Study to Evaluate the Efficacy of the Human Papillomavirus Vaccine in Healthy Adult Women of 26 Years of Age and Older

Phase 3

Completed

• Conditions: Infections, Papillomavirus; Papillomavirus Vaccines
• Interventions: Biological: Cervarix; Biological: Placebo control

• Registration Number: NCT00294047
• Lead Sponsor: GlaxoSmithKline

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.

Basic Information
|
Recruitment & Eligibility
|
Study & Design
|
Trial Locations

Study Timeline

• Study Start: 2006-02-16
• Study First Submitted: 2006-02-17
• Study First Submitted QC: 2006-02-17
• Study First Posted: 2006-02-20
• Results First Submitted: 2011-12-08
• Results First Submitted QC: 2012-02-23
• Results First Posted: 2012-03-27
• Primary Completion: 2014-01-29
• Study Completion: 2014-01-29
• Status Verified: 2019-12
• Last Update Submitted: 2019-12-27
• Last Update Posted: 2020-01-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 5752

Inclusion Criteria

Not provided

Read More

Exclusion Criteria

Not provided

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cervarix Group	Cervarix	Subjects received 3 doses of Cervarix™ vaccine. Cervarix vaccine was administered intramuscularly into the deltoid region of the non-dominant arm according to a 0, 1, 6 months schedule.
Aluminium Hydroxide Group	Placebo control	Subjects received 3 doses of Aluminium Hydroxide \[Al(OH)3\]. Aluminium Hydroxide was administered intramuscularly into the deltoid region of the non-dominant arm according to a 0, 1, 6 months schedule.

Primary Outcome Measures

Name	Time	Method
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).	Up to Month 84	CIN1+ = CIN grades 1, 2 and 3, AIS and invasive cervical cancer. Persistent cervical HPV infection (6-month definition) = detection of the same HPV type(s) by PCR in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. - DNA- and sero-/+: subjects HPV DNA negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative/positive (sero-/+) for HPV-16 and/or HPV-18 by ELISA at baseline (Month 0). - Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.
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.	Up to Month 84	CIN1+ = CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer. Persistent HPV infection = detection of the same HPV type(s) by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. - DNA- and sero-/+: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and 6 and seronegative/positive (sero-/+) at Month 0 for the corresponding HPV-type by Enzyme-linked Immunosorbent Assay (ELISA) - Overall: subjects DNA- at Month 0 and 6 for the corresponding HPV-type, regardless of initial serostatus

