Cervical Intraepithelial Neoplasia Grade I/ II/ III (CIN I/II/III)Phase 4RIFT-HPVNCT05334706
A Study to Assess the Reduction of Human Papillomavirus (HPV) Viral Infectivity and Transmission in HPV-Positive Women After Vaccination With 9vHPV (RIFT-HPV)
A Phase 4 study testing Nonavalent HPV vaccine (9vHPV/Gardasil-9™). in people with Cervical Intraepithelial Neoplasia Grade I/ II/ III (CIN I/II/III) and Human Papillomavirus (HPV) Infections, run by Miquel Angel Pavon Ribas at 1 site in Spain.
Trial summary
This is a non-randomized, open label study to assess the reduction of Human Papillomavirus (HPV) infectivity and transmission in women positive for HPV16 and/or 18 in a cervical, oral and anal sample and vaccinated with 9vHPV/Gardasil-9™. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Cervical Intraepithelial Neoplasia Grade I/ II/ III (CIN I/II/III), Human Papillomavirus (HPV) Infections, High-risk HPV
- What is being tested?
- Nonavalent HPV vaccine (9vHPV/Gardasil-9™).
- Type of treatment
- Vaccines, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 69 participants
- Where
- 1 siteSpain
- Study dates
- 13 Sep 2022to Dec 2026
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Women.
- Aged 18 years or older for RIFT-HPV Cohort 1 and 2, attending a routine cervical cancer screening visit or gynaecological visit.
- Positive for HPV16, 18 or double-positive for 16 and 18 and negative for the rest of high-risk HPV types in a cervical sample.
- Recently diagnosed for their HPV-positivity (within the last 10 months).
- Meet one of the following criteria:
- have no apparent cervical lesion (Cohort 1). have a CIN1/2 lesion which is eligible for conservative treatment (cohort 1). have HPV 16 and/or HPV 18 positive anal test with non-apparent anal lesions or with anal lesions eligible for conservative treatment (Cohort 2).
- have HPV 16 and/or HPV 18 positive cervical test with vulvar premalignant lesion or condylomas, associated to HPV infection (Cohort 2).
Who cannot join
- Presence of any cervical lesion that requires clinical intervention within 7 months that could significantly affect cervical epithelia (and therefore, HPV viral production), such as cervical conization.
- History of severe allergic reaction (e.g., swelling of the mouth and throat, difficulty breathing, hypotension, or shock) that required medical intervention.
- History of allergy to any vaccine component, including aluminum, yeast, or BENZONASETM (nuclease, Nicomedia).
- History of thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injection of study vaccine.
- History of splenectomy.
- History of ano-genital cancer or HPV-related head and neck cancer.
- Pregnancy at the time of signing informed consent or planning to become pregnant within the full duration of the study.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Spain1 site, 1 recruiting
- Recruiting
Gynaecology Unit, Bellvitge University Hospital (HUB)
L'Hospitalet de Llobregat, Catalonia, 08907
Marta López Querol, SC, +34 932607123 ext. 3357, mlopezq@idibell.cat
Miquel Àngel Pabon Ribas, PI, +34 932607123, mpavon@iconcologia.net
About this study
Official title: A Non-Randomized, Open-Label Study to Assess the Reduction of Human Papillomavirus (HPV) Viral Infectivity and Transmission in HPV16/18-Positive Women After Vaccination With 9vHPV, a Multivalent L1 Virus-like Particle Vaccine, Evaluated in Cervical, Anal and Oral Samples Obtained After One, Two, and Three Vaccine Doses (RIFT-HPV1/RIFT-HPV2)
This is a non-randomized, open label study to assess the reduction of Human Papillomavirus (HPV) infectivity and transmission in women positive for HPV16 and/or 18 in a cervical, oral and anal sample and vaccinated with 9vHPV/Gardasil-9™.
The primary objective of the study is to demonstrate that vaccination with a 3-dose regimen of 9vHPV will reduce viral infectivity in HPV 16/18/16+18-positive women. This objective rests upon the hypothesis that, since vaccination with 9vHPV triggers the production of type-specific HPV antibodies which are exudated to the cervical and other infected mucosae, these antibodies adhere to and neutralize newly produced HPV 16/18 viral particles also present in the mucosae, thus reducing HPV's infective capacity and transmission to sexual partners.
Read more
Secondary objectives of the study are:
- To determine HPV antibody levels before and after vaccination for each of the 9vHPV-covered HPV types (6, 11, 16, 18, 31, 33, 45, 52, and 58), to distinguish an induced antibody production due to 9vHPV vaccination from a natural response to an HPV infection (when antibody production is expected to be lower).
