Infections, Papillomavirus
Conditions
Keywords
Cervical neoplasia, AS04, Randomized, Cervical cancer, HPV-16/18 L1 VLP AS04, Phase IIIb, Korea, HPV, Double-blind, Controlled
Brief summary
Human papillomavirus infection has clearly been recognized as the cause of cervical cancer. The infection of the cervix by certain oncogenic types of HPV, if not cleared, can lead to cervical cancer in women. This study will evaluate the immunogenicity and safety of the GSK Biologicals' HPV-16/18 L1 VLP AS04 vaccine (Cervarix TM) vaccine. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.
Interventions
BIOLOGICALHPV-16/18 VLP/AS04 vaccine (Cervarix TM)
Three doses of vaccine administered intramuscularly according to a 0, 1, 6-month schedule.
BIOLOGICALPlacebo
Three doses of placebo administered intramuscularly according to a 0, 1, 6-month schedule.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
15 Years to 25 Years
Healthy volunteers
Yes
Inclusion criteria
* Subjects who the investigator believes that they or their parents/guardians can and will comply with the requirements of the protocol should be enrolled in the study. * A female between, and including, 15 and 25 years of age at the time of the first vaccination. * Written informed assent obtained from the subject and informed consent obtained from the parent or guardian of the subject. * Healthy subjects as established by medical history and clinical examination before entering into the study. * Subjects must have a negative urine pregnancy test. * Subjects of childbearing potential at the time of study entry must be abstinent, or must be using adequate contraceptive precautions for 30 days prior to vaccination and must agree to continue such precautions for two months after completion of the vaccination series.
Exclusion criteria
* Use of any investigational or non-registered product (drug or vaccine) other than the study/ control vaccine within 30 days preceding the first dose of study/ control vaccine, or planned use during the study period. * Pregnant or breastfeeding. * Planning to become pregnant or likely to become pregnant. * Chronic administration (defined as more than 14 days) 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 the first dose of vaccine. However, the administration of routine vaccines up to 8 days before the first dose of study vaccine is allowed. Enrolment will be deferred until the subject is outside of specified window. * Previous administration of components of the investigational vaccine * Previous vaccination against HPV or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period. * Any medically diagnosed or suspected immunodeficient condition such as HIV infection based on medical history and physical examination. * History of thrombocytopenia or hemostatic disorder in which case the study vaccine should under no circumstances be administered intramuscularly. * History of allergic disease, suspected allergy or reactions likely to be exacerbated by any component of the study/control vaccines. * Hypersensitivity to latex. * Known acute or chronic, clinically significant neurologic, pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests. * History of chronic condition(s) requiring treatment. * Administration of immunoglobulins and/or any blood product within three months preceding the first dose of study/control vaccine or planned administration during the study period. Enrolment will be deferred until the subject is outside of specified window. * Acute disease at the time of enrolment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | One month post Dose 3 (Month 7) | Seroconversion is defined as the appearance of anti-HPV-16 and/or anti-HPV-18 antibodies (i.e. antibody titer ≥ cut-off value) in the sera of subjects seronegative before vaccination. Cut-off values were 8 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL) for anti-HPV-16 antibodies and 7 EL.U/mL for anti-HPV-18 antibodies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Reporting Solicited Local Symptoms | During the 7-day (Days 0-6) period following each vaccination | Solicited local symptoms assessed include pain, redness and swelling at the injection site. |
| Number of Subjects Reporting Solicited General Symptoms | During the 7-day (Days 0-6) period following each vaccination | Solicited general symptoms assessed include arthralgia, fatigue, fever, gastrointestinal symptoms, headache, myalgia, rash, and urticaria. |
| Number of Subjects Reporting Unsolicited Adverse Events (AE) | During the 30-day (Days 0-29) period following each vaccination | Unsolicited adverse event= Any adverse event (AE) reported in addition to those solicited during the clinical study. Also any solicited symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited adverse event. |
| Anti-HPV-16 and Anti-HPV-18 Antibody Titres | Before vaccination (PRE) and one month post Dose 3 (Month 7) | Titres are given as geometric mean titres (GMTs) calculated on all subjects. |