Secondary Outcome Measures

Name	Time	Method
Number of Seroconverted Subjects Against HPV-16 in the Immunogenicity Subset.	At pre-vaccination and at Month 7, 12, 18, 24, 36, 48, 60, 72 and 84	Seroconversion was defined as the appearance of antibodies (i.e.; titre greater than or equal to the cut-off value) in the serum of subjects seronegative before vaccination.; HPV-16 assay cut-off value was defined as greater than or equal to 8 ELISA units per millilitre (EL.U/mL). Seronegative (Sero-) subjects are subjects who had an antibody concentration below 8 EL.U/mL prior to vaccination. Seropositive (Sero+) subjects are subjects who had an antibody concentration equal to or above 8 EL.U/mL prior to vaccination.; Immuno subset=subjects from selected sites N≥1000, at least 250 per region
Number of Subjects With Cytological Abnormalities Associated With Oncogenic HPV Types Individually or in Combinations	Up to Month 48	Oncogenic HPV types included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. Detection was done in subjects who were HPV DNA negative for the corresponding HPV type at baseline (at month 0 and Month 6) regardless of initial serostatus. HRW-HPV= All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18 HPV-HR= High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68
Number of Seroconverted Subjects Against HPV-18 in the Immunogenicity Subset.	At pre-vaccination and at Month 7, 12, 18, 24, 36, 48, 60, 72 and 84	Seroconversion was defined as the appearance of antibodies (i.e.; titre greater than or equal to the cut-off value) in the serum of subjects seronegative before vaccination.; HPV-18 assay cut-off value was defined as greater than or equal to 7 ELISA units per millilitre (EL.U/mL). Seronegative (Sero-) subjects are subjects who had an antibody concentration below 7 EL.U/mL prior to vaccination. Seropositive (Sero+) subjects are subjects who had an antibody concentration equal to or above 7 EL.U/mL prior to vaccination.; Immuno subset=subjects from selected sites N≥1000, at least 250 per region
Geometric Mean Concentrations (GMCs) Against HPV-16 Antibody in the Immunogenicity Subset.	At pre-vaccination and at Month 7, 12, 18, 24, 36, 48, 60, 72 and 84	GMCs were expressed in ELISA units per milliliter (EL.U/mL).; Seronegative (Sero-) subjects are subjects who had an antibody concentration below 8 EL.U/mL prior to vaccination. Seropositive (Sero+) subjects are subjects who had an antibody concentration equal to or above 8 EL.U/mL prior to vaccination.; Immuno subset=subjects from selected sites (N≥1000, at least 250 per region)
Geometric Mean Concentrations (GMCs) Against HPV-18 Antibody in the Immunogenicity Subset.	At pre-vaccination and at Month 7, 12, 18, 24, 36, 48, 60, 72 and 84	GMCs were expressed in ELISA units per milliliter (EL.U/mL).; Seronegative (Sero-) subjects are subjects who had an antibody concentration below 7 EL.U/mL prior to vaccination. Seropositive (Sero+) subjects are subjects who had an antibody concentration equal to or above 7 EL.U/mL prior to vaccination.; Immuno subset=subjects from selected sites (N≥1000, at least 250 per region)
Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms.	Within 7 days (Days 0-6) after vaccination	Solicited general symptoms assessed were arthralgia, fatigue, gastrointestinal, headache, myalgia, rash, urticaria and fever (Fever = axillary temperature above 37.5 degrees Celsius (°C)). Any = any solicited general symptom reported irrespective of intensity and relationship to vaccination. Related = symptoms considered by the investigator to have a causal relationship to vaccination. Grade 3 symptoms = symptoms that prevented normal activity. Grade 3 urticaria = urticaria distributed on at least 4 body areas. Grade 3 fever = axillary temperature above 39.0°C.
Number of Subjects With Persistent Infection (6-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18	Up to Month 84	Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type(s) by PCR in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. Detection was done in: - DNA- and sero-/+: subjects HPV DNA negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative/positive (sero-/+) for HPV-16 and/or HPV-18 by ELISA at baseline (Month 0). - Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.
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	Up to Month 84	CIN2+ was defined as CIN grades 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer. Detection was done in: - DNA- and sero-: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative (sero-) for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0). - Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. Note: Results for seropositive status were not analysed.
Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types Individually or in Combinations.	Up to Month 84	Persistent cervical HPV infection (6-month definition) = detection of the same HPV type(s) by PCR in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. Oncogenic HPV types included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. Detection was done in subjects HPV DNA- for the corresponding HPV type at baseline (at month 0 and Month 6) regardless of initial serostatus. HPV-HRW=All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18. HPV-HR=High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.
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	Up to Month 84
Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Irrespective of HPV Cervical Infection and Irrespective of Baseline HPV DNA Status	Up to Month 84	CIN1+ was defined as CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer. Detection was done on all subjects irrespective of their baseline HPV DNA status.
Number of Subjects With Any Cytological Abnormalities Associated With HPV-16 or HPV-18 Cervical Infection	Up to Month 84	Cytological abnormalities = atypical squamous cells of undetermined significance (ASC-US). Detection was done in: - DNA- and sero-: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative (sero-) for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0). - Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. Results for seropositive status were not analysed.
