Clinical trial NCT00128661: Vaccine To Prevent Cervical Intraepithelial Neoplasia or Cervical Cancer in Younger Healthy Participants
Official title: A Double-Blind, Controlled, Randomized, Phase III Study of the Efficacy of an HPV16/18 VLP Vaccine in the Prevention of Advanced Cervical Intraepithelial Neoplasia (CIN2, CIN3, Adenocarcinoma In Situ [AIS] and Invasive Cervical Cancer) Associated With HPV 16 or HPV 18 Cervical Infection in Healthy Young Adult Women in Costa Rica.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cervical Cancer
Precancerous Condition
Keywords: cervical intraepithelial neoplasia grade 2
cervical cancer
cervical intraepithelial neoplasia grade 3
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2005-08-10
Enrollment: 7466
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 25
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: RATIONALE: Chemoprevention is the use of certain drugs to keep cancer form forming, growing, or coming back. Vaccines may help the body build an effective immune response against human papillomavirus and may be effective in preventing cervical intraepithelial neoplasia or cervical cancer. It is not yet known whether human papillomavirus vaccine is more effective than hepatitis A vaccine in preventing cervical intraepithelial neoplasia or cervical cancer.

PURPOSE: This randomized phase III trial is studying human papillomavirus vaccine to see how well it works compared to hepatitis A vaccine in preventing cervical intraepithelial neoplasia or cervical cancer in younger healthy participants.

Detailed description: OBJECTIVES:

Primary

•Demonstrate the efficacy of the candidate vaccine, human papillomavirus 16/18 (HPV 16/18) L1 virus-like particle (VLP)/AS04 vaccine compared with control in preventing grade 2 or 3 cervical intraepithelial neoplasia, adenocarcinoma in situ of the cervix, or invasive cervical cancer (CIN2+) associated with HPV 16 or HPV 18 cervical infection in younger healthy participants who are negative for HPV DNA by polymerase chain reaction (PCR) for the corresponding HPV type at months 0 and 6.

Secondary

* Determine the duration of protection against HPV 16 or HPV 18 cervical infection in participants treated with the HPV 16/18 L1 VLP/AS04 vaccine.
* Determine the safety of this vaccine in these participants, regardless of their initial HPV 16/18 DNA status.
* Evaluate the efficacy of the candidate vaccine, HPV 16/18 L1 VLP/AS04 vaccine compared with control in preventing CIN2+ associated with any oncogenic HPV type cervical infection in participants who are negative for HPV DNA by PCR for the corresponding HPV type at months 0 and 6.
* Compare the efficacy of the candidate vaccine with control in preventing CIN2+ associated with HPV 16 or HPV 18 cervical infection, detected within the lesional component of the cervical tissue specimen by PCR, in participants who are negative for HPV DNA by PCR for the corresponding HPV type at months 0 and 6 and by enzyme-linked immunosorbent assay (ELISA) at month 0.
* Compare the efficacy of the candidate vaccine with control in preventing persistent HPV 16 or HPV 18 cervical infection in these participants.
* Determine the immunogenicity of HPV 16/18 L1 VLP/AS04 vaccine by ELISA and V5/J4 monoclonal antibody inhibition enzyme immunoassay in the first 600 participants randomized to receive HPV 16/18 L1 VLP/AS04 vaccine.

OUTLINE: This is a randomized, controlled, double-blind, parallel-group study. Participants are randomized to 1 of 2 treatment arms.

* Arm I: Participants receive human papillomavirus 16/18 L1 virus-like particle/AS04 vaccine intramuscularly (IM) once in months 0, 1, and 6.
* Arm II: Participants receive hepatitis A vaccine (Havrix®) IM once in months 0, 1, and 6.

After completion of study treatment, participants are followed at 6 months and then at least annually for 3 years.

PROJECTED ACCRUAL: Approximately 7,500 participants will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

•Healthy participants

* Deemed to be in good general health by history and physical examination

  •Resident of Guanacaste Province of Costa Rica and surrounding areas
* Must remain a resident for ≥ 6 months after the first study vaccination

PATIENT CHARACTERISTICS:

Age

* 18 to 25

Performance status

•Not specified

Life expectancy

•Not specified

Hematopoietic

•Not specified

Hepatic

* No history of chronic hepatitis requiring treatment
* No acute or chronic clinically significant hepatic function abnormality by physical examination or laboratory findings
* No known history of hepatitis A infection

Renal

* No history of kidney disease requiring treatment
* No acute or chronic clinically significant kidney function abnormality by physical examination or laboratory findings

