Clinical trial NCT00122681: Human Papilloma Virus (HPV) Vaccine Efficacy Trial Against Cervical Pre-cancer in Young Adults With GlaxoSmithKline (GSK) Biologicals HPV-16/18
Official title: A Phase III, Double-blind, Randomized, Controlled, Multi-center Study to Evaluate the Efficacy of GlaxoSmithKline Biologicals. HPV-16/18 VLP AS04 Vaccine Compared to Hepatitis A Vaccine as Control in Prevention of Persistent HPV-16 or HPV-18 Cervical Infection and Cervical Neoplasia, Administered Intramuscularly According to a 0, 1, 6 Month Schedule in Healthy Females 15-25 Years of Age.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infections, Papillomavirus
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2005-07-22
Enrollment: 18729
Sex: FEMALE
Minimum age (years): 15
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Human Papilloma virus (HPV) are viruses that cause a common infection of the skin and genitals in men and women. Several types of HPV infection are transmitted by sexual activity and, in women, can infect the cervix (part of the uterus or womb). This infection often goes away by itself, but if it does not go away (this is called persistent infection), it can lead in women over a long period of time to cancer of the cervix. If a woman is not infected by HPV, it is very unlikely that she will get cervical cancer. This study will evaluate the efficacy of GSK Biologicals HPV 16/18 VLP/AS04 vaccine to prevent infection associated cervical pre-cancer and vaccine with HPV 16 or 18 and the vaccine safety, over 48 months, in young adolescents and women of 15/25 years of age at study start. Approximately 18.000 study subjects will either receive the HPV vaccine or a control vaccine (hepatitis A vaccine) administered intramuscularly according to a 0-1-6 month schedule.

The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Detailed description: NOTE: Some 178 centers participate in this study. Given that the recruitment is completed, the researchers have listed one center per country in this website. If required, further details of centers available on request.

Eligibility criteria: Inclusion Criteria:

* A woman whom the investigator believes that she and/or her parents/legally acceptable representative can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits).
* A woman between, and including, 15 and 25 years of age at the time of the first vaccination.
* Written informed consent must be obtained from the subject prior to enrollment (for subjects below the legal age of consent, written informed consent must be obtained from a parent or legal guardian of the subject and, in addition, the subject should sign and personally date a written informed assent).
* Subject must be free of obvious health problems as established by medical history and clinical examination before entering into the study.
* Subject must have a negative urine pregnancy test.
* Subject must be of non-childbearing potential or, if of childbearing potential, she must be abstinent or must be using adequate contraceptive precautions for 30 days prior to the first vaccination and must agree to continue such precautions for two months after completion of the vaccination series.
* Has had no more than 6 lifetime sexual partners prior to enrollment. This criterion may not be applicable in subjects less than 18 years of age, according to local regulatory/ethical requirements.
* Subject must have intact cervix.

Exclusion Criteria:

* Pregnant or breastfeeding. Women must be at least 3 months post-pregnancy and not breastfeeding to enter the study.
* A woman planning to become pregnant or planning to discontinue contraceptive precautions during approximately the first nine months of the study (Months 0-8).
* Previous administration of components of the investigational vaccine.
* Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period.
* 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) each dose of vaccine. Administration of some routine vaccines up to 8 days before each dose of study vaccine is allowed. Enrolment will be deferred until the subject is outside of specified window.
* Previous vaccination against human papillomavirus (HPV).
* History of vaccination against Hepatitis A or a known clinical history of Hepatitis A disease.
* History of having had colposcopy or has planned a colposcopy to evaluate an abnormal cervical cytology (Pap smear) test.
* 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 vaccines.
* Hypersensitivity to latex.
* Known acute or chronic, clinically significant pulmonary, cardiovascular, neurologic, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests.
* History of chronic condition(s) requiring treatment.
* Received immunoglobulins and/or blood product within 90 days preceding enrollment. Enrollment 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. Enrollment will be deferred until condition is resolved according to investigator's medical judgement.

