This study is to demonstrate that the administration of the investigational vaccine can reduce the Combined Incidence of HPV types 6/11/16/18/31/33/45/52/58-related high-grade Cervical Intraepithelial Neoplasia (CIN 2/3), Adenocarcinoma in Situ (AIS), Invasive Cervical Carcinoma, high-grade Vulvar Intraepithelial Neoplasia (VIN 2/3), high-grade Vaginal Intraepithelial Neoplasia (VaIN 2/3), high-grade Anal Intraepithelial Neoplasia (AIN 2/3), vulvar cancer, vaginal cancer or anal cancer.
This is a multi-center, blinded, randomized and Gardasil-controlled (quadrivalent HPV vaccine GARDASIL®) Phase III clinical study. The study will recruit a total of approximately 12,000 healthy Chinese women ages 20-45 years with permanent residence, who will be randomized at a 1: 1 ratio to receive the investigational vaccine or the positive control (quadrivalent HPV vaccine GARDASIL®), respectively. Healthy women ages 20-45 eligible for the study will be stratified at a 2: 2: 1 ratio into three age subgroups (i.e. 20-26 years of age, 27-35 years of age and 36-45 years of age), and each subgroup will be randomized at a 1: 1 ratio to receive the investigational vaccine or the positive control (quadrivalent HPV vaccine GARDASIL®), respectively. A total of 1,000 subjects will be allocated to an Immunogenicity Cohort, who will also be randomized at a 1: 1 ratio to receive the investigational vaccine or the positive control. The Immunogenicity Cohort is set up to evaluate the immune responses induced by the investigational vaccine and their persistence. For the Sample allocation plan, twelve thousand (12,000) subjects from the chosen clinical trial sites are stratified at a 2: 2: 1 ratio into 3 age subgroups, i.e. 4,800 in the subgroup of ages 20-26 years, 4,800 in the subgroup of ages 27-35 years, and 2,400 in the subgroup 36-45 years of age. Immunogenicity evaluation will be conducted at a clinical trial site in 1,000 subjects, selected randomly in the order of enrollment. The Primary study objectives also involve: -To demonstrate that administration of the investigational vaccine reduces the Combined Incidence of HPV types 6/11/16/18/31/33/45/52/58-related persistent infections, and cervical, vulvar, vaginal and anal lesions detected in samples from three or more consecutive visits (+/-1 month visit window) 12 months or longer apart. The Secondary study objectives involve: * To evaluate the safety profile of the investigational vaccine in healthy women ages 20-45; * To demonstrate that geometric mean titers of antibody responses specific to HPV types 6/11/16/18 induced by the investigational vaccine are non-inferior to those generated by GARDASIL; * To demonstrate that the investigational vaccine produces antibody responses specific to HPV types 31/33/45/52/58; * To evaluate the levels and persistence of antibody responses against HPV types 6/11/16/18/31/33/45/52/58 generated by the investigational vaccine; * To demonstrate that the investigational vaccine reduces the Combined Incidence of HPV types 6/11/16/18/31/33/45/52/58-related persistent infections detected in samples from 2 or more consecutive visits 6 months (+/-1 month visit window) or longer apart. The Exploratory study objectives involve: * To evaluate the impact of a 3-dose regimen of the investigational vaccine on the incidence of HPV types 6/11/16/18/31/33/45/52/58-related cytological abnormalities (ASC-US, positive for high-risk HPV types, or worse) as determined by the Thinprep cytologic test (TCT test) among subjects, who are naïve (seronegative) to the relevant HPV type(s) (HPV 6/11/16/18/31/33/45/52/58) at baseline and remain negative to the relevant HPV type(s) as determined by HPV-DNA test and without abnormal cervical biopsy result through Month 7; * To evaluate the incidence of non-vaccine HPV type-related Cervical Intraepithelial Neoplasia (CIN), Adenocarcinoma in Situ (AIS) and Cervical Carcinoma as determined by histopathologic examination post 3 doses of the investigational vaccine; * To evaluate the incidence of non-vaccine HPV type-related persistent infections for no less than 6 months, and cervical, vulvar, vaginal and anal diseases as determined by histopathologic examination post 3 doses of the investigational vaccine; * To evaluate the incidence of non-vaccine HPV type-related cytological abnormalities (ASC-US, positive for high-risk HPV types, or worse) as determined by the TCT test post 3 doses of the investigational vaccine.
0.5-mL suspension for injection, each 0.5-mL prefilled syringe dose contains L1 proteins of HPV types 6/11/16/18/31/33/45/52/58 in the amounts of 30mcg, 40mcg, 60mcg, 40mcg, 20mcg, 20mcg, 20mcg, 20mcg and 20mcg, respectively, totaling 270mcg of antigens. A 3-dose regimen administered at months 0, 2 and 6.
