Validation of a Lab-free Low-cost Screening Test for Prevention of Cervical Cancer

Official title

Validation of a Lab-free Low-cost Screening Test for Prevention of Cervical Cancer: Automated Visual Evaluation

Overview

The purpose of this study is to validate Automated Visual Evaluation (AVE), specifically the CINFinder version developed by DL Analytics, a point-of-care screening and triage diagnostic tool for cervical cancer based on the assessment of digital images through artificial intelligence. Several teams around the world have developed versions of AVE as a triage technology but none as a screening tool.

Detailed description

BACKGROUND:

Cervical cancer, caused by persistent infection of carcinogenic types of the human papillomavirus (HPV), is the second leading cause of female cancer in El Salvador. Effective screening and treatment of precancerous lesions have lowered cervical cancer rates in high-income countries, but the disease remains a leading cause of death in low-and middle-income countries (LMICs). Currently, up to 80% of the disease burden and 90% of global deaths occur in LMICs primarily due to lack of resources and poor infrastructure. A new test, Automated Visual Evaluation (AVE), is a point-of-care screening and triage diagnostic tool based on the assessment of digital images through artificial intelligence.

The purpose of this study is to validate Automated Visual Evaluation (AVE), specifically the CINFinder version developed by DL Analytics, 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 (CINFinder version) with traditional screening and triage tests.

STUDY DESIGN:

This is a prospective paired interventional study of 10,000 women in San Salvador, El Salvador, to test the difference in sensitivities between AVE (CINFinder) and with other screening and triage tests, including HPV tests and unaided visual inspection with acetic acid (VIA) to detect CIN2+ as a primary screening method. As a secondary aim, investigators will also validate the use of AVE as a triage test in patients with positive HPV results. Histopathology diagnosis will be used as the reference to determine true disease status.

STUDY PROCEDURES:

The design includes a screening visit, a colposcopy visit, and a result delivery and treatment visit. During the screening visit, participants will undergo routine HPV sample collection, VIA, AVE with the EVA System (digital colposcope), and an additional cervical image capture with an Android smartphone. Women with a positive screening result on any of the three main screening tests (HPV test, VIA, or AVE with the EVA System) will be referred to a second study visit to undergo HPV testing with a genotyping test, 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. 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. Women will receive their histopathology results during the third visit and, if eligible, will be offered ablation treatment the same day. Women ineligible for ablation will be referred to LEEP or other care as appropriate.

DATA COLLECTION \& MANAGEMENT:

This specific version of AVE (CINFinder) is designed to run on both EVA System and an Android phone, alongside additional tools for improving image quality and post-screening management.The AVE software (including CINFinder, CerVisibility, and CervManager modules), will be installed as user-friendly features that can be easily accessed by authorized

Data collection: All data will be recorded in real time on paper forms OR on an electronic tablet filled out by a nurse research assistant. All forms (digital or paper) 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 Android 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.

Data Management: For storage and management, data from paper forms will be transferred to REDCap, an electronic data management system widely used for clinical research. CervManager 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.

Non-participant documentation: Investigators will document the number of eligible women who decline to participate in the study (including main reasons why). If individuals agree, Investigators 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.

STATISTICAL POWER CALCULATIONS AND SAMPLE SIZES

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 the Investigators previous experience working in El Salvador, Investigators estimate the prevalence (lambda) of CIN2+ in the general screening population at 2%.

Objective 2. To compare AVE as a triage test compared to VIA for detecting CIN2+ among HPV-positive women.

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 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.

Interventions

• Diagnostic test HPV Test
  The careHPV (QIAGEN, Gaithersburg, MD) test was developed in a public-private partnership specifically for use in low-resource settings. It is a simplified, robust, and affordable HPV test that does not distinguish specific HPV types; rather, it gives a positive result if any of 14 hrHPV types is present in the specimen. Electricity is necessary to run the test, but it does not need running water or air conditioning. In order to be most cost effective, the samples must be run with a full plate o
• Device EVA System
  Digital colposcope
• Procedure Visual Inspection with Acetic Acid (VIA)
  unaided visual inspection with acetic acid
• Diagnostic test Automated Visual Evaluation (AVE)
  Digital diagnostic classification, quality classifier using captured images from EVA System
• Other Image Capture with Mobile Phone
  Compare performance of AVE installed on a mobile phone vs. on the EVA System
• Diagnostic test Pregnancy test
  Urine based pregnancy test
• Diagnostic test ScreenFire HPV test
  ScreenFire HPV test (Atila BioSystems, Inc, Mountain View, CA) uses isothermal amplification to detect 13 high risk (hr)HPV types directly from clinical samples in approximately one hour. The test can be run on any real-time PCR machine and gives separate results for hrHPV types 16 and 18, as well as a pooled positive result for 13 other hrHPV types. The human cellular gene beta-globin is used as an internal control to measure sample adequacy. ScreenFire can be self-collected and does not requir
• Procedure Colposcopy with biopsy
  A colposcopic exam with biopsy entails visual magnification of the cervix and the removal of a small piece of cervical tissue. After the application of acetic acid 5% onto the cervix, a device called a colposcope allows the clinician to visually identify changes consistent with HPV. Areas of the cervix where lesions appear (or if not, randomly selected sections) are then biopsied (small piece of sample removed) and an endocervical curettage is performed (removing a small section from the inside
• Procedure Thermal Ablation
  Thermal ablation is utilized to treat high-grade cervical precancer. First, a speculum is introduced into the vagina to identify the cervix. Acetic acid 5% is applied to the cervix for one minute and the cervix is observed to look for changes consistent with precancer. If the cervix is able to be fully evaluated and there are no signs of invasive cancer, the tip of the device is heated to 100ºC and applied directly to the cervix for 1-2 minutes, which ablates or destroys the abnormal cells.
• Procedure Loop electrosurgical excision procedure (LEEP)
  LEEP is utilized to remove abnormal tissue from the cervix. This may include tissue with precancerous cells (called cervical dysplasia) or cancerous cells. The loop is heated using electricity to remove the tissue. LEEP may also be called a loop excision or large loop excision of the transformation zone (LLETZ).

