper forms filled out by a nurse research assistant. All 
forms will include the date and study ID to link information to specific patients and visits. 
Collected data will include eligibility criteria, a background questionnaire including relevant 
sociodemographic and medical history traits, clinical procedures, and laboratory results. In 
addition, providers conducting speculum exams during the first (screening) and second 
(colposcopy and biopsy) visits will use the CervManager application to create a profile for each 
patient to input clinical information. Thus, study data will be collected on both paper forms and 
CervManager for added back-up security. Providers will also capture cervical images using the 
CervManager application on both the Eva System and an Adroid mobile phone. Images 
belonging to the same patient will be synchronized under the same study ID. Other clinical data 
(e.g., HPV test results, histopathology) will also be inputted into the CervManager patient 
profile. 
 
4.2 Data Management 
 
For storage and management, data from paper forms will be transferred to REDCap,27-28 an 
electronic data management system widely used for clinical research. CerwvManager and 
REDCap can be downloaded and merged periodically to easily identify and correct any entry 
errors, duplications, or missing data on either database. All AVE algorithms implemented as part 
of this project and used for subsequent analyses will run on DL Analytics servers. 
 
4.3 Non-participant documentation 
 
We will document the number of eligible women who decline to participate in the study 
(including main reasons why). If individuals agree, we will collect general, de-identified 
information (i.e., age range, education, and previous screening). This will be done to identify 
any potential source of sampling bias.  
 
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5. DATA SAFETY AND CONFIDENTIALITY 
 
Data collection forms will be stored in locked filing cabinets in an office with a lock at BHI              
facilities. Informed consents and any documents with personally identifying information will be 
stored separately also in locked filing cabinets for a 5 year period after the study ends. All data 
from paper forms will be transferred to REDCap, which will be housed at an authorized BHI 
server that manages several other projects. Access to REDCap and the CervManager database is 
password-protected and restricted to authorized users. Both databases will only be accessible 
to selected study team members and providers will only be able to enter and access information 
about their own patients on CervManager. DL Analytics servers are HIPAA compliant, password 
protected and encrypted to ensure that participant’s information remains private. All individuals 
with access to study data will be certified in protection of research human subjects.  
 
Participant confidentiality will be maintained through the use of an alphanumeric study ID to 
de-link personal information from study data. Digital cervical images will be saved automatically 
in the CervManager database under each participant’s study ID. The images along with the 
results of VIA, HPV tests, AVE, colposcopy, and biopsy, de-linked from any personnel or 
identifiable data, can be utilized in the further development of AVE technology or shared with 
other research teams working in the same field. Finally, data audits will be conducted every 6 
months to guarantee the accuracy of collected data and troubleshoot any potential issues. 
 
5.1. Dissemination of findings 
 
Findings for this investigation will be shared in aggregated and/or summarized form with 
corresponding authorities in El Salvador and disseminated in medical journals and national and 
international conferences, as is routine in scientific investigations. In case of data or specimen 
transfer for research objectives, information will only be shared with the consent of participants 
and with the express approval of the ethical committee of reference, as appropriate.  
 
6. OTHER RISKS AND SAFETY CONSIDERATIONS 
 
6.1 Clinical risks 
 
The clinical risks of this study to individual patients are minimal. Provider sampling for HPV 
testing, VIA, AVE and ablation treatment are all very safe. HPV testing and thermal ablation are 
the standard of care in El Salvador, and VIA and AVE involve only a visual assessment and 
capturing an image, respectively, during a standard speculum exam. It is possible that the use of 
VIA and AVE as additional screening tests increase the possibility of detecting HPV infections 
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and precancer cases. Colposcopy and biopsy are routine proceedings in gynecological care that 
will provide greater confidence in the results of screening tests.  
 
6.2 Monitoring and adverse events 
 
A monitoring plan consisting of site visits and weekly teleconferences will be carried out by 
study investigators, local personnel, general and local coordinators. Adverse events (AEs), 
serious adverse events (SAEs), unanticipated problems, and any protocol deviation or violation 
will be registered with appropriate documentation by local investigators or coordinators, who 
will notify principal investigators and coordinators within 24 hours after learning about them. 
Similarly, principal investigators must report SAEs to the ethics committee in 48 working hours 
after learning about the event. 
 
6.3 Data Safety and Monitoring Board 
 
A Data Safety and Monitoring Board (DSMB) will be convened. Participants will include at least 
four physicians, statisticians, and/or other investigators that are not directly involved in the 
study. After participant enrollment begins, the group will include a telephone conference every 
six months and on additional occasions if there is a SAEs. Evaluating enrollment, loss to 
follow-up, participant safety, confidentiality violations, side-effects or other problems or 
concerns that may arise during the study. 
 
6.4 Ethics Committees 
 
The study protocol will be submitted to the consideration of the corresponding Salvadoran 
ethics committee, and this will be the committee of record for this study. The protocol will be 
presented also to the committees that oversee the participation of co-investigators as 
necessary.  
 
7. TIMELINE AND MILESTONES 
 
Enrollment and data collection will take place over 18 months. Data audits will be carried out 
regularly during the project. Final analyses will begin after enrollment visits are completed. 
Project timelines and milestones are presented below. 
 
Timeline and Milestones 
 
Year 1 
Year 2 
Milestone 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
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15 
Enrollment/screening (555 women/mo.) 
 
 
 
 
 
 
 
 
Colposcopy and biopsy visits 
 
 
 
 
 
 
 
 
Local pathology and treatment 
 
 
 
 
 
 
 
 
QA pathology review 
 
 
 
 
 
 
 
 
Data audits 
 
 
 
 
 
 
 
 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
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