HPV (Human Papilloma Virus) Vaccination After Treatment of Anal Intraepithelial Neoplasia (AIN) (VACCAIN-P)
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
|Official Title:||Quadrivalent HPV Vaccination After Effective Treatment of Anal Intraepithelial Neoplasia in HIV+ Men|
- Cumulative recurrence of intra-anal or peri-anal HG AIN at 12 months after the last vaccination (18 months after inclusion), as assessed by HRA, with biopsies taken of suspect lesions. [ Time Frame: 18 months ] [ Designated as safety issue: No ]
- Toxicity/ safety of the Gardasil vaccine in HIV+ MSM. [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]One week after each vaccination and during all follow up visits the most common adverse events of Gardasil and other eventually occuring complaints will be evaluated by history taking. Adverse events will be graded according to the CTCAE v4 (Common Terminology Criteria for Adverse Events), which grades events on a scale of 1 to 5, with higher grades indicating greater severity.
- Recurrence of intra-anal or peri-anal HG AIN at the moment of last vaccination and 6 months afterwards. [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]
- Cumulative occurrence of intra-anal or peri-anal LG AIN at 12 months after the last vaccination. [ Time Frame: 18 months ] [ Designated as safety issue: No ]The patients with LG AIN at inclusion are excluded from this analysis.
- Cumulative occurrence of anogenital warts at 12 months after the last vaccination. [ Time Frame: 18 months ] [ Designated as safety issue: No ]Evaluated by physical examination and history taking.
- Causative HPV type in recurrent AIN lesions, as assessed by LCM/ PCR. [ Time Frame: 18 months ] [ Designated as safety issue: No ]
- HPV type-specific antibody response. [ Time Frame: 9 months (3 months after last vaccination) ] [ Designated as safety issue: No ]
|Study Start Date:||March 2014|
|Estimated Study Completion Date:||September 2018|
|Estimated Primary Completion Date:||September 2018 (Final data collection date for primary outcome measure)|
Intramuscular Gardasil vaccination at 0, 2 and 6 months.
Placebo Comparator: Placebo
Intramuscular Saline 0.9% vaccination at 0, 2 and 6 months
injection of 0.9% saline
Other Name: intramuscular Saline 0.9%
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Rationale: Since the introduction of combination antiretroviral therapy (cART), human immunodeficiency virus (HIV)-related morbidity and mortality have considerably decreased. However, as a result of the significantly prolonged life span, new causes of morbidity and mortality have become evident. In particular, anal cancer incidence has increased dramatically in HIV-positive men. Like cervical cancer, anal cancer is causally linked to infections with high-risk papillomaviruses, and is preceded by precursor lesions: anal intraepithelial neoplasia (AIN). Over 90% of HIV-positive MSM (men who have sex with men) have persisting anal HPV (human papilloma virus) infection, and high-grade (HG) AIN is present in 30% of all HIV+ MSM.
As in cervical intraepithelial neoplasia, early diagnosis and treatment of AIN have been advocated to prevent malignancy. Electrocoagulation/ cauterization is standard of care for intra-anal AIN, but after treatment, recurrence of lesions occurs in approx. 50% of cases. This is a major problem in an effective screening program for AIN.
In a nonconcurrent, non-blinded cohort study qHPV (quadrivalent human papilloma virus) vaccination significantly (HR 0.50) reduced HG AIN recurrence among MSM successfully treated for AIN. This is in accordance with findings in women treated for cervical intraepithelial neoplasia. Previous vaccination with quadrivalent HPV vaccine among women who had surgical treatment for HPV related disease significantly reduced the incidence of subsequent HPV related disease, including high grade disease.
Therefore, a strategy that is worth investigating is vaccination with the qHPV vaccine to prevent recurrences in HIV+ MSM who were successfully treated for HG AIN.
Objective: The primary objective of the current study is to assess the efficacy of qHPV vaccination in preventing recurrence of high-grade AIN in HIV+ MSM with CD4 counts >350 x 10E6/l who were successfully treated for high-grade intra-anal AIN in the past year.
