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Cervical Intraepithelial Neoplasia

Double freeze treatment consists of three-minute freeze, five-minute thaw, three-minute freeze

Single freeze treatment consists of one five-minute freeze

Thermoablation for 60-seconds at 100 degrees Celsius

Standard therapy using carbon dioxide for freezing of tissue

CO2 standard therapy

Provides a means of freezing tissue without the use of gases or liquids

CryoPen

Thermocoagulator

Miriam Cremer, MD

The purpose of this academic-industrial partnership will compare the CryoPen® and thermoablator to traditional CO2-based cryotherapy for the treatment of cervical precancer in low and middle income countries (LMICs) and investigate whether the cure rates of cervical intraepithelial neoplasia 2 and more severe diagnoses (CIN2+) with these devices are non-inferior compared to that of conventional cryotherapy. The results of this study will affect other research areas by serving as a springboard to exploring treatment alternatives that are amenable to low-resource settings and thus will reach the most vulnerable populations.

Cryotherapy is the current gold standard for treatment of precancerous cervical lesions in low resource settings. However, in recent years a number of issues-particularly the use of compressed gas, which requires storage and replenishment of large and potentially dangerous tanks-have emerged as clear limitations. Two technologies-the LMICs-adapted CryoPen®, manufactured and sold by CryoPen®, Inc. (TX, USA), and the thermoablator commercialized by WISAP Medical Technology (Germany) are treatment options for precancerous cervical lesions that run on electricity and avoid the difficulties associated with compressed gas. The LMIC-adapted CryoPen® (hereafter, CryoPen®) differs from previous cryotherapy methods in that it does not require an external source of gas (a tank), since the gas for cooling is built into the system. Thermoablation (also called thermocoagulation) has been used since the 1970s for treatment of cervical lesions. This is treatment with a probe heated to temperatures of 100 to 120ºC. It is also an effective, inexpensive method that does not require high-level healthcare providers.

The purpose of this study is to conduct a randomized non-inferiority clinical trial to compare the CryoPen® and WiSAP thermoablator to CO2-based cryotherapy for the treatment of CIN2 or more severe diagnoses ("CIN2+") but excluding microinvasive or invasive cervical cancer. The primary objective is to compare CIN2+ cure rates after treatment with the LMIC-adapted CryoPen®, the WISAP thermoablator, and CO2-based cryotherapy.

Women will be recruited from the Salvadorian Social Security Hospital (ISSS) in San Salvador, El Salvador, La Liga Contra el Cancer in Lima, Peru and Hospital Universitario San Ignacio in Bogota, Colombia. All are referral sites for women with abnormal cytology.

The investigators will approach approximately 1,602 women with CIN2+ during a 2.5 year enrollment phase (30 months). Assuming an approximately 80% participation rate, approximately 1,281 women will be enrolled- 1,152 (90%) will be eligible for cryotherapy (i.e. no contraindications) and 129 will be ineligible and undergo alternative treatments. The investigators estimate that approximately 20% will be lost to follow-up at the twelve-month visit, so that complete data will be available on a total of 922 women (57.55% of 1,602) treated with either CO2-based cryotherapy, LMIC-adapted CryoPen®, or thermoablation.

Eligible women with biopsy-confirmed CIN2+ will undergo HPV genotyping with next-generation sequencing. The specimen is taken prior to treatment to establish a baseline of which HPV types are present. If a different HPV type is present in the post-treatment specimen, this will be classified as a new rather than persistent infection. Testing will be conducted at the National Cancer Institute in Rockville, MD. Women will be randomly assigned to one of three study arms:

A. CO2-based cryotherapy (double freeze), B. CryoPen® (single freeze), or C. Thermoablation for 40 seconds at 100ºC.

At a pre-treatment visit, consented women will receive a pregnancy test as part of the eligibility criteria for enrollment in the study. Pre-vaginal cultures will be collected to be analyzed for bacterial vaginosis, yeast, gonorrhea and chlamydia. The same cultures will be collected at a 6-week follow-up visit. Consented women will be enrolled and undergo a pelvic exam and visual inspection of the cervix following placement of diluted acetic acid on the cervix. Images of the cervix will be taken with a mobile ODT device will be taken before and after treatment. Women deemed ineligible for cryotherapy will undergo LEEP immediately. In the case of suspected cancer, women will be appropriately referred.

Six weeks post-treatment, women who return for a visit for evaluation of treatment side effects; these women will complete a questionnaire to assess the presence of pain or cramps, bleeding, stenosis, watery discharge, malodorous discharge and be evaluated for evidence of cervicitis. In addition, vaginal cultures will be collected and analyzed for bacterial vaginosis, yeast, gonorrhea, and chlamydia.

