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.
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- GlaxoSmithKline
- Enrollment
- 7,466
- Locations
- 1
- Primary Endpoint
- Number of Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Cases Associated With HPV16 and/or HPV18 Infection Detected in the Preceding Cervical Cytology Specimen.
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Prevention
- Masking
- Triple (Participant, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 25 Years (Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- Yes
Inclusion 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:
- •Performance status
- •Not specified
- •Life expectancy
- •Not specified
- •Hematopoietic
- •Not specified
- •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
- •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
- +9 more not shown
Exclusion Criteria
- Not provided
Arms & Interventions
Cervarix Group
Subjects received 3 doses of Cervarix vaccine at study Months 0, 1 and 6. All the vaccine doses were administered intramuscularly in the deltoid region of the non-dominant arm.
Intervention: human papillomavirus 16/18 L1 virus-like particle/AS04 vaccine (Biological)
Havrix Group
Subjects received 3 doses of Havrix vaccine at study Months 0, 1 and 6. All the vaccine doses were administered intramuscularly in the deltoid region of the non-dominant arm.
Intervention: hepatitis A inactivated virus vaccine (Biological)
Outcomes
Primary Outcomes
Number of Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Cases Associated With HPV16 and/or HPV18 Infection Detected in the Preceding Cervical Cytology Specimen.
Time Frame: From Month 6 up to Month 48
CIN2+ was defined as CIN grade 2 (CIN2), CIN grade 3 (CIN3), adenocarcinoma in situ (AIS) or invasive cervical cancer. Preceding cervical cytology means the last cervical cytology specimen collected before the histopathology specimen was obtained. Subjects were human papillomavirus (HPV) deoxyribonucleic acid (DNA) negative (DNA-) by polymerase chain reaction (PCR) at Month 0 and Month 6 for the corresponding HPV-type.
Secondary Outcomes
- Number of Cervical Infection With HPV16 or HPV18.(From the fourth year follow-up period)
- Number of Histopathologically Confirmed CIN2+ Cases Associated With Infection by Any Oncogenic HPV Type(From Month 6 up to Month 48)
- Geometric Mean Titers (GMTs) for HPV-16 Antibody in the Immunogenicity Subcohort.(Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48)
- Geometric Mean Titers (GMTs) for HPV-18 Antibody in the Immunogenicity Subcohort(Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48)
- HPV-16 Geometric Mean Titers (GMTs) (V5 Monoclonal Antibody Inhibition Test)(Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48)
- HPV-18 Geometric Mean Titers (GMTs) (J4 Monoclonal Antibody Inhibition Test)(Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48)
- Number of Subjects Reporting Any and Grade 3 Solicited General Symptoms.(Within 60 minutes after vaccination)
- Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms on a 10% Random Subset of Participants.(From Day 3 to Day 6 after vaccination)
- Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms.(Within 60 minutes after vaccination)
- Number of Subjects Reporting Any and Grade 3 Solicited General Symptoms on a 10% Random Subset of Participants.(From Day 3 to Day 6 after vaccination)
- Number of Subjects Reporting Serious Adverse Events (SAEs).(During the entire study period (From Month 0 up to Month 48).)
- Number of Subjects Reporting Unsolicited Adverse Events (AEs).(within 30 days (Days 0-29) after vaccination)
- Number of Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 Cases(From Month 6 up to Month 48)
- Number of Subjects With All Possible Pregnancy Outcomes(During the entire study period (From Month 0 up to Month 48).)
- Number of Cervical Infection With HPV16 or HPV18.(From Month 6 up to Month 48)
- Number of Subjects Reporting Unsolicited Adverse Events (AEs).(During the entire study period (From Month 0 up to Month 48).)
- Number of Cervical Infection With HPV16 or HPV18.(During the first year of follow-up period)
- Number of Cervical Infection With HPV16 or HPV18.(During the second year of follow-up period)
- Number of Cervical Infection With HPV16 or HPV18.(During the third year of follow-up period)