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An Innovative Treatment for Cervical Precancer (UH3) (UH3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03084081
Recruitment Status : Recruiting
First Posted : March 20, 2017
Last Update Posted : March 5, 2020
National Cancer Institute (NCI)
Basic Health International
CryoPen, Inc.
University of Southern California
Albert Einstein College of Medicine
Harvard School of Public Health
Instituto Salvadoreno del Seguro Social
Hospital Universitario San Ignacio
Medical College of Wisconsin
Shanxi Academy of Medical Sciences Shanxi Dayi Hospital
Information provided by (Responsible Party):
The Cleveland Clinic

Tracking Information
First Submitted Date  ICMJE March 14, 2017
First Posted Date  ICMJE March 20, 2017
Last Update Posted Date March 5, 2020
Actual Study Start Date  ICMJE August 1, 2017
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 14, 2017)
Residual CIN2+ [ Time Frame: 12-months post treatment ]
Diagnosis of recurrent and or untreated cervical intraepithelial neoplasia grade 2 or with cervical cancer diagnosis
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 14, 2017)
Pain [ Time Frame: Immediately after treatment ]
Patient pain scores using the Wong-Baker FACES Pain Rating Scale
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE An Innovative Treatment for Cervical Precancer (UH3)
Official Title  ICMJE 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)
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Cervical Intraepithelial Neoplasia
Intervention  ICMJE
  • Device: CO2 standard therapy
    Standard therapy using carbon dioxide for freezing of tissue
  • Device: CryoPen
    Provides a means of freezing tissue without the use of gases or liquids
  • Device: Thermocoagulator
Study Arms  ICMJE
  • Active Comparator: CO2 standard therapy
    Double freeze treatment consists of three-minute freeze, five-minute thaw, three-minute freeze
    Intervention: Device: CO2 standard therapy
  • Experimental: CryoPen
    Single freeze treatment consists of one five-minute freeze
    Intervention: Device: CryoPen
  • Experimental: Thermocoagulator
    Thermoablation for 60-seconds at 100 degrees Celsius
    Intervention: Device: Thermocoagulator
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 14, 2017)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Miriam Cremer, MD 216-312-0618
Contact: Mauricio Maza, MD 503-7854-8873
Listed Location Countries  ICMJE China,   Colombia,   El Salvador
Removed Location Countries Peru
Administrative Information
NCT Number  ICMJE NCT03084081
Other Study ID Numbers  ICMJE 17-294
UH3CA189883 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: IDP data will be shared at the completion of the study.
Responsible Party The Cleveland Clinic
Study Sponsor  ICMJE The Cleveland Clinic
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Basic Health International
  • CryoPen, Inc.
  • University of Southern California
  • Albert Einstein College of Medicine
  • Harvard School of Public Health
  • Instituto Salvadoreno del Seguro Social
  • Hospital Universitario San Ignacio
  • Medical College of Wisconsin
  • Shanxi Academy of Medical Sciences Shanxi Dayi Hospital
Investigators  ICMJE
Principal Investigator: Miriam Cremer, MD The Cleveland Clinic
PRS Account The Cleveland Clinic
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP