Clinical trial NCT00294047: Study to Evaluate the Efficacy of the Human Papillomavirus Vaccine in Healthy Adult Women of 26 Years of Age and Older
Official title: A Study to Evaluate Safety, Immunogenicity and Efficacy of GSK Biologicals HPV-16/18 L1/AS04 Vaccine Administered Intramuscularly According to a Three-dose Schedule (0, 1, 6 Month) in Healthy Adult Female Subjects Aged 26 Years and Above
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infections, Papillomavirus
Papillomavirus Vaccines
Keywords: Vaccine
Human papillomavirus
Cervical Cancer
Cervical Infection
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2006-02-20
Enrollment: 5752
Sex: FEMALE
Minimum age (years): 26
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This is a multicentre study in which women were planned to receive either the Human Papillomavirus Vaccine (HPV) vaccine or control. Under Protocol Amendment 3, study participation will last approximately 48 months and involves a total of eleven scheduled visits. Under Protocol Amendment 4, study participation will last up to 84 months and involves a maximum of seventeen scheduled visits.

Detailed description: The Protocol Posting has been updated due to protocol amendment 5 and in order to comply with the FDA Amendment Act, Sep 2007.

Eligibility criteria: Inclusion criteria:

* A woman who the investigator believes that she can and will comply with the requirements of the protocol.
* A women of at least 26 years of age at the time of the first vaccination.
* Written informed consent obtained from the subject prior to enrolment.
* Free of obvious health problems as established by medical history and clinical examination before entering into the study.
* Subject must have intact cervix.
* Subject must have a negative urine pregnancy test. This test is not applicable to women of non-childbearing potential.
* Subject must be of non-childbearing potential or, if of childbearing potential, she must be abstinent or must be using an effective method of birth control for 30 days prior to the first vaccination and must agree to continue such precautions for two months after completion of the vaccination series.

Exclusion criteria:

* Pregnant or breastfeeding (women must be at least three months post-pregnancy and not breastfeeding to enter the study).
* A women planning to become pregnant, likely to become pregnant (as determined by the investigator) or planning to discontinue contraceptive precautions during the vaccination phase of the study, i.e. up to two months after the last vaccine dose (Month 0 - 8).
* Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period (up to Month 84).
* Chronic administration of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose.
* Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before and 30 days after (i.e. days 0 - 29) the first dose of study vaccine. Planned administration/administration of routine vaccines up to 8 days before the first dose of study vaccine is allowed. Enrolment will be deferred until the subject is outside of specified window.
* Previous administration of components of the investigational vaccine
* Previous vaccination against HPV or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period.
* History of HPV infection/treatment or planned treatment to evaluate an abnormal cervical cytology (Pap smear) test, e.g. colposcopy.
* Any medically diagnosed or suspected immunodeficient condition based on medical history and physical examination.
* History of allergic disease, suspected allergy or reactions likely to be exacerbated by any component of the study vaccine.
* Hypersensitivity to latex.
* Known acute or chronic, clinically significant neurologic, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests.
* History of chronic condition(s) requiring treatment.
* Administration of immunoglobulins and/or any blood product within three months preceding the first dose of study vaccine, or planned administration during the study period. Enrolment will be deferred until the subject is outside of specified window.
* Acute disease at the time of enrolment.
* Heavy bleeding (menstruation or other) or heavy vaginal discharge in which a pelvic exam cannot be performed (and no cervical sample can be taken). Enrolment will be deferred until condition is resolved according to investigators medical judgement.

Primary outcomes:
measure: Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 and/or With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection.
timeFrame: Up to Month 48
measure: Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18 and/or With Histopathologically-CIN1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Using the HPV Type Assignment Algorithm (TAA).
timeFrame: Up to Month 48
measure: Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 and/or With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection.
timeFrame: Up to Month 84
measure: Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18 and/or With Histopathologically-CIN1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Using the HPV Type Assignment Algorithm (TAA).
timeFrame: Up to Month 84
Secondary outcomes:
measure: Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18
timeFrame: Up to Month 48
measure: Number of Subjects With Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18
timeFrame: Up to Month 48
measure: Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types Individually or in Combinations.
timeFrame: Up to Month 48
measure: Number of Subjects With Persistent Infection (12-month Definition) With Oncogenic HPV Types Individually or in Combinations.
timeFrame: Up to Month 48
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection Detected Within the Lesional Component of the Cervical Tissue Specimen
timeFrame: Up to Month 48
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Within the Lesional Component of the Cervical Tissue Specimen
timeFrame: Up to Month 48
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Within the Lesional Component of the Cervical Tissue Specimen
timeFrame: Up to Month 48
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Irrespective of HPV Cervical Infection and Irrespective of Baseline HPV DNA Status
timeFrame: Up to Month 48
measure: Number of Subjects With Any Cytological Abnormalities Associated With HPV-16 or HPV-18 Cervical Infection
timeFrame: Up to Month 48
measure: Number of Subjects With Cytological Abnormalities Associated With Oncogenic HPV Types Individually or in Combinations
timeFrame: Up to Month 48
measure: Number of Subjects With Histopathologically Confirmed Reduction of Local Cervical Therapy
timeFrame: Up to Month 48
measure: Number of Subjects With First Colposcopy
timeFrame: Up to Month 48
measure: Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 and/or With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection
timeFrame: Up to Month 48
measure: Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18 and/or With Histopathologically-confirmed CIN1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Using the HPV Type Assignment Algorithm (TAA).
timeFrame: Up to Month 48
measure: Number of Seroconverted Subjects Against HPV-16 in the Immunogenicity Subset.
timeFrame: At pre-vaccination and at Month 7, 12, 18, 24, 36, 48, 60, 72 and 84
measure: Number of Seroconverted Subjects Against HPV-18 in the Immunogenicity Subset.
timeFrame: At pre-vaccination and at Month 7, 12, 18, 24, 36, 48, 60, 72 and 84
measure: Geometric Mean Concentrations (GMCs) Against HPV-16 Antibody in the Immunogenicity Subset.
timeFrame: At pre-vaccination and at Month 7, 12, 18, 24, 36, 48, 60, 72 and 84
measure: Geometric Mean Concentrations (GMCs) Against HPV-18 Antibody in the Immunogenicity Subset.
timeFrame: At pre-vaccination and at Month 7, 12, 18, 24, 36, 48, 60, 72 and 84
measure: Number of Seroconverted Subjects Against HPV-16 and HPV-18 Viral Neutralization in a Selected Subset of Subjects.
timeFrame: Prior to vaccination and at Months 7, 12, 18, 24, 48 and 84.
measure: Geometric Mean Titers (GMTs) Against HPV-16 and HPV-18 Viral Neutralization Antibodies in a Selected Subset of Subjects.
timeFrame: Prior to vaccination and at Months 7, 12, 18, 24, 48 and 84.
measure: Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms.
timeFrame: Within 7 days (Days 0-6) after vaccination
measure: Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms.
timeFrame: Within 7 days (Days 0-6) after vaccination
measure: Number of Subjects Reporting Any, Grade 3 and Related Unsolicited Adverse Events (AEs).
timeFrame: Within 30 days (Days 0 - 29) post-vaccination period.
measure: Number of Subjects Reporting Any and Related Serious Adverse Events (SAEs).
timeFrame: Up to Month 48 and up to Month 84
measure: Number of Subjects Reporting Related or Fatal Serious Adverse Event.
timeFrame: Up to Month 84
measure: Number of Subjects Reporting Any AE/SAE Leading to Premature Discontinuation of the Study.
timeFrame: Up to Month 84
measure: Number of Subjects Reporting New Onset of Chronic Disease (NOCDs).
timeFrame: Up to Month 48
measure: Number of Subjects Reporting New Onset of Autoimmune Disease (NOADs).
timeFrame: Up to Month 48
measure: Number of Subjects Reporting Medically Significant Conditions (MAEs).
timeFrame: Up to Month 48
measure: Number of Subjects With Pregnancies and Their Outcomes.
timeFrame: Up to Month 48
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Using the Type Assignment Algorithm (TAA)
timeFrame: Up to Month 48
measure: Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18
timeFrame: Up to Month 84
measure: Number of Subjects With Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18
timeFrame: Up to Month 84
measure: Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types Individually or in Combinations.
timeFrame: Up to Month 84
measure: Number of Subjects With Persistent Infection (12-month Definition) With Oncogenic HPV Types Individually or in Combinations.