Cardiovascular

* No acute or chronic clinically significant cardiovascular function abnormality by physical examination or laboratory findings Pulmonary
* No acute or chronic clinically significant pulmonary function abnormality by physical examination or laboratory findings Immunology
* No history of allergic disease
* No history of autoimmune disorder requiring treatment
* No history of allergic reaction (e.g., difficulty breathing) to any vaccine
* No suspected allergy or reaction likely to be exacerbated by a component of the study vaccines (e.g., 2-phenoxyethanol or neomycin)
* No hypersensitivity to latex
* No diagnosis or suspicion of any immunodeficient condition by medical history or physical examination Other
* Not pregnant or nursing

  ◦No delivery within the past 3 months
* Negative pregnancy test
* Fertile patients must use effective contraception for 30 days before, during, and for 60 days after completion of study treatment
* Able to speak or understand Spanish
* Mentally competent
* Able to undergo pelvic exam (i.e., no heavy bleeding \[menstruation or otherwise\] or heavy vaginal discharge)
* No history of cancer requiring treatment
* No history of diabetes requiring treatment
* No history of other chronic conditions requiring treatment
* No acute or chronic clinically significant neurologic function abnormality by physical examination or laboratory findings
* No other acute disease
* No fever ≥ 37.5º C

PRIOR CONCURRENT THERAPY:

Biologic therapy

* More than 6 months since prior chronic administration (i.e., \> 14 days) of immune-modulating drugs
* More than 90 days since prior immunoglobulins
* More than 30 days since prior and no other concurrent investigational or non-registered vaccines
* More than 30 days since prior registered vaccines
* More than 8 days since prior routine meningococcal, hepatitis B, influenza, or diphtheria/tetanus vaccine
* No prior vaccination against hepatitis A
* No prior vaccination against human papillomavirus
* No prior monophosphoryl lipid A or AS04 adjuvant

Chemotherapy

•Not specified

Endocrine therapy

* More than 6 months since prior chronic administration (i.e., \> 14 days) of corticosteroids (e.g., ≥ 0.5 mg/kg/day of prednisone or equivalent)
* Concurrent inhaled or topical steroids allowed

Radiotherapy

•Not specified

Surgery

•No prior hysterectomy

Other

* More than 6 months since prior chronic administration (i.e., \> 14 days) of immunosuppressants
* More than 30 days since prior and no other concurrent investigational or non-registered drugs

