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Randomized Controlled Trial Comparing Routine Colposcopy to HPV Testing to Identify Persistent or Recurrent High Grade Cervical Cancer Precursors

18 Years
Open (Enrolling by invite only)
High Grade Cervical Intra-epithelial Neoplasia

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Trial Information

Randomized Controlled Trial Comparing Routine Colposcopy to HPV Testing to Identify Persistent or Recurrent High Grade Cervical Cancer Precursors

Background and rational: Cervical cancer ranks twelfth in terms of cancer mortality in
Canadian women, but remains the second most frequent cancer in Canadian women aged 20-44.
Fortunately, its natural history makes it an ideal candidate for successful prevention.
Cervical cancer and its precursors are caused by a persistent infection of the cervical
epithelium by one of the 15 oncogenic (or high risk) types of human papillomaviruses (HPVs).
The preinvasive changes of cervical intra-epithelial neoplasia (CIN) can be identified
through cervical cytology (also known as the Pap test). When cellular abnormalities are
identified, women are referred for diagnostic testing. High-grade precursor lesions (CIN2/3)
carry a high risk of progression to invasive cancer and for this reason their treatment is
recommended. Treatment success rates of CIN2/3 are 85%. However, those who fail treatment
need to be identified promptly because their risk of invasive disease is increased more
then 10 fold. The current strategy used in Canada to identify treatment failures consists of
a follow-up every 6 months in colposcopy clinics for 2 years. Recent research underlines the
fact that routine colposcopy is unreliable and may miss significant lesions. The
identification of oncogenic HPV DNA in the cervical secretions is known as HPV testing. A
few studies have investigated the use of HPV testing in the identification of treatment
failures. Although they point to a very good sensitivity (90-95%) there were methodological
limitations: studies were small; the HPV test used was often not suitable for clinical
laboratory use; endpoints were not assessed by histological confirmation. Most importantly,
none compared HPV testing to colposcopy, the strategy used in Canada. Research question: Is
HPV testing more sensitive than routine colposcopy to identify CIN2/3 treatment failures?
Methodology: Design: We propose a parallel randomized controlled trial, where participants
will be randomized 1:1 to routine colposcopy vs. HPV testing after treatment of CIN2/3
lesions. Study Population: Women treated for high-grade precursor lesions. Exclusion
criteria are: pregnancy, less than 18 years of age, known immunosuppression or
immunodeficiency, unable to provide informed consent. Study interventions: (1) HPV testing
with Hybrid Capture 2. (2) Routine colposcopy. In order to evaluate the performance of the
current follow-up strategy, there will be no standardized protocol for the colposcopy
intervention, but documentation of procedures will be done. Patients will receive the study
interventions 6 months after treatment. All participants will undergo expert diagnostic
assessment at 12 and 24. Sample size calculation and recruitment rate. The sample size was
calculated to have 80% power to detect an increase in sensitivity of 15%, with an alpha set
at 0.05 (double sided test). Assuming a conservative baseline sensitivity of 70% for
colposcopy, 134 cases of recurrent/persistent disease will be necessary in each study group.
Assuming a 15% failure rate of treatment and a 20% drop out rate, a total of 2250
participants will need to be accrued. Recruitment will take place in high volume colposcopy
clinics across Canada over 2 years. Analysis: The primary analysis will consist of the
comparison of the diagnostic indices of the 2 follow-up strategies: sensitivity,
specificity, positive and negative predictive values (with their 95% asymptotic confidence
intervals). Cumulative persistent/recurrent cases identified during the 2 year follow-up
will make up the case group. Since all participants will undergo expert diagnostic
assessment. No subgroup analysis will be performed. 4. Expected contribution: The result
from this trial will provide high quality data on which to base management recommendation.
If HPV testing is found to be more sensitive than routine colposcopy, follow-up of treated
lesion may occur mainly in primary care physician's office with HPV testing, reducing costs,
and making it possible to focus colposcopy activities on a group of women truly at risk of
significant disease.

Inclusion Criteria:

- Woman ≥ 18 years old 19 in British Columbia, Nova Scotia and Newfoundland)

- Understands English or French (for sites where French speaking coordinator is

- Is treated for biopsy proven CIN II, III or AIS

- Understands study procedures, available alternatives treatment, risks related to
study, and accepts voluntarily to participate by signing the ICF.

Exclusion Criteria:

- has been treated for cervical cancer or pre-cancer in the past

- Participant has known immunosuppression or immunodeficiency

- Planned hysterectomy

- Participant is receiving or has received one of the following treatment :

- Immunosuppressive therapy in the three months prior to enrollment

- Corticosteroid therapy in the two weeks prior to enrollment

- Two or more courses of corticosteroids (orally or parenterally) lasting at least
one week in duration in the year prior to enrollment (inhalation, nasal or
topical corticosteroids are permitted)

- There is a strong probability that the participant will not follow the procedures of
study, will not come to its appointment, or plans a delocalization throughout study.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Investigator, Outcomes Assessor), Primary Purpose: Diagnostic

Outcome Measure:

Sensitivity of HPV testing and sensitivity of routine colposcopy to identify CIN2 or worse disease after treatment for CIN 2/3

Outcome Time Frame:

6 months post treatment

Safety Issue:


Principal Investigator

Marie-Hélène Mayrand, MD,PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Centre de Recherche du Centre Hospitalier de l'Université de Montréal


Canada: Health Canada

Study ID:




Start Date:

January 2010

Completion Date:

December 2015

Related Keywords:

  • High Grade Cervical Intra-epithelial Neoplasia
  • Cervical intra-epithelial neoplasia
  • Colposcopy
  • HPV DNA testing
  • treatment failure
  • Neoplasms
  • Cervical Intraepithelial Neoplasia
  • Carcinoma in Situ