- To demonstrate viral infectivity reduction in HPV 16/18/16+18 after vaccination with 1-dose or 2-dose regimen of 9vHPV. Since antibody production after administration of 2 vaccine doses is not inferior to 3 doses, infectivity reduction is expected to be detected after 2 doses, and at least partially after one dose.
The main endpoint of the study is the evaluation of the HPV infective capacity in cervical, anal and oral samples from HPV 16, 18 or 16+18-positive women, using a cellular assay that models in-vitro the cervical mucosa. In brief, the specific HPV biomarker E1^E4 is measured in HaCaT keratinocytes after being cultured with study samples and thus, exposed to HPV16/18 viral particles. A reduction in E1^E4 expression is expected for keratinocytes exposed to samples taken after vaccination with 9vHPV, since the specific HPV antibodies also present in these samples would bind HPV viral particles and prevent infection of cultured keratinocytes.
Other endpoints included in the study are:
- Detection of antibodies against HPV types covered by 9vHPV (6/11/16/18/31/33/45/52/58) by specific immunoassays (ELISA, cLIA).
- HPV16/18 virion detection using ELISA and electronic microscopy.
- HPV DNA detection and genotyping, using Anyplex HPV28. These endpoints are performed in cervical, anal and oral samples from HPV 16, 18 or 16+18-positive women
- Titration of antibodies against HPV types covered by 9vHPV in serum samples from HPV 16, 18 or 16+18-positive women using ELISA or cLIA.
A minimum of 39 and 30 women will be enrolled in two different study population cohorts, respectively:
- RIFT-HPV 1 cohort: non-vaccinated adult women aged 35 years or older, positive for HPV16-, 18-, or double positive for 16 and 18, without lesion or with cervical intraepithelial neoplasia (CIN) 1/2 lesion eligible for conservative treatment.
- RIFT-HPV 2 cohort: non-vaccinated adult women aged 27 years or older, positive for HPV16-, 18-, or double positive for 16 and 18, with multiple cervical, vulvar and/or anal lesions, with cervical lesions eligible for conservative treatment.
Candidates to participate in the study are selected according to the HPV DNA test result in a cervical sample taken in their routine cervical cancer screening visit or in their routine gynaecological follow-up visit.
There is no control group in this study: all participants are expected to complete all the per-protocol procedures in a total of 4 study visits within an average of 7 months' duration: Visit 1/ Day1, Visit 2/Month 2, Visit 3/Month 6, and Visit 4/Month 7.
The study procedures are the following:
- Pregnancy test on a urine sample in Visit 1 (pregnant women are excluded from the study).
- Completion of a questionnaire about the participant's health status, use of oral contraception and sexual activity in Visits 1 and 4.
- Cervical, anal oral and blood sample collection Visits 1, 2 and 3 before receiving 9vHPV vaccination, and in Visit 4.
- Intramuscular administration of 9vHPV in a three-dose regimen in Visits 1, 2 and 3.
Regarding data analysis for primary objective assessment, differences in the infectivity rate before (Day 1/ Visit 1) and after vaccination with 3 doses of 9vHPV (Month 7/ Visit 4) will be compared in cervical, anal and oral samples using non-parametric Wilcoxon signed rank test. The same assessment will be done in 1- or 2-dose vaccination scenario.
Antibody production before and after vaccination will be summarized for each of the 9vHPV-covered HPV types.
- Conditions
- Cervical Intraepithelial Neoplasia Grade I/ II/ III (CIN I/II/III), Human Papillomavirus (HPV) Infections, High-risk HPV, HPV-16/ 18
- Being tested
- Nonavalent HPV vaccine (9vHPV/Gardasil-9™).
- Keywords
- Cervical cancer, Cervical Intraepithelial Neoplasia Grade I/ II/ III (CIN I/II/III), Squamous Intraepithelial Lesions of the Cervix, High/ Low Grade., Uterine Cervical Neoplasms, Human Papillomavirus (HPV) Infections, High-risk HPV, HPV-16/ 18, HPV DNA Tests, Anyplex HPV28, HPV Vaccines, HPV Nonavalent Vaccine, Gardasil-9, 9vHPV, cLIA, HaCaT Cells, Keratinocytes, Cell Culture, ELISA, Immunoassay, Electron Microscopy
- Medical subject headings
- Papillomavirus Infections, Infections, Uterine Cervical Neoplasms, Squamous Intraepithelial Lesions of the Cervix
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nonavalent HPV vaccine (9vHPV/Gardasil-9™).Biological
Sterile suspension, 0.5 ml dose, intramuscular administration in a 3 dose-regimen (Day 1, Month 2, Month 6), prepared from the highly purified virus-like particles (VLPs) of the major capsid L1 protein from 9 HPV types: 6/11/16/18/31/33/45/52/58.