One year post-treatment, women will return for a follow-up visit to determine residual disease, which is the primary endpoint. Residual disease will be determined by colposcopy and four-quadrant biopsies. In addition, VIA, cytology, and high-risk HPV DNA testing with careHPV will be performed. Genotyping and next-generation sequencing will be repeated to differentiate between persistent and new infections. The goal is to evaluate sensitivity of VIA, cytology, and HPV testing post-treatment. Women diagnosed with recurrent/untreated CIN2+ on biopsy will be asked to return to undergo LEEP. Women with suspected cancer on biopsy will be referred to the local cancer hospital for standard of care.

An Innovative Treatment for Cervical Precancer (UH3)

A Randomized Controlled Trial Comparing Cure Rates of Cervical Intraepithelial Neoplasia Grade 2 and Higher (CIN2+) Treated With CO2-based Cryotherapy, CropPen, and Thermoablation (UH3)

IDP data will be shared at the completion of the study.

Diagnosis of recurrent and or untreated cervical intraepithelial neoplasia grade 2 or with cervical cancer diagnosis

Patient pain scores using the Wong-Baker FACES Pain Rating Scale

National Cancer Institute (NCI)

Basic Health International

University of Southern California

Instituto Salvadoreno del Seguro Social

Hospital Universitario San Ignacio

Medical College of Wisconsin

Shanxi Bethune Hospital

The Cleveland Clinic

Thermoablator outfitted with a 19mm conical tip

Thermoablator outfitted with detachable probes

Standard C02 Cryotherapy

Single Tip Thermoablation

Multiple Tip Thermoablation

The purpose of this academic-industrial partnership will be to compare two thermoablation modalities using devices adapted to low and middle income countries (LMICs) to traditional CO2-based cryotherapy for the treatment of cervical precancer. The investigators will investigate whether the cure rates of cervical intraepithelial neoplasia 2 and more severe diagnoses (CIN2+) with these devices are non-inferior compared to that of conventional cryotherapy. The results of this study will affect other research areas by serving as a springboard to exploring treatment alternatives that are amenable to low-resource settings and thus will reach the most vulnerable populations.

The standard treatment for cervical pre-cancer is gas-based cryotherapy, the freezing of tissue to ablate (destroy) lesions. Although cryotherapy is relatively simple to perform, the necessary gas tanks are generally expensive, difficult to obtain and transport, and pose a danger of explosion. An urgent need exists for a point-of-care treatment technology that is accessible, portable, and inexpensive. An alternative ablative procedure in use since the 1970s is thermoablation (also known as cold coagulation or thermocoagulation), which utilizes heat to destroy pre-cancer. Despite its long-standing use, there are no standardized guidelines for thermoablation. There is also little data on patient and provider acceptability, potential side effects, and the impact of different treatment protocols on quality of life. For these reasons, international and national agencies have been hesitant to adopt the technique as an alternative to cryotherapy. The purpose of this research study is to develop a patient-centered thermoablation protocol that is simple, safe, and effective.

Currently, the most common treatment technique for thermoablation involves a multiple-tip protocol, which uses differently shaped probe-tips to cover the affected area. This technique requires a considerable degree of expertise, and may not be the most appropriate strategy for settings where highly trained healthcare providers are scarce. In collaboration with WiSAP Medical Technology (Brunnthal, Germany), the manufacturer of the most widely used thermoablator, the investigators modified the original device to meet the needs of low-resource settings. The LMIC-adapted thermoablator is lightweight, portable, and easy to operate. The investigators will further modify the LMIC-adapted thermoablator to test the non-inferiority of two thermoablation treatment approaches against the standard of care (i.e. gas-based cryotherapy). The experimental approaches include:

1. Single tip: A 19mm conical tip with a nipple is applied to the cervix for 40-seconds at 100ºC, a single application of which should ablate the squamocolumnar junction (SCJ) in the majority of women. In the rare instance that the SCJ is not completely ablated, additional 20 second applications can be applied, or
2. Multiple tips: A narrow nipple shaped tip at 100ºC is placed in the endocervix for 20 seconds. This is followed by the placement of a 12 mm flat tip at 100ºC on the ectocervix for as many 20-second applications as necessary to ablate the entire SCJ.

These will be tested against traditional CO2 cryotherapy treatment using a MedGyn device in a standard double-freeze procedure (3 minute freeze, 5 minute thaw, 3 minute freeze).

Women will be recruited at colposcopy clinics run by the Ministry of Health and the Mexican Institute of Social Security (Instituto Mexicano del Seguro Social) in the Mexico City metropolitan region. Eligible women will be those over the age of 18, who are able and willing to provide informed consent and a reliable or permanent address, and with a biopsy-confirmed CIN2+ diagnosis. Women wo are pregnant, plan to become pregnant during the study duration, with a history of total hysterectomy, past surgeries destructive to the cervix within the last 5 years, with a disfigure or hard-to-reach cervix, and those with contraindications for ablative treatment will be excluded from the study.