Primary outcomes:
measure: Number of Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Cases Associated With HPV16 and/or HPV18 Infection Detected in the Preceding Cervical Cytology Specimen.
timeFrame: From Month 6 up to Month 48
Secondary outcomes:
measure: Number of Cervical Infection With HPV16 or HPV18.
timeFrame: From Month 6 up to Month 48
measure: Number of Histopathologically Confirmed CIN2+ Cases Associated With Infection by Any Oncogenic HPV Type
timeFrame: From Month 6 up to Month 48
measure: Number of Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 Cases
timeFrame: From Month 6 up to Month 48
measure: Geometric Mean Titers (GMTs) for HPV-16 Antibody in the Immunogenicity Subcohort.
timeFrame: Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48
measure: Geometric Mean Titers (GMTs) for HPV-18 Antibody in the Immunogenicity Subcohort
timeFrame: Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48
measure: HPV-16 Geometric Mean Titers (GMTs) (V5 Monoclonal Antibody Inhibition Test)
timeFrame: Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48
measure: HPV-18 Geometric Mean Titers (GMTs) (J4 Monoclonal Antibody Inhibition Test)
timeFrame: Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48
measure: Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms.
timeFrame: Within 60 minutes after vaccination
measure: Number of Subjects Reporting Any and Grade 3 Solicited General Symptoms.
timeFrame: Within 60 minutes after vaccination
measure: Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms on a 10% Random Subset of Participants.
timeFrame: From Day 3 to Day 6 after vaccination
measure: Number of Subjects Reporting Any and Grade 3 Solicited General Symptoms on a 10% Random Subset of Participants.
timeFrame: From Day 3 to Day 6 after vaccination
measure: Number of Subjects Reporting Serious Adverse Events (SAEs).
timeFrame: During the entire study period (From Month 0 up to Month 48).
measure: Number of Subjects Reporting Unsolicited Adverse Events (AEs).
timeFrame: During the entire study period (From Month 0 up to Month 48).
measure: Number of Subjects With All Possible Pregnancy Outcomes
timeFrame: During the entire study period (From Month 0 up to Month 48).
measure: Number of Cervical Infection With HPV16 or HPV18.
timeFrame: During the first year of follow-up period
measure: Number of Cervical Infection With HPV16 or HPV18.
timeFrame: During the second year of follow-up period
measure: Number of Cervical Infection With HPV16 or HPV18.
timeFrame: During the third year of follow-up period
measure: Number of Cervical Infection With HPV16 or HPV18.
timeFrame: From the fourth year follow-up period
measure: Number of Subjects Reporting Unsolicited Adverse Events (AEs).
timeFrame: within 30 days (Days 0-29) after vaccination
Other outcomes:
Locations:
city: Liberia
country: Costa Rica
facility: Proyecto Epidemiologico Guanacaste
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Kreimer AR, Rodriguez AC, Hildesheim A, Herrero R, Porras C, Schiffman M, Gonzalez P, Solomon D, Jimenez S, Schiller JT, Lowy DR, Quint W, Sherman ME, Schussler J, Wacholder S; CVT Vaccine Group. Proof-of-principle evaluation of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine. J Natl Cancer Inst. 2011 Oct 5;103(19):1444-51. doi: 10.1093/jnci/djr319. Epub 2011 Sep 9.
citation: Kemp TJ, Hildesheim A, Safaeian M, Dauner JG, Pan Y, Porras C, Schiller JT, Lowy DR, Herrero R, Pinto LA. HPV16/18 L1 VLP vaccine induces cross-neutralizing antibodies that may mediate cross-protection. Vaccine. 2011 Mar 3;29(11):2011-4. doi: 10.1016/j.vaccine.2011.01.001. Epub 2011 Jan 15.
citation: Sierra MS, Tsang SH, Porras C, Herrero R, Sampson JN, Cortes B, Schussler J, Wagner S, Carvajal L, Quint W, Kreimer AR, Hu S, Rodriguez AC, Romero B, Hildesheim A; Costa Rica HPV Vaccine Trial (CVT) Group. Analysis of cervical HPV infections among unvaccinated young adult women to inform vaccine strategies in this age group: the Costa Rica HPV Vaccine Trial. Sex Transm Infect. 2022 Jul 16;99(3):180-6. doi: 10.1136/sextrans-2022-055434. Online ahead of print.
