Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02087384 |
| Other study ID # |
NL45200.018.13 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
March 2014 |
| Est. completion date |
February 2019 |
Study information
| Verified date |
March 2021 |
| Source |
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This study evaluates vaccination with the quadrivalent HPV vaccine (Gardasil) versus placebo
vaccination on prevention of high grade AIN recurrence in HIV-positive MSM (men who have sex
with men) who were successfully treated for high grade AIN.
Description:
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.