Primary outcomes:
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline)
timeFrame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post-dose 3
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline)
timeFrame: at Month 48
Secondary outcomes:
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 or HPV-18 Detected Within the Lesional Component of the Cervical Tissue Specimen
timeFrame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3
measure: Number of Subjects Reporting Solicited Local and General Symptoms
timeFrame: Within 7 days after any vaccination
measure: Number of Subjects Reporting Unsolicited Adverse Events
timeFrame: Within 30 days after any vaccination
measure: Number of Subjects Reporting Serious Adverse Events (SAEs)
timeFrame: Throughout the entire study period (Month 0 to Month 48)
measure: Number of Subjects Reporting New Onset of Chronic Disease (NOCDs)
timeFrame: Throughout the entire study (Month 0 to 48)
measure: Number of Subjects Reporting Medically Significant Conditions
timeFrame: Throughout entire study period (Month 0 to Month 48)
measure: Number of Subjects With Outcome of Pregnancies, Overall and Stratified by Initial (Month 0) HPV-16/18 DNA Status and According to HPV-16 or -18 Serostatus
timeFrame: Throughout the entire study period (Month 0 to Month 48)
measure: Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18
timeFrame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3
measure: Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18
timeFrame: at Month 48
measure: Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types
timeFrame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3
measure: Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types
timeFrame: at Month 48
measure: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 or HPV-18 Detected Within the Lesional Component of the Cervical Tissue Specimen
timeFrame: at Month 48
measure: Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18
timeFrame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3
measure: Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18
timeFrame: at Month 48
measure: Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen
timeFrame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3
measure: Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen
timeFrame: at Month 48
measure: Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen
timeFrame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3
measure: Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen
timeFrame: at Month 48
measure: Number of Seropositive Subjects for Anti-HPV-16 and Anti-HPV-18 Antibody Titers by ELISA in the Immunogenicity Subset, According to Initial (Month 0) HPV-16 or HPV-18 Serostatus
timeFrame: At Months 6, 7, 12, 24, 36 & 48
measure: Anti-HPV-16 and Anti-HPV-18 ELISA Titers in the Immunogenicity Subset
timeFrame: At Months 6, 7, 12, 24, 36 and 48
measure: HPV-16 and HPV-18 Seroconversion (V5/J4 Monoclonal Inhibition Test)
timeFrame: Month 0, 7, 12 and 24
measure: HPV-16 and HPV-18 Geometric Mean Titers (GMT) (V5/J4 Monoclonal Inhibition Test)
timeFrame: Month 0, 7, 12, 24
measure: Number of Subjects Seropositive for Anti-HPV-16 and Anti-HPV-18 Antibodies Using Pseudovirion Based Neutralizing Assay (PBNA)
timeFrame: At Month 0, 7, 12, 24, 36 and 48
measure: Titers for Anti-HPV-16 and Anti-HPV-18 Antibodies Using Pseudovirion Based Neutralizing Assay (PBNA)
timeFrame: At month 0, 7, 12, 24, 36 and 48
measure: Geometric Mean Titers of Anti-HPV-16 in Subjects Without and With 6-month Persistent Infection
timeFrame: At Month 7
measure: Number of Seroconverted Subjects for Anti-HPV-16 Without and With 6-month Persistent Infection.
timeFrame: At Month 7
measure: Geometric Mean Titers of Anti-HPV-16 in Subjects Without and With 12-month Persistent Infection
timeFrame: At Month 7
measure: Number of Seroconverted Subjects for Anti-HPV-16 Without and With 12-month Persistent Infection
timeFrame: At Month 7
measure: Geometric Mean Titers of Anti-HPV-18 in Subjects Without and With 6-month Persistent Infection
timeFrame: At Month 7
measure: Number of Seroconverted Subjects for Anti-HPV-18 Without and With 6-month Persistent Infection.
timeFrame: At Month 7
measure: Geometric Mean Titers of Anti-HPV-18 in Subjects Without and With 12-month Persistent Infection
timeFrame: At Month 7
measure: Number of Seroconverted Subjects for Anti-HPV-18 Without and With 12-month Persistent Infection
timeFrame: At Month 7
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Fountain Valley
country: United States
facility: GSK Investigational Site
state: California
city: San Diego
country: United States
facility: GSK Investigational Site
state: California
city: San Francisco
country: United States
facility: GSK Investigational Site
state: California
city: Boulder
country: United States
facility: GSK Investigational Site
state: Colorado
city: Boulder
country: United States
facility: GSK Investigational Site
state: Colorado
city: Denver
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facility: GSK Investigational Site
state: Colorado
city: Louisville
country: United States
facility: GSK Investigational Site
state: Colorado
city: Clearwater
country: United States
facility: GSK Investigational Site
state: Florida
city: Coral Gables
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: West Palm Beach
country: United States
facility: GSK Investigational Site
state: Florida
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Honolulu
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facility: GSK Investigational Site
state: Hawaii
city: Iowa City
country: United States
facility: GSK Investigational Site
state: Iowa
city: Arkansas City
country: United States
facility: GSK Investigational Site
state: Kansas
city: Wichita
country: United States
facility: GSK Investigational Site
state: Kansas
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: Minneapolis
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: Morristown
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Albuquerque
country: United States
facility: GSK Investigational Site
state: New Mexico
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Poughkeepsie
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: 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: 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: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Pittsburgh
