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Impact on Disease Relapse of HPV Vaccination in Women Treated With LEEP for Cervical Intraepithelial Neoplasia. HOPE9 (HOPE9)

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ClinicalTrials.gov Identifier: NCT03848039
Recruitment Status : Not yet recruiting
First Posted : February 20, 2019
Last Update Posted : September 16, 2020
Sponsor:
Information provided by (Responsible Party):
Alessandro Ghelardi, Azienda USL Toscana Nord Ovest

Tracking Information
First Submitted Date  ICMJE February 19, 2019
First Posted Date  ICMJE February 20, 2019
Last Update Posted Date September 16, 2020
Estimated Study Start Date  ICMJE October 2020
Estimated Primary Completion Date October 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 19, 2019)
evaluation of disease recurrence reduction (cervical intraepithelial neoplasia up to microinvasive cancer of the cervix) [ Time Frame: 5 years after surgical treatment ]
evaluation of disease recurrence reduction (cervical intraepithelial neoplasia up to microinvasive cancer of the cervix) by comparing the number of recurrences in the two arms of the study
Original Primary Outcome Measures  ICMJE
 (submitted: February 19, 2019)
1. Cumulative recurrence of CIN2+ during the follow-up period, as assessed by colposcopy, HPV test and paptest with biopsies taken of suspect lesions confirming CIN2+ recurrence. [ Time Frame: 5 years after surgical treatment ]
To evaluate the impact of presurgical HPV 9-valent HPV vaccination in patients submitted to conization for the management of high-grade cervical intraepithelial neoplasia (HG-CIN) and initially invasive cervical cancer in terms of possible reduction of disease recurrence.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 21, 2020)
  • impact of the vaccine on prevalent post-surgery infections [ Time Frame: 5 years after surgical treatment ]
    Analysis of the impact of the vaccine on prevalent post-surgery infections by comparing the prevalence of persistent HPV infections (duration greater than 12 months after surgery) in the two arms.
  • impact of the vaccine in the post-surgical surveillance times, comparison of viral wash-out times (negativity of the HPV test), times of negativization of the pap test and of the colposcopic picture in the post-operative period [ Time Frame: 5 years after surgical treatment ]
    Analysis of the impact of the vaccine in the post-surgical surveillance times, comparison of the viral wash-out times (negativity of the HPV test), times of negativization of the pap test and of the colposcopic picture in the post-operative period: comparison of the times of negativization overexposed in the two arms.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 19, 2019)
  • 1. cumulative incidence/persistence of HPV infection after the surgical treatment. [ Time Frame: 5 years after surgical treatment ]
    To evaluate the effects of 9-valent vaccine on incidence/persistence of HPV infection after the surgical treatment.
  • 2. cumulative occurrence/recurrence of anogenital warts after treatment. [ Time Frame: 5 years after surgical treatment ]
    To evaluate the effects of 9-valent vaccine on anogenital warts (GW) relapse
  • 3. causative HPV type in recurrent CIN lesions, as assessed by HPV test and PCR (polymerase chain reaction). [ Time Frame: 5 years after surgical treatment ]
    To evaluate the effects of 9-valent vaccine on HPV types
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Impact on Disease Relapse of HPV Vaccination in Women Treated With LEEP for Cervical Intraepithelial Neoplasia. HOPE9
Official Title  ICMJE A Randomised, Double-Blind, Placebo-Controlled, Phase III Study to Investigate the Efficacy of Presurgical 9-valent HPV Vaccination in Women Treated With LEEP for CIN 2+ and Initially Invasive Cervical Cancer.
Brief Summary This study evaluates the impact on disease relapse of presurgical 9-valent HPV vaccination versus placebo vaccination in women treated with LEEP (loop electrosurgical excision procedure) for CIN2+ (high grade cervical intraepithelial neoplasia) and initially invasive cervical cancer.
Detailed Description

Rationale:

In 2006 HPV vaccination was licensed for primary prevention programs worldwide. Only a few years after, several studies have raised new scenarios about HPV related diseases with strong implications on clinical management in adult women. Some findings from retrospective data have shown a significant effect of HPV vaccine on women and men treated for HPV pathologies. Although vaccination is not effective in patients with prevalent HPV infection, some studies have suggested that HPV vaccine could influence the incidence of the disease relapse after a surgical treatment. Reduction in disease recurrence after surgical treatment in vaccinated patients comes from gastroenterological, gynecological and dermatological evidences concerning both benign lesions (warts) and precancerous lesions.