0.5-mL suspension for injection, each 0.5-mL single-dose syringe contains approximately 20 mcg of HPV Type 6 L1 protein, 40 mcg of HPV Type 11 L1 protein, 40 mcg of HPV Type 16 L1 protein, 20 mcg of HPV Type 18 L1 protein, totaling 120 mcg of antigens
CDC, Guangdong Provinc
Guangzhou, Guangdong, China
CDC, Jiangsu Province
Nanjing, Jiangsu, China
CDC, Shanxi Province
Taiyuan, Shanxi, China
The combined incidence of HPV types 6/11/16/18/31/33/45/52/58-related high-grade diseases
The combined incidence of HPV types 6/11/16/18/31/33/45/52/58-related high-grade Cervical Intraepithelial Neoplasia (CIN 2/3), Adenocarcinoma in Situ (AIS), Invasive Cervical Carcinoma, high-grade Vulvar Intraepithelial Neoplasia (VIN 2/3), high-grade Vaginal Intraepithelial Neoplasia (VaIN 2/3), high-grade Anal Intraepithelial Neoplasia (AIN 2/3), vulvar cancer, vaginal cancer and anal cancer post 3 doses of the investigational vaccine as determined by histopathologic examination among subjects, who are naïve (seronegative) to the relevant HPV type(s) (HPV 6/11/16/18/31/33/45/52/58) at baseline and remain negative to the relevant HPV type(s) as determined by HPV-DNA test and without abnormal cervical biopsy result through Month 7 (composite end point)
Time frame: Up to 60th month after full immunization
The combined incidence of specific HPV types related persistent infections for no less than 12 months and related diseases
The combined incidence of HPV types 6/11/16/18/31/33/45/52/58-related persistent infections for no less than 12 months as determined by testing samples from consecutive visits, and cervical, vulvar, vaginal and anal diseases among subjects, who are naïve (seronegative) to the relevant HPV type(s) (HPV 6/11/16/18/31/33/45/52/58) at baseline and remain negative to the relevant HPV type(s) as determined by HPV-DNA test and without abnormal cervical biopsy result through Month 7.
Time frame: Up to 60th month after full immunization.
Overall incidence of adverse events post vaccination
Overall incidence of adverse events post vaccination
Time frame: 0-30 days after each immunization
Overall incidence of adverse reactions post vaccination
Overall incidence of adverse reactions post vaccination
Time frame: 0-30 days after each immunization
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Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
DOUBLE
Enrollment
12,000
Incidence of adverse reactions by severity post vaccination
Incidence of adverse reactions by severity post vaccination
Time frame: 0-30 days after each immunization
Percentage of subjects with one or more injection-site or non-injection-site
Percentage of subjects with one or more injection-site or non-injection-site
Time frame: 0-30 days after each immunization
Incidence of adverse event/adverse reaction by sign/symptom post vaccination
Incidence of adverse event/adverse reaction by sign/symptom post vaccination
Time frame: 0-30 days after each immunization
Severity of adverse event/adverse reaction post vaccination
Severity of adverse event/adverse reaction post vaccination
Time frame: 0-30 days after each immunization
Incidence of adverse reactions post each vaccination
Incidence of adverse reactions post each vaccination
Time frame: 0-30 days after each immunization
Incidence of serious adverse events that occur during the observation period
Incidence of serious adverse events that occur during the observation period
Time frame: Through study completion, an average of 5 years
Follow up the information on Pregnancy events through the interview, telephone call, and Safety follow-up Diary Card (Questionnaire).
Follow up the information on Pregnancy events through the interview, telephone call, and Safety follow-up Diary Card (Questionnaire).
Time frame: Through study completion, an average of 5 years
Follow up the information on birth/infant outcomes through the interview, telephone call, and Safety follow-up Diary Card (Questionnaire).
Follow up the information on birth/infant outcomes through the interview, telephone call, and Safety follow-up Diary Card (Questionnaire).
Time frame: Through study completion, an average of 5 years
Incidence of HPV types 6/11/16/18/31/33/45/52/58-related persistent infections for no less than 6 months
Incidence of HPV types 6/11/16/18/31/33/45/52/58-related persistent infections for no less than 6 months as determined by testing samples from consecutive visits among subjects, who are naïve (seronegative) to the relevant HPV type(s) (HPV 6/11/16/18/31/33/45/52/58) at baseline and remain negative to the relevant HPV type(s) as determined by HPV-DNA test and without abnormal cervical biopsy result through Month 7
Time frame: Up to 60th month after the first immunization
GMTs of neutralizing antibody responses to vaccine HPV types determined among subjects who are seronegative
GMTs of neutralizing antibody responses and seroconversion rates to vaccine HPV types, as determined by Pseudovirus-based Neutralization Assay at week 4 post dose 3 in subjects who are naïve (seronegative) to the relevant HPV type(s) (HPV 6/11/16/18/31/33/45/52/58) at baseline and remain negative to the relevant HPV type(s) as determined by HPV-DNA test and without abnormal cervical biopsy result through Month 7
Time frame: 7th month after the first immunization
Seroconversion rates to vaccine HPV types determined among subjects who are seronegative
Seroconversion rates to vaccine HPV types, as determined by Pseudovirus-based Neutralization Assay at week 4 post dose 3 in subjects who are naïve (seronegative) to the relevant HPV type(s) (HPV 6/11/16/18/31/33/45/52/58) at baseline and remain negative to the relevant HPV type(s) as determined by HPV-DNA test and without abnormal cervical biopsy result through Month 7
Time frame: 7th month after the first immunization
The immune responses to HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58, and their persistence in terms of GMTs of vaccine HPV type-specific neutralizing antibodies among the group who are seronegative
To evaluate immune responses to HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58, and their persistence in terms of GMTs of vaccine HPV type-specific neutralizing antibodies, as determined by Pseudovirus-based Neutralization Assay , respectively among the group who are seronegative to the relevant HPV type(s) (HPV 6/11/16/18/31/33/45/52/58) at baseline and remain
Time frame: Up to the 60 months after the first immunization
The immune responses to HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58, and their persistence in terms of GMTs of vaccine HPV type-specific IgG antibodies among the group who are seronegative
To evaluate immune responses to HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58, and their persistence in terms of GMTs of vaccine HPV type-specific IgG antibodies, as determined by ELISA assay, respectively among the group who are seronegative to the relevant HPV type(s) (HPV 6/11/16/18/31/33/45/52/58) at baseline and remain
Time frame: Up to the 60 months after the first immunization