| Number of Subjects Reporting Serious Adverse Events (SAE) | From Day 0 up to Month 7 | Serious adverse events assessed include medical occurrences that result in death, is life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. |
| Number of Subjects With Pregnancies and Their Outcome | from Day 0 up to Month 7 | Total: the total number of pregnancies in a group. The specific outcomes are also listed. |
| Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions | From Day 0 up to Month 7 | NOCDs assessed include e.g. autoimmune disorders, asthma, type I diabetes. Medically significant AEs assessed include AEs prompting emergency room visits and physician office visits not related to common illnesses or Serious Adverse Events (SAEs) that are not related to common illnesses. |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cervarix Group Subjects received 3 doses of HPV-16/18 VLP/AS04 vaccine (Cervarix TM) vaccine administered intramuscularly according to a 0, 1, 6-month schedule. | 149 |
| Placebo Group Subjects received 3 doses of placebo according to a 0, 1, 6-month schedule. | 76 |
| Total | 225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | Withdrawal by Subject | 5 | 4 |
Baseline characteristics
| Characteristic | Cervarix Group | Placebo Group | Total |
|---|---|---|---|
| Age, Continuous | 22.0 years STANDARD_DEVIATION 2.24 | 21.9 years STANDARD_DEVIATION 2.63 | 22.0 years STANDARD_DEVIATION 2.37 |
| Sex: Female, Male Female | 149 Participants | 76 Participants | 225 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 144 / 149 | 70 / 76 |
| serious Total, serious adverse events | 2 / 149 | 1 / 76 |
Outcome results
Primary
Number of Subjects Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies
Seroconversion is defined as the appearance of anti-HPV-16 and/or anti-HPV-18 antibodies (i.e. antibody titer ≥ cut-off value) in the sera of subjects seronegative before vaccination. Cut-off values were 8 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL) for anti-HPV-16 antibodies and 7 EL.U/mL for anti-HPV-18 antibodies.
Time frame: One month post Dose 3 (Month 7)
Population: Analysis was performed on initially seronegative subjects from the According-to-Protocol (ATP) cohort for immunogenicity.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cervarix Group | Number of Subjects Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-16 | 125 Participants |
| Cervarix Group | Number of Subjects Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-18 | 122 Participants |
| Placebo Group | Number of Subjects Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-16 | 2 Participants |
| Placebo Group | Number of Subjects Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-18 | 3 Participants |
Secondary
Anti-HPV-16 and Anti-HPV-18 Antibody Titres
Titres are given as geometric mean titres (GMTs) calculated on all subjects.
Time frame: Before vaccination (PRE) and one month post Dose 3 (Month 7)
Population: Analysis was performed on the ATP cohort for immunogenicity.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Cervarix Group | Anti-HPV-16 and Anti-HPV-18 Antibody Titres | Anti-HPV-16 (PRE) | 4.6 titre |
| Cervarix Group | Anti-HPV-16 and Anti-HPV-18 Antibody Titres | Anti-HPV-16 (Month 7) | 9226.4 titre |
| Cervarix Group | Anti-HPV-16 and Anti-HPV-18 Antibody Titres | Anti-HPV-18 (PRE) | 4.1 titre |
| Cervarix Group | Anti-HPV-16 and Anti-HPV-18 Antibody Titres | Anti-HPV-18 (Month 7) | 4240.2 titre |
| Placebo Group | Anti-HPV-16 and Anti-HPV-18 Antibody Titres | Anti-HPV-18 (Month 7) | 4.3 titre |
| Placebo Group | Anti-HPV-16 and Anti-HPV-18 Antibody Titres | Anti-HPV-16 (PRE) | 4.8 titre |
| Placebo Group | Anti-HPV-16 and Anti-HPV-18 Antibody Titres | Anti-HPV-18 (PRE) | 4.0 titre |
| Placebo Group | Anti-HPV-16 and Anti-HPV-18 Antibody Titres | Anti-HPV-16 (Month 7) | 4.9 titre |
Secondary
Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions
NOCDs assessed include e.g. autoimmune disorders, asthma, type I diabetes. Medically significant AEs assessed include AEs prompting emergency room visits and physician office visits not related to common illnesses or Serious Adverse Events (SAEs) that are not related to common illnesses.
Time frame: From Day 0 up to Month 7
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cervarix Group | Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions | NOCD | 5 Participants |
| Cervarix Group | Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions | Medically Significant Conditions | 34 Participants |
| Placebo Group | Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions | NOCD | 6 Participants |
| Placebo Group | Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions | Medically Significant Conditions | 10 Participants |
Secondary
Number of Subjects Reporting Serious Adverse Events (SAE)
Serious adverse events assessed include medical occurrences that result in death, is life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject.
