An Innovative Treatment for Cervical Precancer (UH3) (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)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Cervical Intraepithelial Neoplasia
• Intervention / Treatment: Device: CO2 standard therapy; Device: CryoPen; Device: Thermocoagulator

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1130
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Taiyuan, China
    • Shanxi Academy of Medical Sciences Shanxi Bethune Hospital
• Colombia
  • Bogota, Colombia
    • Hospital Universitario San Ignacio
• El Salvador
  • San Salvador, El Salvador
    • Instituto Salvadoreno del Seguro Social (ISSS)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women aged 18 and older
• Biopsy results of CIN2, CIN2-3, CIN3, or high-grade CIN not otherwise specified
• Willing and able to provide informed consent
• Willing and able to provide permanent or reliable address

Exclusion Criteria:

• Pregnant or plans to become pregnant during study
• History of total hysterectomy (verified by medical record or pelvic evaluation)
• Previous surgery destructive to the cervix within the last 5 years
• Patient not eligible for cryotherapy (lesion >75% of cervix, lesion extends into canal or there is suspicion for invasive cancer)
• Cervix shape disfigured or hard to reach

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CO2 standard therapy; Double freeze treatment consists of three-minute freeze, five-minute thaw, three-minute freeze	Device: CO2 standard therapy; Standard therapy using carbon dioxide for freezing of tissue
Experimental: CryoPen; Single freeze treatment consists of one five-minute freeze	Device: CryoPen; Provides a means of freezing tissue without the use of gases or liquids
Experimental: Thermocoagulator; Thermoablation for 60-seconds at 100 degrees Celsius	Device: Thermocoagulator; Thermoablation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Residual CIN2+	Diagnosis of recurrent and or untreated cervical intraepithelial neoplasia grade 2 or with cervical cancer diagnosis	12-months post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain	Patient pain scores using the Wong-Baker FACES Pain Rating Scale	Immediately after treatment

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: National Cancer Institute (NCI); University of Southern California; Medical College of Wisconsin; Hospital Universitario San Ignacio; Basic Health International; Shanxi Bethune Hospital; Instituto Salvadoreno del Seguro Social
• Investigators: Principal Investigator: Miriam Cremer, MD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2017
• Primary Completion (Estimated): July 31, 2024
• Study Completion (Estimated): July 31, 2024

Study Registration Dates

• First Submitted: March 14, 2017
• First Submitted That Met QC Criteria: March 14, 2017
• First Posted (Actual): March 20, 2017

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Cryotherapy; Thermoablation; Thermocoagulation; Low and Middle Income Countries (LMICs); Human Papilloma Virus (HPV)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Carcinoma; Neoplasms, Glandular and Epithelial; Uterine Cervical Diseases; Uterine Diseases; Precancerous Conditions; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Neoplasms; Carcinoma in Situ; Uterine Cervical Dysplasia
• Other Study ID Numbers: 17-294; UH3CA189883 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IDP data will be shared at the completion of the study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No