An Innovative Treatment for Cervical Precancer (UH3)

Brief Title

An Innovative Treatment for Cervical Precancer (UH3)

Official Title

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

Interventional

Primary Outcome

Residual CIN2+

Secondary Outcome

 Pain

Condition

Cervical Intraepithelial Neoplasia

Intervention

CO2 standard therapy

Study Arms / Comparison Groups

 CO2 standard therapy

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Device

Estimated Enrollment

1130

Start Date

August 1, 2017

Completion Date

July 31, 2023

Primary Completion Date

July 31, 2023

Eligibility Criteria

        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
      

Gender

Female

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

Miriam Cremer, MD, , 

Location Countries

China

Location Countries

China

NCT ID

NCT03084081

Organization ID

17-294

Secondary IDs

UH3CA189883

Responsible Party

Sponsor

Study Sponsor

The Cleveland Clinic

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

Miriam Cremer, MD, Principal Investigator, The Cleveland Clinic

Verification Date

January 2023