Study population: HIV-positive MSM with a CD4 count > 350 cells/ul and intra-anal high-grade AIN (grade 2-3) that was successfully treated in the past year with conventional cauterization, cryotherapy, or other forms of local treatment.
Study design: A multicenter, randomised, double-blind clinical trial in four hospitals in the Netherlands.
Intervention: Patients are randomised for vaccination with the quadrivalent HPV vaccine (Gardasil ®) or vaccination with a matching placebo at months 0, 2 and 6.
Randomisation will be stratified for complete response versus partial response (from HG AIN to low-grade (LG) AIN) of the initial HG AIN lesion, for treatment less than 6 months ago versus treatment 6 months and longer ago, and for AMC versus other hospitals.
Main study parameters/endpoints: Screening for AIN will be performed by high-resolution anoscopy (HRA), at inclusion (first vaccination) and at last vaccination (6 months), and repeated at 6 and 12 months after the last vaccination. Safety Monitoring for adverse events and injection-site reactions will be performed one week after each vaccination and thereafter every 6 months for a total of 12 months of follow-up.
Primary end point will be the cumulative recurrence of HG AIN at 12 months after the last vaccination, as assessed by HRA (High-Resolution Anoscopy), with biopsies taken of suspect lesions.
Secondary outcome measures are toxicity/ safety, recurrence of HG AIN at last vaccination and 6 months afterwards, cumulative occurrence of LG AIN at 12 months after the last vaccination, cumulative occurrence of anogenital warts at 12 months after the last vaccination, causative HPV type in recurrent AIN lesions, as assessed by LCM (Laser Capture Microdissection)/ PCR (polymerase chain reaction), and HPV type-specific antibody response.
The total sample size is estimated to be 125 patients based on an expected recurrence rate of 50% within 12 months. Statistical analysis will be based on the intention-to-treat principle. Both primary and secondary endpoints will be analyzed by descriptive statistics and the chi-square test with a 0,05 two-sided significance level.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
HIV+ MSM who were successfully treated for HG AIN are still at a 50% risk for recurrences, with additional treatment sessions needed, and an ongoing risk for malignant degeneration of lesions.
Costs of 3 vaccinations are approx. € 400, but if vaccination reduces recurrence rates by 50%, this will be a highly cost-effective intervention, very likely to be introduced into regular care.
For the study, patients will be vaccinated 3 times with the quadrivalent vaccine Gardasil ® or placebo, and will undergo two extra HRAs. Clinical trial data show that the most common adverse events of Gardasil ® were mild or moderate, so few risks are associated with study participation.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02087384
|Contact: Karien CM Gosens, MDfirstname.lastname@example.org|
|Contact: Jan M Prins, prof, MD, email@example.com|
|DC Klinieken Oud Zuid||Recruiting|
|Amsterdam, Noord-Holland, Netherlands, 1071 NX|
|Contact: Arne van Eeden, MD 0031205730315 firstname.lastname@example.org|
|Principal Investigator: Arne van Eeden, MD|
|Onze Lieve Vrouwe Gasthuis||Recruiting|
|Amsterdam, Noord-Holland, Netherlands, 1090 HM|
|Contact: Guido Berk van den, MD 0031205993503 email@example.com|
|Contact: Irina Cairo, MD 0031205992789 I.Cairo@olvg.nl|
|Principal Investigator: Guido van den Berk, MD|
|Academic Medical Center||Recruiting|
|Amsterdam, Noord-Holland, Netherlands, 1105 AZ|
|Contact: Karien CM Gosens, MD 0031205662575 firstname.lastname@example.org|
|Sub-Investigator: Karien CM Gosens, MD|
|Principal Investigator: Jan M Prins, MD, prof|
|Principal Investigator:||Jan M Prins, prof, MD, infectiologist||Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)|
|Principal Investigator:||Henry JC de Vries, prof, MD, dermatologist||Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)|