Last updated: 11/07/2018 15:00:58
Human Papilloma virus (HPV) vaccine efficacy trial against cervical pre-cancer in young adults with GlaxoSmithKline (GSK) Biologicals HPV-16/18
EudraCT ID
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Trial overview
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.
Trial description: 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.
Primary purpose:
Prevention
Trial design:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Allocation:
Randomized
Primary outcomes:
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
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:
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
Number of subjects reporting solicited local and general symptoms
Timeframe: Within 7 days after any vaccination
Number of subjects reporting unsolicited adverse events
Timeframe: Within 30 days after any vaccination
Number of subjects reporting serious adverse events (SAEs)
Timeframe: Throughout the entire study period (Month 0 to Month 48)
Number of subjects reporting new onset of chronic disease (NOCDs)
Timeframe: Throughout the entire study (Month 0 to 48)
Number of subjects reporting medically significant conditions
Timeframe: Throughout entire study period (Month 0 to Month 48)
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)
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
Number of subjects with persistent infection (6-month definition) with HPV-16 or HPV-18
Timeframe: at Month 48
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
Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types
Timeframe: at Month 48
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
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
Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18
Timeframe: at Month 48
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
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
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
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
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
Anti-HPV-16 and anti-HPV-18 ELISA titers in the immunogenicity subset
Timeframe: At Months 6, 7, 12, 24, 36 and 48
HPV-16 and HPV-18 seroconversion (V5/J4 monoclonal inhibition test)
Timeframe: Month 0, 7, 12 and 24
HPV-16 and HPV-18 Geometric Mean Titers (GMT) (V5/J4 monoclonal inhibition test)
Timeframe: Month 0, 7, 12, 24
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
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
Geometric mean titers of anti-HPV-16 in subjects without and with 6-month persistent infection
Timeframe: At Month 7
Number of seroconverted subjects for anti-HPV-16 without and with 6-month persistent infection.
Timeframe: At Month 7
Geometric mean titers of anti-HPV-16 in subjects without and with 12-month persistent infection
Timeframe: At Month 7
Number of seroconverted subjects for anti-HPV-16 without and with 12-month persistent infection
Timeframe: At Month 7
Geometric mean titers of anti-HPV-18 in subjects without and with 6-month persistent infection
Timeframe: At Month 7
Number of seroconverted subjects for anti-HPV-18 without and with 6-month persistent infection.
Timeframe: At Month 7
Geometric mean titers of anti-HPV-18 in subjects without and with 12-month persistent infection
Timeframe: At Month 7
Number of seroconverted subjects for anti-HPV-18 without and with 12-month persistent infection
Timeframe: At Month 7
Interventions:
Enrollment:
18729
Primary completion date:
2006-03-11
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Castellsagué X et al. (2014) Risk of first cervical HPV infection and pre-cancerous lesions after onset of sexual activity: analysis of women in the control arm of the randomized, controlled PATRICIA trial. BMC Infectious Diseases 2014, 14(1):551.
Castellsagué X et al. (2014) Risk of newly detected infections and cervical abnormalities in women seropositive for naturally acquired Human Papillomavirus Type 16/18 antibodies: Analysis of the control arm of PATRICIA. J Infect Dis. 210(4):517-534.
Coursaget P et al. (2011) Priming as a basis for long-term protection and implications for HPV vaccination. Gynecologic Oncology . 121:S1–S9.
Descamps D et al. (2009) Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: A pooled analysis of 11 clinical trials. Hum Vaccin. 5(5):332-340.
Garland SM et al. (2016) Prior human papillomavirus-16/18 AS04-adjuvanted vaccination prevents recurrent high grade cervical intraepithelial neoplasia after definitive surgical therapy: Post-hoc analysis from a randomized controlled trial. Int J Cancer. 139(12):2812-2826.
Jaisamrarn U et al. (2013) Natural history of progression of HPV infection to cervical lesion or clearance: analysis of the control arm of the large, randomised PATRICIA study. PLoS One. 8(11):e79260.
Kreimer AR et al. (2015) 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. 16(7):775-786.
Lehtinen M et al. (2012) Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncology. 13(1):89-99.
Paavonen J et al. (2007) Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 369(9580):2161-2170.
Paavonen J et al. (2009) Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 374(9686):301-314.
Palmroth J et al. (2012) Occurrence of vaccine and non-vaccine human papillomavirus types in adolescent Finnish females 4 years post-vaccination. Int J Cancer. 131(12):2832-2838.
Schwarz TF et al. (2011) Overview of clinical evidence: Cervarix. Future Medicine - Human Papillomavirus Vaccines. 38-50.
Seoud M et al. (2011) Cervical adenocarcinoma: moving towards better prevention. Vaccine. 29(49):9148-9158.
Struyf F et al. (2015) Post hoc analysis of the PATRICIA randomized trial of the efficacy of human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against incident and persistent infection with nonvaccine oncogenic HPV types using an alternative multiplex type-specific PCR assay for HPV DNA. Clin Vaccine Immunol. 22(2):235-244.
Szarewski A et al. (2012) Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18. Int J Cancer. 131(1):106-116.
Szarewski A et al. (2013) Efficacy of the HPV-16/18 AS04-adjuvanted vaccine against low risk HPV Types (PATRICIA randomised trial): an unexpected observation. J Infect Dis. doi: 10.1093/infdis/jit360.
Verstraeten T et al. (2008) Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines. Vaccine. 26(51):6630–6638.
Wacholder S et al. (2010) Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials. BMJ. 340:c712.
Wheeler CM et al. (2012) Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncology. 13(1):100-110.
Medical condition
Infections, Papillomavirus
Product
SB208109, SB580299
Collaborators
Not applicable
Study date(s)
May 2004 to November 2009
Type
Interventional
Phase
3
Participation criteria
Sex
Female
Age
15 - 25 years
Accepts healthy volunteers
Yes
- 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.
- 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).
Inclusion and exclusion 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.
Trial location(s)
Location
GSK Investigational Site
Vancouver, Washington, United States, 98664
Status
Study Complete
Location
GSK Investigational Site
Muenchen, Bayern, Germany, 80331
Status
Terminated/Withdrawn
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Study documents
Clinical study report
Available language(s): English
Scientific result summary
Available language(s): English
Protocol
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Study complete
Actual primary completion date
2006-03-11
Actual study completion date
2009-26-11
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
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