Primary outcome measures

• Sensitivity [Time frame: 12 months, non-randomized]
• Positive Predictive Value (PPV) [Time frame: 12 months, non-randomized]

Eligibility criteria

Inclusion criteria

• Women between 30 and 59 years of age

Exclusion criteria

• Pregnancy at the time of colposcopy/biopsy
• Hysterectomy with surgically absent cervix
• HPV test in the last 5 years independently of negative or positive result
• Previous cervical cancer diagnosis or treatment in the last 5 years
• Lack of willingness or capacity to provide informed consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Screening

Study locations

El Salvador · 1 center

• Ministerio de Salud — San Salvador

Publications

• Rao DW, Bayer CJ, Liu G, Chikandiwa A, Sharma M, Hathaway CL, Tan N, Mugo N, Barnabas RV. Modelling cervical cancer elimination using single-visit screening and treatment strategies in the context of high HIV prevalence: estimates for KwaZulu-Natal, South Africa. J Int AIDS Soc. 2022 Oct;25(10):e26021. doi: 10.1002/jia2.26021. PMID 36225139
• Parham GP, Egemen D, Befano B, Mwanahamuntu MH, Rodriguez AC, Antani S, Chisele S, Munalula MK, Kaunga F, Musonda F, Malyangu E, Shibemba AL, de Sanjose S, Schiffman M, Sahasrabuddhe VV. Validation in Zambia of a cervical screening strategy including HPV genotyping and artificial intelligence (AI)-based automated visual evaluation. Infect Agent Cancer. 2023 Oct 16;18(1):61. doi: 10.1186/s13027-023 PMID 37845724
• Hull R, Mbele M, Makhafola T, Hicks C, Wang SM, Reis RM, Mehrotra R, Mkhize-Kwitshana Z, Kibiki G, Bates DO, Dlamini Z. Cervical cancer in low and middle-income countries. Oncol Lett. 2020 Sep;20(3):2058-2074. doi: 10.3892/ol.2020.11754. Epub 2020 Jun 19. PMID 32782524
• Desai KT, Befano B, Xue Z, Kelly H, Campos NG, Egemen D, Gage JC, Rodriguez AC, Sahasrabuddhe V, Levitz D, Pearlman P, Jeronimo J, Antani S, Schiffman M, de Sanjose S. The development of "automated visual evaluation" for cervical cancer screening: The promise and challenges in adapting deep-learning for clinical testing: Interdisciplinary principles of automated visual evaluation in cervical scree PMID 34800038
• Xue Z, Novetsky AP, Einstein MH, Marcus JZ, Befano B, Guo P, Demarco M, Wentzensen N, Long LR, Schiffman M, Antani S. A demonstration of automated visual evaluation of cervical images taken with a smartphone camera. Int J Cancer. 2020 Nov 1;147(9):2416-2423. doi: 10.1002/ijc.33029. Epub 2020 May 19. PMID 32356305
• Ebrahimi N, Yousefi Z, Khosravi G, Malayeri FE, Golabi M, Askarzadeh M, Shams MH, Ghezelbash B, Eskandari N. Human papillomavirus vaccination in low- and middle-income countries: progression, barriers, and future prospective. Front Immunol. 2023 May 12;14:1150238. doi: 10.3389/fimmu.2023.1150238. eCollection 2023. PMID 37261366
• Desai KT, Ajenifuja KO, Banjo A, Adepiti CA, Novetsky A, Sebag C, Einstein MH, Oyinloye T, Litwin TR, Horning M, Olanrewaju FO, Oripelaye MM, Afolabi E, Odujoko OO, Castle PE, Antani S, Wilson B, Hu L, Mehanian C, Demarco M, Gage JC, Xue Z, Long LR, Cheung L, Egemen D, Wentzensen N, Schiffman M. Design and feasibility of a novel program of cervical screening in Nigeria: self-sampled HPV testing pa PMID 33072178
• de Sanjose S, Perkins RB, Campos N, Inturrisi F, Egemen D, Befano B, Rodriguez AC, Jeronimo J, Cheung LC, Desai K, Han P, Novetsky AP, Ukwuani A, Marcus J, Ahmed SR, Wentzensen N, Kalpathy-Cramer J, Schiffman M; PAVE Study Group. Design of the HPV-automated visual evaluation (PAVE) study: Validating a novel cervical screening strategy. Elife. 2024 Jan 15;12:RP91469. doi: 10.7554/eLife.91469. PMID 38224340

Identifiers

NCT: NCT06815939 · 4R44CA247137 · 4R44CA247137

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