Time frame: From Day 0 up to Month 7
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cervarix Group | Number of Subjects Reporting Serious Adverse Events (SAE) | 2 Participants |
| Placebo Group | Number of Subjects Reporting Serious Adverse Events (SAE) | 1 Participants |
Secondary
Number of Subjects Reporting Solicited General Symptoms
Solicited general symptoms assessed include arthralgia, fatigue, fever, gastrointestinal symptoms, headache, myalgia, rash, and urticaria.
Time frame: During the 7-day (Days 0-6) period following each vaccination
Population: Analysis was performed on the Total vaccinated cohort on the subjects with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cervarix Group | Number of Subjects Reporting Solicited General Symptoms | Rash | 29 Participants |
| Cervarix Group | Number of Subjects Reporting Solicited General Symptoms | Gastrointestinal symptoms | 52 Participants |
| Cervarix Group | Number of Subjects Reporting Solicited General Symptoms | Fatigue | 103 Participants |
| Cervarix Group | Number of Subjects Reporting Solicited General Symptoms | Headache | 73 Participants |
| Cervarix Group | Number of Subjects Reporting Solicited General Symptoms | Arthralgia | 35 Participants |
| Cervarix Group | Number of Subjects Reporting Solicited General Symptoms | Myalgia | 97 Participants |
| Cervarix Group | Number of Subjects Reporting Solicited General Symptoms | Fever | 7 Participants |
| Cervarix Group | Number of Subjects Reporting Solicited General Symptoms | Urticaria | 12 Participants |
| Placebo Group | Number of Subjects Reporting Solicited General Symptoms | Fever | 2 Participants |
| Placebo Group | Number of Subjects Reporting Solicited General Symptoms | Rash | 8 Participants |
| Placebo Group | Number of Subjects Reporting Solicited General Symptoms | Arthralgia | 8 Participants |
| Placebo Group | Number of Subjects Reporting Solicited General Symptoms | Fatigue | 39 Participants |
| Placebo Group | Number of Subjects Reporting Solicited General Symptoms | Urticaria | 2 Participants |
| Placebo Group | Number of Subjects Reporting Solicited General Symptoms | Gastrointestinal symptoms | 16 Participants |
| Placebo Group | Number of Subjects Reporting Solicited General Symptoms | Headache | 30 Participants |
| Placebo Group | Number of Subjects Reporting Solicited General Symptoms | Myalgia | 33 Participants |
Secondary
Number of Subjects Reporting Solicited Local Symptoms
Solicited local symptoms assessed include pain, redness and swelling at the injection site.
Time frame: During the 7-day (Days 0-6) period following each vaccination
Population: Analysis was performed on the Total vaccinated cohort on the subjects with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cervarix Group | Number of Subjects Reporting Solicited Local Symptoms | Pain | 140 Participants |
| Cervarix Group | Number of Subjects Reporting Solicited Local Symptoms | Redness | 109 Participants |
| Cervarix Group | Number of Subjects Reporting Solicited Local Symptoms | Swelling | 89 Participants |
| Placebo Group | Number of Subjects Reporting Solicited Local Symptoms | Pain | 64 Participants |
| Placebo Group | Number of Subjects Reporting Solicited Local Symptoms | Redness | 35 Participants |
| Placebo Group | Number of Subjects Reporting Solicited Local Symptoms | Swelling | 19 Participants |
Secondary
Number of Subjects Reporting Unsolicited Adverse Events (AE)
Unsolicited adverse event= Any adverse event (AE) reported in addition to those solicited during the clinical study. Also any solicited symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited adverse event.
Time frame: During the 30-day (Days 0-29) period following each vaccination
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cervarix Group | Number of Subjects Reporting Unsolicited Adverse Events (AE) | 66 Participants |
| Placebo Group | Number of Subjects Reporting Unsolicited Adverse Events (AE) | 19 Participants |
Secondary
Number of Subjects With Pregnancies and Their Outcome
Total: the total number of pregnancies in a group. The specific outcomes are also listed.
Time frame: from Day 0 up to Month 7
Population: Analysis was performed on subjects with a pregnancy.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo Group | Number of Subjects With Pregnancies and Their Outcome | Total | 1 Participants |
| Placebo Group | Number of Subjects With Pregnancies and Their Outcome | Elective abortion | 1 Participants |