9vHPV is currently indicated in the EU in individuals from 9 years of age for the prevention of diseases caused by vaccine's 9 HPV types: genital warts (HPV6 and 11) and premalignant lesions and cancers affecting the cervix, vulva, vagina and anus (HPV16, 18, 31, 22, 45, 52 and 58). It was authorized for marketing in the EU on June 9th, 2015.
| Study group | Role | What they receive |
|---|---|---|
| Vaccination | Experimental | Single arm, vaccination with 9vHPV in a 3-dose regimen (Day 1, Month 2, Month 6). Receives: Biological: Nonavalent HPV vaccine (9vHPV/Gardasil-9™). |
What is being measured
The primary outcome is the main question the study is designed to answer.
To demonstrate that vaccination with a 3-dose regimen of 9vHPV will change viral infectivity in cervical, anal and oral samples from HPV 16/18/16+18-positive women.
In-vitro infectivity evaluation of cervical, anal, and oral samples collected before and after 9vHPV vaccination, by expression of E1^E4 HPV biomarker in HaCaT keratinocytes.
Measured: 7 month
Detection of HPV 6/11/16/18/31/33/45/52/58 L1 antibodies in cervical, anal and oral samples collected before and after 9vHPV vaccination, using ELISA and cLIA.
This endpoint will allow to associate the reduction in viral infectivity with the presence of neutralizing antibodies.
Measured: 7 month
HPV16/18 virion detection in cervical, anal and oral samples collected before and after 9vHPV vaccination.
HPV16/18 virion detection will be carried out using ELISA and electronic microscopy in cervical, anal and oral samples collected before and after 9vHPV vaccination.
Measured: 7 month
HPV DNA detection in cervical, anal and oral samples collected before and after 9vHPV vaccination.
HPV DNA detection will be performed using Anyplex HPV28 in cervical, anal and oral samples collected before and after 9vHPV vaccination.
Measured: 7 month
HPV DNA genotyping in cervical, anal and oral samples collected before and after 9vHPV vaccination.
HPV DNA genotyping will be performed using Anyplex HPV28 in cervical, anal and oral samples collected before and after 9vHPV vaccination.
Measured: 7 month
Secondary outcomes (2)
To determine HPV antibody titration before and after vaccination for each of the 9vHPV-covered HPV types (6, 11, 16, 18, 31, 33, 45, 52, and 58).
To determine HPV 6/11/16/18/31/33/45/52/58 L1 antibody titration in serum samples collected before and after 9vHPV vaccination, using ELISA for types 16 and 18 in samples from RIFT-HPV 1 and 2 study cohorts, using cLIA for all 9vHPV-covered types except 16 and 18, in samples from RIFT-HPV 1 study cohort.
Measured: 7 month
To demonstrate viral infectivity change in cervical, oral and anal samples from HPV 16/18/16+18-positive women after vaccination with 1-dose or 2-dose regimen of 9vHPV.
In-vitro infectivity evaluation of cervical, anal, and oral samples collected before and after 9vHPV vaccination with 1st dose and 2nd dose, by expression of E1^E4 HPV biomarker in HaCaT keratinocytes.
Measured: 7 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Apr 2022
- Study start13 Sep 2022
- Primary completionDec 2026 (estimated)
- Study completionDec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Cervical Intraepithelial Neoplasia Grade I/ II/ III (CIN I/II/III)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 69 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Miquel Angel Pavon Ribas
- Sponsor type
- University, hospital or other
- Collaborators
- Hospital del Mar, Catalan Institute of Health
- Responsible party
- Sponsor-investigator, Miquel Angel Pavon Ribas, Institut d'Investigació Biomèdica de Bellvitge
- Investigators
- Miquel Àngel Pavón Ribas, PhD, Principal investigator, Cancer Epidemiology Research Program (PREC), Catalan Institute of Oncology (ICO-Hospitalet)/Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Spain.Francesc Xavier Bosch José, PhD - MD, Principal investigator, Cancer Epidemiology Research Program (PREC), Catalan Institute of Oncology (ICO-Hospitalet)/Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Spain.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05334706
- Sponsor's protocol ID
- RIFT-HPV
- Other IDs
- 2021-005229-26
- Acronym
- RIFT-HPV
- Status last verified
- Feb 2026
- First submitted
- 5 Apr 2022
- Last updated
- 23 Feb 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Bosch FX, Broker TR, Forman D, Moscicki AB, Gillison ML, Doorbar J, Stern PL, Stanley M, Arbyn M, Poljak M, Cuzick J, Castle PE, Schiller JT, Markowitz LE, Fisher WA, Canfell K, Denny LA, Franco EL, Steben M, Kane MA, Schiffman M, Meijer CJ, Sankaranarayanan R, Castellsague X, Kim JJ, Brotons M, Alemany L, Albero G, Diaz M, de Sanjose S; ICO Monograph 'Comprehensive Control of HPV Infections and Related Diseases' Vaccine Volume 30, Supplement 5, 2012. Comprehensive control of human papillomavirus infections and related diseases. Vaccine. 2013 Dec 30;31 Suppl 6:G1-31. doi: 10.1016/j.vaccine.2013.10.002.