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facility: GSK Investigational Site
state: Pennsylvania
city: Austin
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facility: GSK Investigational Site
state: Texas
city: Houston
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facility: GSK Investigational Site
state: Texas
city: Houston
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state: Texas
city: Webster
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facility: GSK Investigational Site
state: Texas
city: Salt Lake City
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facility: GSK Investigational Site
state: Utah
city: Charlottesville
country: United States
facility: GSK Investigational Site
state: Virginia
city: Spokane
country: United States
facility: GSK Investigational Site
state: Washington
city: Spokane
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facility: GSK Investigational Site
state: Washington
city: Vancouver
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facility: GSK Investigational Site
state: Washington
city: Wenatchee
country: United States
facility: GSK Investigational Site
state: Washington
city: Sydney
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Adelaide
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Hobart
country: Australia
facility: GSK Investigational Site
state: Tasmania
city: Carlton, Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Perth
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Brussels
country: Belgium
facility: GSK Investigational Site
city: Edegem
country: Belgium
facility: GSK Investigational Site
city: Leuven
country: Belgium
facility: GSK Investigational Site
city: Curitiba
country: Brazil
facility: GSK Investigational Site
state: Paraná
city: Porto Alegre
country: Brazil
facility: GSK Investigational Site
state: Rio Grande Do Sul
city: Campinas
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Langley
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Winnipeg
country: Canada
facility: GSK Investigational Site
state: Manitoba
city: St. John's
country: Canada
facility: GSK Investigational Site
state: Newfoundland and Labrador
city: Truro
country: Canada
facility: GSK Investigational Site
state: Nova Scotia
city: Oshawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Waterloo
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Beauport
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Espoo
country: Finland
facility: GSK Investigational Site
city: Helsinki
country: Finland
facility: GSK Investigational Site
city: Helsinki
country: Finland
facility: GSK Investigational Site
city: Jarvenpaa
country: Finland
facility: GSK Investigational Site
city: Jyvaskyla
country: Finland
facility: GSK Investigational Site
city: Kerava
country: Finland
facility: GSK Investigational Site
city: Kotka
country: Finland
facility: GSK Investigational Site
city: Kouvola
country: Finland
facility: GSK Investigational Site
city: Kuopio
country: Finland
facility: GSK Investigational Site
city: Lahti
country: Finland
facility: GSK Investigational Site
city: Lappeenranta
country: Finland
facility: GSK Investigational Site
city: Mikkeli
country: Finland
facility: GSK Investigational Site
city: Oulu
country: Finland
facility: GSK Investigational Site
city: Pori
country: Finland
facility: GSK Investigational Site
city: Rauma
country: Finland
facility: GSK Investigational Site
city: Seinajoki
country: Finland
facility: GSK Investigational Site
city: Tampere
country: Finland
facility: GSK Investigational Site
city: Turku
country: Finland
facility: GSK Investigational Site
city: Vaasa
country: Finland
facility: GSK Investigational Site
city: Karlsruhe
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Ravensburg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Rheinstetten
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Wuerzburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Dietzenbach
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Mainz
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Nordhausen
country: Germany
facility: GSK Investigational Site
state: Thueringen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Modena
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Cuenavaca
country: Mexico
facility: GSK Investigational Site
state: Morelos
city: Cavite
country: Philippines
facility: GSK Investigational Site
city: Laguna
country: Philippines
facility: GSK Investigational Site
city: Las Pinas City
country: Philippines
facility: GSK Investigational Site
city: Los Banos, Laguna
country: Philippines
facility: GSK Investigational Site
city: Makati City
country: Philippines
facility: GSK Investigational Site
city: Manila
country: Philippines
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: L'Hospitalet de Llobregat
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Marid
country: Spain
facility: GSK Investigational Site
city: Móstoles
country: Spain
facility: GSK Investigational Site
city: Taipei
country: Taiwan
facility: GSK Investigational Site
city: Taipei
country: Taiwan
facility: GSK Investigational Site
city: Taipei
country: Taiwan
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Aberdeen
country: United Kingdom
facility: GSK Investigational Site
city: London
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
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
city: Waterloo, Liverpool
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Lehtinen M, Lagheden C, Luostarinen T, Eriksson T, Apter D, Bly A, Gray P, Harjula K, Heikkila K, Hokkanen M, Karttunen H, Kuortti M, Nieminen P, Nummela M, Paavonen J, Palmroth J, Petaja T, Pukkala E, Soderlund-Strand A, Veivo U, Dillner J. Human papillomavirus vaccine efficacy against invasive, HPV-positive cancers: population-based follow-up of a cluster-randomised trial. BMJ Open. 2021 Dec 30;11(12):e050669. doi: 10.1136/bmjopen-2021-050669.
citation: Welby S, Rosillon D, Feng Y, Borys D. Progression from human papillomavirus (HPV) infection to cervical lesion or clearance in women (18-25 years): Natural history study in the control arm subjects of AS04-HPV-16/18 vaccine efficacy study in China between 2008 and 2016. Expert Rev Vaccines. 2022 Mar;21(3):407-413. doi: 10.1080/14760584.2022.2021077. Epub 2022 Jan 24.
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