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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 : July 23, 2020
Sponsor:
Information provided by (Responsible Party):
Alessandro Ghelardi, Azienda USL Toscana Nord Ovest

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.

Condition or disease Intervention/treatment Phase
Cervical Intraepithelial Neoplasia Biological: Gardasil-9 Drug: Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1220 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: 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.
Estimated Study Start Date : September 2020
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : February 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Gardasil-9
Intramuscular Gardasil-9 vaccination at 0, 2 and 6 months.
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

Placebo Comparator: Placebo
Placebo injection at 0, 2 and 6 months
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.




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03848039


Contacts
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Contact: Alessandro Ghelardi, MD +39 0585 6571 alessandro.ghelardi@uslnordovest.toscana.it
Contact: Paola Bay, MD +39 0585 6571 paola.bay@uslnordovest.toscana.it

Sponsors and Collaborators
Alessandro Ghelardi
Investigators
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Principal Investigator: Alessandro Ghelardi, MD Az. USL Toscana Nord Ovest
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Responsible Party: Alessandro Ghelardi, Principal Investigator, Department of Obstetrics and Gynaecology Azienda USL Toscana Nord Ovest, Presidio Ospedaliero delle Apuane (MS)- Italy, Azienda USL Toscana Nord Ovest
ClinicalTrials.gov Identifier: NCT03848039    
Other Study ID Numbers: HOPE9 STUDY
2018-003507-19 ( EudraCT Number )
First Posted: February 20, 2019    Key Record Dates
Last Update Posted: July 23, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alessandro Ghelardi, Azienda USL Toscana Nord Ovest:
Cervical Cancer
cervical intraepithelial neoplasia
Papillomavirus Vaccines
Additional relevant MeSH terms:
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Carcinoma in Situ
Cervical Intraepithelial Neoplasia
Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Vaccines
Immunologic Factors
Physiological Effects of Drugs