PubMed 24331817Schiffman M, Doorbar J, Wentzensen N, de Sanjose S, Fakhry C, Monk BJ, Stanley MA, Franceschi S. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers. 2016 Dec 1;2:16086. doi: 10.1038/nrdp.2016.86.
PubMed 27905473Castle PE, Rodriguez AC, Bowman FP, Herrero R, Schiffman M, Bratti MC, Morera LA, Schust D, Crowley-Nowick P, Hildesheim A. Comparison of ophthalmic sponges for measurements of immune markers from cervical secretions. Clin Diagn Lab Immunol. 2004 Mar;11(2):399-405. doi: 10.1128/cdli.11.2.399-405.2004.
PubMed 15013994Schwarz TF, Kocken M, Petaja T, Einstein MH, Spaczynski M, Louwers JA, Pedersen C, Levin M, Zahaf T, Poncelet S, Hardt K, Descamps D, Dubin G. Correlation between levels of human papillomavirus (HPV)-16 and 18 antibodies in serum and cervicovaginal secretions in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine. Hum Vaccin. 2010 Dec;6(12):1054-61. doi: 10.4161/hv.6.12.13399. Epub 2010 Dec 1.
PubMed 21157180Parker KH, Kemp TJ, Pan Y, Yang Z, Giuliano AR, Pinto LA. Evaluation of HPV-16 and HPV-18 specific antibody measurements in saliva collected in oral rinses and merocel(R) sponges. Vaccine. 2018 May 3;36(19):2705-2711. doi: 10.1016/j.vaccine.2018.03.034. Epub 2018 Apr 6.
PubMed 29631883Dillner L, Bekassy Z, Jonsson N, Moreno-Lopez J, Blomberg J. Detection of IgA antibodies against human papillomavirus in cervical secretions from patients with cervical intraepithelial neoplasia. Int J Cancer. 1989 Jan 15;43(1):36-40. doi: 10.1002/ijc.2910430109.
PubMed 2536005Wang Z, Hansson BG, Forslund O, Dillner L, Sapp M, Schiller JT, Bjerre B, Dillner J. Cervical mucus antibodies against human papillomavirus type 16, 18, and 33 capsids in relation to presence of viral DNA. J Clin Microbiol. 1996 Dec;34(12):3056-62. doi: 10.1128/jcm.34.12.3056-3062.1996.
PubMed 8940448Cameron JE, Snowhite IV, Chaturvedi AK, Hagensee ME. Human papillomavirus-specific antibody status in oral fluids modestly reflects serum status in human immunodeficiency virus-positive individuals. Clin Diagn Lab Immunol. 2003 May;10(3):431-8. doi: 10.1128/cdli.10.3.431-438.2003.
PubMed 12738644MacCosham A, El-Zein M, Burchell AN, Tellier PP, Coutlee F, Franco EL. Transmission reduction and prevention with HPV vaccination (TRAP-HPV) study protocol: a randomised controlled trial of the efficacy of HPV vaccination in preventing transmission of HPV infection in heterosexual couples. BMJ Open. 2020 Aug 11;10(8):e039383. doi: 10.1136/bmjopen-2020-039383.
PubMed 32788190Ozbun MA. Infectious human papillomavirus type 31b: purification and infection of an immortalized human keratinocyte cell line. J Gen Virol. 2002 Nov;83(Pt 11):2753-2763. doi: 10.1099/0022-1317-83-11-2753.
PubMed 12388811Lopez-Codony V, de Andres-Pablo A, Ferrando-Diez A, Fernandez-Montoli ME, Lopez-Querol M, Tous S, Ortega-Exposito C, Torrejon-Becerra JC, Perez Y, Ferrer-Artola A, Sole-Sedeno JM, Grau C, Ruperez B, Saumoy M, Sanchez M, Peremiquel-Trillas P, Bruni L, Alemany L, Bosch FX, Pavon MA. Assessing the reduction of viral infectivity in HPV16/18-positive women after one, two, and three doses of Gardasil-9 (RIFT): Study protocol. PLoS One. 2024 May 20;19(5):e0304080. doi: 10.1371/journal.pone.0304080. eCollection 2024.
PubMed 38768231