timeFrame: Up to Month 84
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection Detected Within the Lesional Component of the Cervical Tissue Specimen
timeFrame: Up to Month 84
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Within the Lesional Component of the Cervical Tissue Specimen
timeFrame: Up to Month 84
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Within the Lesional Component of the Cervical Tissue Specimen
timeFrame: Up to Month 84
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Irrespective of HPV Cervical Infection and Irrespective of Baseline HPV DNA Status
timeFrame: Up to Month 84
measure: Number of Subjects With Any Cytological Abnormalities Associated With HPV-16 or HPV-18 Cervical Infection
timeFrame: Up to Month 84
measure: Number of Subjects With Cytological Abnormalities Associated With Oncogenic HPV Types Individually or in Combinations
timeFrame: Up to Month 48
measure: Number of Subjects With Histopathologically Confirmed Reduction of Local Cervical Therapy
timeFrame: Up to Month 84
measure: Number of Subjects With First Colposcopy
timeFrame: Up to Month 84
measure: Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 and/or With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 and/or -18 Cervical Infection
timeFrame: Up to Month 84
measure: Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18 and/or With Histopathologically-confirmed CIN1+ Associated With HPV-16 and/or -18 Cervical Infection Detected Using the HPV Type Assignment Algorithm (TAA).
timeFrame: Up to Month 84
Other outcomes:
Locations:
city: Fountain Valley
country: United States
facility: GSK Investigational Site
state: California
city: Aurora
country: United States
facility: GSK Investigational Site
state: Colorado
city: Golden
country: United States
facility: GSK Investigational Site
state: Colorado
city: Coral Gables
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Iowa City
country: United States
facility: GSK Investigational Site
state: Iowa
city: Wichita
country: United States
facility: GSK Investigational Site
state: Kansas
city: Bardstown
country: United States
facility: GSK Investigational Site
state: Kentucky
city: Louisville
country: United States
facility: GSK Investigational Site
state: Kentucky
city: Chaska
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Omaha
country: United States
facility: GSK Investigational Site
state: Nebraska
city: Lebanon
country: United States
facility: GSK Investigational Site
state: New Hampshire
city: Albuquerque
country: United States
facility: GSK Investigational Site
state: New Mexico
city: Syracuse
country: United States
facility: GSK Investigational Site
state: New York
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: New Bern
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Akron
country: United States
facility: GSK Investigational Site
state: Ohio
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Tulsa
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Portland
country: United States
facility: GSK Investigational Site
state: Oregon
city: Carnegie
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Erie
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Erie
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Wexford
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: South Jordan
country: United States
facility: GSK Investigational Site
state: Utah
city: Wenatchee
country: United States
facility: GSK Investigational Site
state: Washington
city: La Crosse
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Parkville
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Perth
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Halifax
country: Canada
facility: GSK Investigational Site
state: Nova Scotia
city: Truro
country: Canada
facility: GSK Investigational Site
state: Nova Scotia
city: Waterloo
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Sherbrooke
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Quebec
country: Canada
facility: GSK Investigational Site
city: Cuenavaca
country: Mexico
facility: GSK Investigational Site
state: Morelos
city: Jojutla / Morelos
country: Mexico
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Delft
country: Netherlands
facility: GSK Investigational Site
city: Rotterdam
country: Netherlands
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Laguna
country: Philippines
facility: GSK Investigational Site
city: San Pablo City
country: Philippines
facility: GSK Investigational Site
city: Taft Avenue, Manila
country: Philippines
facility: GSK Investigational Site
city: Almada
country: Portugal
facility: GSK Investigational Site
city: Coimbra
country: Portugal
facility: GSK Investigational Site
city: Lisboa
country: Portugal
facility: GSK Investigational Site
city: Porto
country: Portugal
facility: GSK Investigational Site
city: Setúbal
country: Portugal
facility: GSK Investigational Site
city: Ekaterinburg
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Sankt-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Sankt-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Singapore
country: Singapore
facility: GSK Investigational Site
city: Singapore
country: Singapore
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Northwood
country: United Kingdom
facility: GSK Investigational Site
state: Middlesex
city: Aberdeen
country: United Kingdom
facility: GSK Investigational Site
city: Cardiff
country: United Kingdom
facility: GSK Investigational Site
city: Gateshead
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Descamps D, Hardt K, Spiessens B, Izurieta P, Verstraeten T, Breuer T, Dubin G. Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials. Hum Vaccin. 2009 May;5(5):332-40. doi: 10.4161/hv.5.5.7211. Epub 2009 May 20.