citation: Shing JZ, Hu S, Herrero R, Hildesheim A, Porras C, Sampson JN, Schussler J, Schiller JT, Lowy DR, Sierra MS, Carvajal L, Kreimer AR; Costa Rica HPV Vaccine Trial Group. Precancerous cervical lesions caused by non-vaccine-preventable HPV types after vaccination with the bivalent AS04-adjuvanted HPV vaccine: an analysis of the long-term follow-up study from the randomised Costa Rica HPV Vaccine Trial. Lancet Oncol. 2022 Jul;23(7):940-949. doi: 10.1016/S1470-2045(22)00291-1. Epub 2022 Jun 13.
citation: Usyk M, Schlecht NF, Pickering S, Williams L, Sollecito CC, Gradissimo A, Porras C, Safaeian M, Pinto L, Herrero R, Strickler HD, Viswanathan S, Nucci-Sack A, Diaz A; Costa Rica HPV Vaccine Trial (CVT) Group; Burk RD. molBV reveals immune landscape of bacterial vaginosis and predicts human papillomavirus infection natural history. Nat Commun. 2022 Jan 11;13(1):233. doi: 10.1038/s41467-021-27628-3.
citation: Usyk M, Zolnik CP, Castle PE, Porras C, Herrero R, Gradissimo A, Gonzalez P, Safaeian M, Schiffman M, Burk RD; Costa Rica HPV Vaccine Trial (CVT) Group. Cervicovaginal microbiome and natural history of HPV in a longitudinal study. PLoS Pathog. 2020 Mar 26;16(3):e1008376. doi: 10.1371/journal.ppat.1008376. eCollection 2020 Mar.
citation: Safaeian M, Castellsague X, Hildesheim A, Wacholder S, Schiffman MH, Bozonnat MC, Baril L, Rosillon D; Costa Rica HPV Vaccine Trial and the PATRICIA study groups. Risk of HPV-16/18 Infections and Associated Cervical Abnormalities in Women Seropositive for Naturally Acquired Antibodies: Pooled Analysis Based on Control Arms of Two Large Clinical Trials. J Infect Dis. 2018 Jun 5;218(1):84-94. doi: 10.1093/infdis/jiy112.
citation: Hildesheim A, Gonzalez P, Kreimer AR, Wacholder S, Schussler J, Rodriguez AC, Porras C, Schiffman M, Sidawy M, Schiller JT, Lowy DR, Herrero R; Costa Rica HPV Vaccine Trial (CVT) Group. Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment. Am J Obstet Gynecol. 2016 Aug;215(2):212.e1-212.e15. doi: 10.1016/j.ajog.2016.02.021. Epub 2016 Feb 16.
citation: Beachler DC, Kreimer AR, Schiffman M, Herrero R, Wacholder S, Rodriguez AC, Lowy DR, Porras C, Schiller JT, Quint W, Jimenez S, Safaeian M, Struijk L, Schussler J, Hildesheim A, Gonzalez P; Costa Rica HPV Vaccine Trial (CVT) Group. Multisite HPV16/18 Vaccine Efficacy Against Cervical, Anal, and Oral HPV Infection. J Natl Cancer Inst. 2015 Oct 14;108(1):djv302. doi: 10.1093/jnci/djv302. Print 2016 Jan.
citation: Panagiotou OA, Befano BL, Gonzalez P, Rodriguez AC, Herrero R, Schiller JT, Kreimer AR, Schiffman M, Hildesheim A, Wilcox AJ, Wacholder S; Costa Rica HPV Vaccine Trial (CVT) Group (see end of manuscript for full list of investigators). Effect of bivalent human papillomavirus vaccination on pregnancy outcomes: long term observational follow-up in the Costa Rica HPV Vaccine Trial. BMJ. 2015 Sep 7;351:h4358. doi: 10.1136/bmj.h4358.
citation: Kreimer AR, Struyf F, Del Rosario-Raymundo MR, Hildesheim A, Skinner SR, Wacholder S, Garland SM, Herrero R, David MP, Wheeler CM; Costa Rica Vaccine Trial Study Group Authors; Gonzalez P, Jimenez S, Lowy DR, Pinto LA, Porras C, Rodriguez AC, Safaeian M, Schiffman M, Schiller JT, Schussler J, Sherman ME; PATRICIA Study Group Authors; Bosch FX, Castellsague X, Chatterjee A, Chow SN, Descamps D, Diaz-Mitoma F, Dubin G, Germar MJ, Harper DM, Lewis DJ, Limson G, Naud P, Peters K, Poppe WA, Ramjattan B, Romanowski B, Salmeron J, Schwarz TF, Teixeira JC, Tjalma WA; HPV PATRICIA Principal Investigators/Co-Principal Investigator Collaborators; GSK Vaccines Clinical Study Support Group. Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA Trials. Lancet Oncol. 2015 Jul;16(7):775-86. doi: 10.1016/S1470-2045(15)00047-9. Epub 2015 Jun 9.
citation: Gonzalez P, Hildesheim A, Herrero R, Katki H, Wacholder S, Porras C, Safaeian M, Jimenez S, Darragh TM, Cortes B, Befano B, Schiffman M, Carvajal L, Palefsky J, Schiller J, Ocampo R, Schussler J, Lowy D, Guillen D, Stoler MH, Quint W, Morales J, Avila C, Rodriguez AC, Kreimer AR; Costa Rica HPV Vaccine Trial (CVT) Group. Rationale and design of a long term follow-up study of women who did and did not receive HPV 16/18 vaccination in Guanacaste, Costa Rica. Vaccine. 2015 Apr 27;33(18):2141-51. doi: 10.1016/j.vaccine.2015.03.015. Epub 2015 Mar 18.