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).	Up to Month 84	Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type(s) by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. Detection was done on all subjects irrespective of their baseline HPV DNA and serostatus. The lesion was assigned to an HPV type found in the lesion if (1) the same HPV type was found in at least 1 of the 2 (closest) preceding cytology samples, or (2) none of the HPV types found in the lesion were found in any of the 2 preceding cytology samples (isolate HPV types)
Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms.	Within 7 days (Days 0-6) after vaccination	Solicited local symptoms assessed were pain, redness and swelling. Any was defined as any solicited local symptom reported irrespective of intensity. Grade 3 pain was defined as pain that prevented normal activity. Grade 3 redness and swelling was defined as redness/swelling above 50 millimeter (mm).
Number of Subjects Reporting Any and Related Serious Adverse Events (SAEs).	Up to Month 48 and up to Month 84	SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects. A related SAE was defined as an event assessed by the investigator as causally related to the study vaccination.
Number of Subjects With Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18	Up to Month 84	Persistent cervical HPV infection (12-month definition) was defined as the detection of the same HPV type(s) PCR in cervical samples at all available time points over approximately a 12-month interval (evaluations are planned at approximately 6-month intervals). - DNA- and sero-/+: subjects HPV DNA negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative/positive (sero-/+) for HPV-16 and/or HPV-18 by ELISA at baseline (Month 0). - Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.
Number of Subjects With Persistent Infection (12-month Definition) With Oncogenic HPV Types Individually or in Combinations.	Up to Month 84	Oncogenic HPV types included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. subjects HPV DNA- for the corresponding HPV type at Month 0 6, regardless of initial serostatus. HPV-HRW=All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18 HPV-HR=High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 , 68
Number of Subjects With Histopathologically Confirmed Reduction of Local Cervical Therapy	Up to Month 84	Detection was done on all subjects irrespective of their baseline HPV DNA status.
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	Up to Month 84	Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type(s) by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. CIN1+ was defined as CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer. Detection was done on all subjects irrespective of their baseline HPV DNA and serostatus.
Number of Subjects With First Colposcopy	Up to Month 84	Detection was done on all subjects irrespective of their baseline HPV DNA status.
Number of Seroconverted Subjects Against HPV-16 and HPV-18 Viral Neutralization in a Selected Subset of Subjects.	Prior to vaccination and at Months 7, 12, 18, 24, 48 and 84.	Seroconversion was defined as the appearance of antibodies (i.e.; titre greater than or equal to the cut-off value) in the serum of subjects seronegative before vaccination. HPV-16/18 assay cut-off value was defined as greater than or equal to 40 Estimated dose 50% (ED50). Sero- subjects are subjects who had an antibody concentration below 40 ED50 prior to vaccination. Sero+ subjects are subjects who had an antibody concentration equal to or above 50 ED50 prior to vaccination. ED50 = the estimated serum dilution reducing the signal generated by viral infection by 50%
Geometric Mean Titers (GMTs) Against HPV-16 and HPV-18 Viral Neutralization Antibodies in a Selected Subset of Subjects.	Prior to vaccination and at Months 7, 12, 18, 24, 48 and 84.	Titers are expressed as geometric mean antibody titers (GMTs).; Seronegative (Sero-) subjects are subjects who had an antibody titer below 40 ED50 prior to vaccination. Seropositive (Sero+) subjects are subjects who had an antibody titer equal to or above 40 ED50 prior to vaccination.; ED50 = Estimated dose 50%, the estimated serum dilution reducing the signal generated by viral infection by 50%
Number of Subjects Reporting Any, Grade 3 and Related Unsolicited Adverse Events (AEs).	Within 30 days (Days 0 - 29) post-vaccination period.	An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Grade 3 unsolicited AE = an event that prevented normal activity.; A related AE = event assessed by the investigator as causally related to the study vaccination.
Number of Subjects Reporting New Onset of Autoimmune Disease (NOADs).	Up to Month 48
Number of Subjects Reporting Medically Significant Conditions (MAEs).	Up to Month 48	Medically significant conditions were defined as: AEs prompting emergency room or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that were not related to common diseases. Common diseases included: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities and injury.
Number of Subjects Reporting Related or Fatal Serious Adverse Event.	Up to Month 84	Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.
Number of Subjects Reporting New Onset of Chronic Disease (NOCDs).	Up to Month 48	NOCDs include autoimmune disorders, asthma and type I diabetes.
Number of Subjects With Pregnancies and Their Outcomes.	Up to Month 48	Pregnancy outcomes are live infant, premature live infant, elective termination, ectopic pregnancy, spontaneous abortion, lost to follow-up and pregnancy ongoing. For each category it was specified if the infant presents congenital anomaly (CA) or no apparent congenital anomaly (No ACA).
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)	Up to Month 48	CIN1+ was defined as CIN grades 1, 2 and 3, adenocarcinoma in situ (AIS) and invasive cervical cancer.; Detection was done on subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.; TAA: Type assignment algorithm. The lesion was assigned to an HPV type found in the lesion if; 1. the same HPV type was found in at least one of the two (closest) preceding cytology samples, or; 2. none of the HPV types found in the lesion were found in any of the two preceding cytology samples (isolate HPV types)
Number of Subjects Reporting Any AE/SAE Leading to Premature Discontinuation of the Study.	Up to Month 84	An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.; Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

Trial Locations

Locations (1)

GSK Investigational Site; 🇬🇧 Manchester, United Kingdom