citation: Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano-Ponce E, Salmeron J, Del Rosario-Raymundo MR, Verheijen RH, Quek SC, da Silva DP, Kitchener H, Fong KL, Bouchard C, Money DM, Ilancheran A, Cruickshank ME, Levin MJ, Chatterjee A, Stapleton JT, Martens M, Quint W, David MP, Meric D, Hardt K, Descamps D, Geeraerts B, Struyf F, Dubin G; VIVIANE Study Group. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet. 2014 Dec 20;384(9961):2213-27. doi: 10.1016/S0140-6736(14)60920-X. Epub 2014 Sep 1.
citation: Verstraeten T, Descamps D, David MP, Zahaf T, Hardt K, Izurieta P, Dubin G, Breuer T. Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines. Vaccine. 2008 Dec 2;26(51):6630-8. doi: 10.1016/j.vaccine.2008.09.049.
citation: Wheeler CM, Skinner SR, Del Rosario-Raymundo MR, Garland SM, Chatterjee A, Lazcano-Ponce E, Salmeron J, McNeil S, Stapleton JT, Bouchard C, Martens MG, Money DM, Quek SC, Romanowski B, Vallejos CS, Ter Harmsel B, Prilepskaya V, Fong KL, Kitchener H, Minkina G, Lim YKT, Stoney T, Chakhtoura N, Cruickshank ME, Savicheva A, da Silva DP, Ferguson M, Molijn AC, Quint WGV, Hardt K, Descamps D, Suryakiran PV, Karkada N, Geeraerts B, Dubin G, Struyf F; VIVIANE Study Group. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet Infect Dis. 2016 Oct;16(10):1154-1168. doi: 10.1016/S1473-3099(16)30120-7. Epub 2016 Jun 28.
citation: Wheeler CM, Struyf F; HPV-015 study group. The safety of Cervarix? - Authors' reply. Lancet Infect Dis. 2017 Jan;17(1):20-21. doi: 10.1016/S1473-3099(16)30540-0. No abstract available.
citation: Chen J, Gopala K, Akarsh PK, Struyf F, Rosillon D. Prevalence and Incidence of Human Papillomavirus (HPV) Infection Before and After Pregnancy: Pooled Analysis of the Control Arms of Efficacy Trials of HPV-16/18 AS04-Adjuvanted Vaccine. Open Forum Infect Dis. 2019 Dec 4;6(12):ofz486. doi: 10.1093/ofid/ofz486. eCollection 2019 Dec.
citation: Rosillon D, Baril L, Del Rosario-Raymundo MR, Wheeler CM, Skinner SR, Garland SM, Salmeron J, Lazcano-Ponce E, Vallejos CS, Stoney T, Ter Harmsel B, Lim TYK, Quek SC, Minkina G, McNeil SA, Bouchard C, Fong KL, Money D, Ilancheran A, Savicheva A, Cruickshank M, Chatterjee A, Fiander A, Martens M, Bozonnat MC, Struyf F, Dubin G, Castellsague X. Risk of newly detected infections and cervical abnormalities in adult women seropositive or seronegative for naturally acquired HPV-16/18 antibodies. Cancer Med. 2019 Aug;8(10):4938-4953. doi: 10.1002/cam4.1879. Epub 2019 Jul 5.
citation: Skinner SR, Wheeler CM, Romanowski B, Castellsague X, Lazcano-Ponce E, Del Rosario-Raymundo MR, Vallejos C, Minkina G, Pereira Da Silva D, McNeil S, Prilepskaya V, Gogotadze I, Money D, Garland SM, Romanenko V, Harper DM, Levin MJ, Chatterjee A, Geeraerts B, Struyf F, Dubin G, Bozonnat MC, Rosillon D, Baril L; VIVIANE Study Group. Progression of HPV infection to detectable cervical lesions or clearance in adult women: Analysis of the control arm of the VIVIANE study. Int J Cancer. 2016 May 15;138(10):2428-38. doi: 10.1002/ijc.29971.