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Female Urogenital Diseases and Pregnancy Complications

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

Single heat application at 100 ºC for 40 seconds

CO2 standard cryotherapy

The use of heat produced by high-frequency electric current to bring about local destruction of tissues

The purpose of this study is to test two innovative devices, the CryoPen® and thermocoagulator, against gas-based cryotherapy to determine whether the novel devices produce equivalent or improved destruction of cervical tissue compared to gas-based cryotherapy. Tissue destruction with single freeze versus double freeze treatments with the CryoPen and gas-based cryotherapy will also be compared.

The primary objectives of the study are to test the hypothesis that the CryoPen® and thermocoagulator provide a non-inferior depth of cervical tissue necrosis compared with traditional CO2-based cryotherapy and to test single versus double freeze applications. The secondary objectives of the study are to determine if the CryoPen® or thermocoagulator achieves a depth of necrosis of 3.5 mm, the accepted depth required for eradicating 95% of cervical precancer, and to observe the relationship between depth of necrosis and variations in cervical anatomy.

An Innovative Treatment for Cervical Pre Cancer

CryoPen: An Innovative Treatment for Cervical Precancer in Low-Resource Settings

Scale Title: Pain scale during treatment Minimal value = 0 (no pain) Maximum value = 10 (most pain) This is a one item 11-point scale to measure self-reported pain during each of the treatments which lasted between 40 seconds (thermoablation) and 13 minutes (double freeze cryotherapy and double freeze CryoPen).

CryoPen, Inc.

Albert Einstein College of Medicine

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

CO2 standard cryotherapy: Standard therapy using carbon dioxide for freezing of tissue

CO2 Standard Cryotherapy- Double Freeze

Single freeze treatment consists of one five-minute freeze

CO2 standard cryotherapy: Standard therapy using carbon dioxide for freezing of tissue

CO2 Standard Cryotherapy- Single Freeze

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

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

CryoPen- Double Freeze

Single freeze treatment consists of one five-minute freeze

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

CryoPen- Single Freeze

Single heat application at 100 ºC for 40 seconds

Thermocoagulator: The use of heat produced by high-frequency electric current to bring about local destruction of tissues

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

El Salvador

Peru

Region of Enrollment

Dr. Miriam Cremer

Mean Depth of Necrosis Achieved With the LMIC-adapted CryoPen and the Thermocoagulator Compared to Mean Depth of Necrosis Achieved With CO2-based Cryotherapy

Mean Pain During Treatment Reported by Patients Treated With Double and Single Freeze CO2 Cryotherapy, Double and Single Freeze CryoPen and Thermoablation

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
An Innovative Treatment for Cervical Precancer (UH3)	NCT03084081	Cervical Intrae...	CO2 standard th... CryoPen Thermocoagulato...	18 Years - 65 Years	The Cleveland Clinic
An Innovative Treatment for Cervical Pre Cancer	NCT02814448	Cervical Intrae...	CryoPen CO2 standard cr... Thermocoagulato...	25 Years - 65 Years	The Cleveland Clinic
An Innovative Treatment for Cervical Pre Cancer	NCT02814448	Cervical Intrae...	CryoPen CO2 standard cr... Thermocoagulato...	25 Years - 65 Years	The Cleveland Clinic

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