citation: Lang Kuhs KA, Porras C, Schiller JT, Rodriguez AC, Schiffman M, Gonzalez P, Wacholder S, Ghosh A, Li Y, Lowy DR, Kreimer AR, Poncelet S, Schussler J, Quint W, van Doorn LJ, Sherman ME, Sidawy M, Herrero R, Hildesheim A, Safaeian M; Costa Rica Vaccine Trial Group. Effect of different human papillomavirus serological and DNA criteria on vaccine efficacy estimates. Am J Epidemiol. 2014 Sep 15;180(6):599-607. doi: 10.1093/aje/kwu168. Epub 2014 Aug 19.
citation: Hildesheim A, Wacholder S, Catteau G, Struyf F, Dubin G, Herrero R; CVT Group. Efficacy of the HPV-16/18 vaccine: final according to protocol results from the blinded phase of the randomized Costa Rica HPV-16/18 vaccine trial. Vaccine. 2014 Sep 3;32(39):5087-97. doi: 10.1016/j.vaccine.2014.06.038. Epub 2014 Jul 10.
citation: Lang Kuhs KA, Gonzalez P, Rodriguez AC, van Doorn LJ, Schiffman M, Struijk L, Chen S, Quint W, Lowy DR, Porras C, DelVecchio C, Jimenez S, Safaeian M, Schiller JT, Wacholder S, Herrero R, Hildesheim A, Kreimer AR; Costa Rica Vaccine Trial Group. Reduced prevalence of vulvar HPV16/18 infection among women who received the HPV16/18 bivalent vaccine: a nested analysis within the Costa Rica Vaccine Trial. J Infect Dis. 2014 Dec 15;210(12):1890-9. doi: 10.1093/infdis/jiu357. Epub 2014 Jun 23.
citation: Lang Kuhs KA, Gonzalez P, Struijk L, Castro F, Hildesheim A, van Doorn LJ, Rodriguez AC, Schiffman M, Quint W, Lowy DR, Porras C, Delvecchio C, Katki HA, Jimenez S, Safaeian M, Schiller J, Solomon D, Wacholder S, Herrero R, Kreimer AR; Costa Rica Vaccine Trial Group. Prevalence of and risk factors for oral human papillomavirus among young women in Costa Rica. J Infect Dis. 2013 Nov 15;208(10):1643-52. doi: 10.1093/infdis/jit369. Epub 2013 Sep 6.
citation: Herrero R, Quint W, Hildesheim A, Gonzalez P, Struijk L, Katki HA, Porras C, Schiffman M, Rodriguez AC, Solomon D, Jimenez S, Schiller JT, Lowy DR, van Doorn LJ, Wacholder S, Kreimer AR; CVT Vaccine Group. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One. 2013 Jul 17;8(7):e68329. doi: 10.1371/journal.pone.0068329. Print 2013.
citation: Clarke M, Schiffman M, Wacholder S, Rodriguez AC, Hildesheim A, Quint W; Costa Rican Vaccine Trial Group. A prospective study of absolute risk and determinants of human papillomavirus incidence among young women in Costa Rica. BMC Infect Dis. 2013 Jul 8;13:308. doi: 10.1186/1471-2334-13-308.
citation: Castro FA, Quint W, Gonzalez P, Katki HA, Herrero R, van Doorn LJ, Schiffman M, Struijk L, Rodriguez AC, DelVecchio C, Lowy DR, Porras C, Jimenez S, Schiller J, Solomon D, Wacholder S, Hildesheim A, Kreimer AR; Costa Rica Vaccine Trial Group. Prevalence of and risk factors for anal human papillomavirus infection among young healthy women in Costa Rica. J Infect Dis. 2012 Oct 1;206(7):1103-10. doi: 10.1093/infdis/jis458. Epub 2012 Jul 30.
citation: Kreimer AR, Gonzalez P, Katki HA, Porras C, Schiffman M, Rodriguez AC, Solomon D, Jimenez S, Schiller JT, Lowy DR, van Doorn LJ, Struijk L, Quint W, Chen S, Wacholder S, Hildesheim A, Herrero R; CVT Vaccine Group. Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial. Lancet Oncol. 2011 Sep;12(9):862-70. doi: 10.1016/S1470-2045(11)70213-3. Epub 2011 Aug 22.
citation: Wacholder S, Chen BE, Wilcox A, Macones G, Gonzalez P, Befano B, Hildesheim A, Rodriguez AC, Solomon D, Herrero R, Schiffman M; CVT group. Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials. BMJ. 2010 Mar 2;340:c712. doi: 10.1136/bmj.c712.
citation: Dessy FJ, Giannini SL, Bougelet CA, Kemp TJ, David MP, Poncelet SM, Pinto LA, Wettendorff MA. Correlation between direct ELISA, single epitope-based inhibition ELISA and pseudovirion-based neutralization assay for measuring anti-HPV-16 and anti-HPV-18 antibody response after vaccination with the AS04-adjuvanted HPV-16/18 cervical cancer vaccine. Hum Vaccin. 2008 Nov-Dec;4(6):425-34. doi: 10.4161/hv.4.6.6912. Epub 2008 Nov 11.
citation: Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon D, Bratti MC, Schiller JT, Gonzalez P, Dubin G, Porras C, Jimenez SE, Lowy DR; Costa Rican HPV Vaccine Trial Group. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA. 2007 Aug 15;298(7):743-53. doi: 10.1001/jama.298.7.743.