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