The investigators will approach 1,602 women with CIN2+ during a four-year enrollment phase (48 months). Assuming an 80% participation rate, approximately 1,282 women will be enrolled; of these, 1,155 (90%) will be eligible for ablation treatment (i.e. no contraindications) and 129 will be ineligible and undergo alternative treatments (i.e. LEEP or invasive cancer treatment). The investigators estimate that approximately 20% will be lost to follow-up at the 12-month visit, resulting in complete data on a total of 924 women (57.7% of 1,602) treated with CO2-based cryotherapy, single-tip thermoablation, or multiple-tip thermoablation. The investigators will monitor the percentages of ineligible women, contraindications, and loss to follow-up in real time and adjust recruitment accordingly to achieve the target sample size.

The clinical endpoint of the study will be residual disease at the 12-month follow-up visit as determined by colposcopy, four-quadrant biopsy, and endocervical curettage (ECC). HPV testing will also be performed at this visit to differentiate between persistent or new infection. Cytology, VIA and care HPV tests will also be performed to evaluate the most effective post treatment screening strategy.

At a pre-treatment visit, consented women will receive a pregnancy test as part of the eligibility criteria for enrollment in the study. Pre-vaginal cultures will be collected to be analyzed for bacterial vaginosis, yeast, gonorrhea and chlamydia. The same cultures will be collected at a 6-week follow-up visit. Consented women will be enrolled and undergo a pelvic exam and visual inspection of the cervix following placement of diluted acetic acid on the cervix. Images of the cervix will be taken with a mobile colposcopy device will be taken before and after treatment. Women will be asked to evaluate their pain level after speculum insertion, immediately before treatment, and immediately after treatment. These women will also complete a quality of life assessment. Women deemed ineligible for cryotherapy will undergo LEEP immediately. In the case of suspected cancer, women will be appropriately referred.

Six weeks post-treatment, women who return for a visit for evaluation of treatment side effects; these women will be administered a post-treatment patient satisfaction survey, and complete a questionnaire to assess the presence of pain or cramps, bleeding, stenosis, watery discharge, malodorous discharge and be evaluated for evidence of cervicitis. In addition, vaginal cultures will be collected and analyzed for bacterial vaginosis, yeast, gonorrhea, and chlamydia.

One year post-treatment, women will return for a follow-up visit to determine residual disease, which is the primary endpoint. Residual disease will be determined by colposcopy and four-quadrant biopsies. In addition, VIA, cytology, and high-risk HPV DNA testing with careHPV will be performed. Genotyping and next-generation sequencing will be repeated to differentiate between persistent and new infections. The investigators will evaluate sensitivity of VIA, cytology, and HPV testing post-treatment. Women will be asked to again complete the quality of life assessment and treatment acceptability instrument. Women diagnosed with recurrent/untreated CIN2+ on biopsy will be asked to return to undergo LEEP. Women with suspected cancer on biopsy will be referred to the local cancer hospital for standard of care.

Comparison of Cervical CIN II/III Treatment Outcomes With Thermal Ablation Device

Comparison of Cervical Intraepithelial Neoplasia 2/3 Treatment Outcomes With a Portable LMIC-adapted Thermal Ablation Device vs. Gas-based Cryotherapy

FACIT-CD Version 4: 5-subscales. For all subscales and the scale, 0 is the worst outcome, higher scores are better outcomes. All subscales are summed. Subscale ranges are as follows: Physical well-being:0 to 32, Treatment satisfaction: 0 to 16, General perceptions: 0 to 28, Emotional well-being:0 to 44, Relationship support: 0 to 16

Herth Hope Index. The construct is hope in adults in clinical settings. Scale ranges: 1 to 4. For the total index, 12 is the worst outcome. Higher scores are better outcomes. There are no subscales.

To compare CIN2+ cure rates 12-months post-treatment for CO2-based cryotherapy and both single versus multiple tips thermoablation strategies

Functional Assessment of Chronic Illness Therapy for Patients with Cervical Dysplasia Version 4 (FACIT-CD). Consists of 5-subscales listed below. For all subscales and the scale, 0 is the worst outcome, higher scores are better outcomes. All subscales are summed.

Subscale ranges are as follows: Physical well-being:0 to 32, Treatment satisfaction:0 to 16, General perceptions:0 to 28, Emotional well-being:0 to 44, Relationship support: 0 to 16 Wong-Baker FACES® Pain Rating Scale, construct being measured is pain for anyone over the age of 3. Scale range: Minimum = 0, Maximum = 10. For each scale range, what is a better or worse outcome: 0 is a better outcome (no pain), higher scores are worse outcomes, and 10 is the worst outcome (worst pain). There are no subscales.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
An Innovative Treatment for Cervical Precancer (UH3)	NCT03084081	Cervical Intrae...	CO2 standard th... CryoPen Thermocoagulato...	18 Years - 65 Years	The Cleveland Clinic
Comparison of Cervical CIN II/III Treatment Outcomes With Thermal Ablation Device	NCT03429582	Cervical Intrae...	Standard C02 Cr... Single Tip Ther... Multiple Tip Th...	18 Years -	The Cleveland Clinic

Spots Global Cancer Trial Database for low and middle income countries (lmics)