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

• ClinicalTrials.gov Identifier: NCT03848039
• Recruitment Status: Not yet recruiting
• First Posted: February 20, 2019
• Last Update Posted: November 5, 2020
• Sponsor: Alessandro Ghelardi
• Information provided by (Responsible Party): Alessandro Ghelardi, Azienda USL Toscana Nord Ovest

Study Description

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.

Study Design

• 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: December 2020
• Estimated Primary Completion Date: December 2022
• Estimated Study Completion Date: May 2028

Arms and Interventions

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.

Outcome Measures

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.

Eligibility Criteria

• 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

Contacts and Locations

Contacts

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

• Principal Investigator: Alessandro Ghelardi, MD; Az. USL Toscana Nord Ovest

More Information

• 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
• Last Update Posted: November 5, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

Neoplasms; Carcinoma in Situ; Uterine Cervical Dysplasia; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Precancerous Conditions; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Vaccines; Immunologic Factors; Physiological Effects of Drugs