If vaccination reduces recurrence rates by 80%, according to our previous pilot study data, peri-surgical HPV vaccination will be a strong effective clinical intervention, very likely to be introduced into standard high grade cervical intraepithelial neoplasia management.

Objective:

The primary objective of the current study is to assess the efficacy of 9-valent HPV vaccination in preventing recurrence of CIN2+ in participants treated for high-grade CIN.

Study population: participants treated for CIN2+ with LEEP technique. Study design: A multicenter, randomised, double-blind clinical trial in 9 hospitals in Italy.

Intervention: Participants will be randomized in a 1:1 ratio to receive presurgical 9-valent HPV vaccination (Gardasil-9 ®) or placebo at months 0 (at pre-surgical enrollment time), at 2 months (the same day of surgical treatment) and 6 moths (during the first follow-up visit after surgery). The randomization list will be generated before the start of the study.

Main study parameters/endpoints:

Primary end point will be the cumulative recurrence of CIN2+ after conization, as assessed by biopsies taken of suspect lesions, histologically confirmed for high grade cervical intraepithelial neoplasia recurrence.

Secondary outcome measures are cumulative incidence/persistence of HPV infection after the surgical treatment, causative HPV type in recurrent CIN lesions, as assessed by HPV test and PCR (polymerase chain reaction).

The total sample size is estimated to be 1220 patients based on an expected recurrence rate of less than 6% within 5 years. Statistical analysis will be based on the intention-to-treat protocol. Both primary and secondary endpoints will be analyzed by descriptive statistics and the chi-square test with a 0,05 two-sided significance level.

Follow-up schedule (FUP) will be the same in both arms, with a FUP evaluation every 6 months in the first year followed by an annual evaluation for a total of 5 years. FUP visit will include HPV test, Pap-test and colposcopy. HPV test will be collected in order to evaluate the HPV infection clearance rate in both arms. HPV test will be part of all the follow-up visits allowing to study the natural history of HPV infection after the surgical treatment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE Cervical Intraepithelial Neoplasia
Intervention  ICMJE
  • Biological: Gardasil-9
    administration by intramuscular injection of the 9-valent HPV vaccine according to a 3-dose vaccination schedule (0, 2, 6 months).
    Other Names:
    • 9-valent HPV vaccine
    • Vaccine against HPV-6, 11, 16, 18, 31, 33, 45, 52, 58
  • Drug: Placebo
    administration by intramuscular injection of the placebo according to vaccination schedule of the 9-valent HPV vaccine (0, 2, 6 months)
    Other Name: Sterile Water for Injection Ph. Eur.
Study Arms  ICMJE
  • Experimental: Gardasil-9
    Intramuscular Gardasil-9 vaccination at 0, 2 and 6 months.
    Intervention: Biological: Gardasil-9
  • Placebo Comparator: Placebo
    Placebo injection at 0, 2 and 6 months
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: February 19, 2019)
1220
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2028
Estimated Primary Completion Date October 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients aged ≥ 18 and ecog performance status ≤ 1
  2. Patients with a diagnosis of high-grade cervical intraepithelial neoplasia or initially invasive cervical cancer (histological results ≥ CIN2 + and ≤ Ia1 according to the FIGO staging of cervical cancer)
  3. No fever at the time of vaccination
  4. No previous HPV vaccination
  5. Ability to understand and write Italian
  6. Signed informed and privacy consent

Exclusion Criteria:

  1. Patients enrolled in other clinical studies
  2. History of allergic reaction or serious adverse events to previous vaccinations
  3. Positive pregnancy test at the time of vaccination
  4. Patient in treatment with immunosuppressive therapy
  5. Subjects who received immunoglobulins or blood products in 3 months prior to vaccination.
  6. Thrombocytopenia or any other clotting disorder that may lead to bleeding as a result of intramuscular administration
  7. Clinical criteria contraindicating the surgical act of conization
  8. ECOG performance status ≥2
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Alessandro Ghelardi, MD +39 0585 6571 alessandro.ghelardi@uslnordovest.toscana.it
Contact: Paola Bay, MD +39 0585 6571 paola.bay@uslnordovest.toscana.it
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03848039
Other Study ID Numbers  ICMJE HOPE9 STUDY
2018-003507-19 ( EudraCT Number )
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Alessandro Ghelardi, Azienda USL Toscana Nord Ovest
Study Sponsor  ICMJE Alessandro Ghelardi
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Alessandro Ghelardi, MD Az. USL Toscana Nord Ovest
PRS Account Azienda USL Toscana Nord Ovest
Verification Date September 2020

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