Infections, Papillomavirus
Conditions
Keywords
HPV, cervical cancer, papillomavirus, Human papillomavirus (HPV) vaccine
Brief summary
Infection with human papillomavirus (HPV) has been clearly established as the central cause of cervical cancer. The current phase 3b study is designed to assess the immunogenicity and safety of GlaxoSmithKline Biologicals' HPV vaccine GSK580299 administered according to an alternative dosing schedule as compared to the standard dosing schedule in young female subjects aged 15 - 25 years. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.
Interventions
BIOLOGICALCervarix TM
Intramuscular administration into the deltoid region of the non-dominant arm according to a 0, 1, 12-month schedule.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
15 Years to 25 Years
Healthy volunteers
Yes
Inclusion criteria
* Subjects who the investigator believes that they and/or their parent(s)/Legally acceptable representative(s) (LAR) can and will comply with the requirements of the protocol * A female between and including 15 and 25 years of age at the time of the first vaccination. * Written informed consent obtained from the subject prior to enrolment. For subjects below the legal age of consent, written informed consent must be obtained from the subject's parents/legally acceptable representative (LAR), and written informed assent must be obtained from the subject. * Healthy subjects as established by medical history and/or clinical examination before entering into the study. * Subject must be of non-childbearing potential, or if she is of child bearing potential, she must practice adequate contraception for 30 days prior to vaccination, have a negative urine pregnancy test and continue such precautions for 2 months after completion of the vaccination series. * Subject who had no more than 6 lifetime sexual partners prior to enrolment.
Exclusion criteria
* Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine 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 the first dose of vaccine. Planned administration/administration of routine vaccines up to 8 days before the first dose of study vaccine is allowed. Enrolment will be deferred until the patient is outside of specified window. * Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device). * Previous vaccination against HPV or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period. * previous administration of components of the investigational vaccine * Cancer or autoimmune disease under treatment. * Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. * History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. * Hypersensitivity to latex * Acute disease at the time of enrolment. * Administration of immunoglobulins and/or any blood products within the three months preceding blood sampling. * Pregnant or breastfeeding female. * Female planning to become pregnant, likely to become pregnant (as determined by the investigator) or planning to discontinue contraceptive precautions during the study period starting at visit one and up to two months after the last vaccine dose. * Acute or chronic clinically significant pulmonary, cardiovascular, hepatic or renal function abnormality as determined by physical examination or lab tests.
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 after the third vaccine dose | 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. |
| Titer of Anti-HPV-16 and Anti-HPV-18 Antibodies | One month after the third vaccine dose | Titer given as geometric mean titer (GMT). |
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 | An AE is 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. |
| Number of Subjects Seroconverted for Anti-HPV-16 and Anti-HPV-18 Antibodies | One month after the second vaccine dose | 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. |
| Number of Subjects With Pregnancies and Their Outcomes | During the entire study period (up to Month 18 or Month 12) | Entire study period = up to Month 18 Cervarix-12 & Month 12 Cervarix-6 Number of pregnancies and pregnancy outcomes. |
| Number of Subjects Completing the 3-dose Vaccination Schedule | After the third vaccine dose | — |
| Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs), New Onset Autoimmune Diseases (NOADs), Serious Adverse Events (SAEs), and Medically Significant Conditions (MSCs) | During the entire study period (up to Month 18 or up to Month 12) | Entire study period = up to Month 18 Cervarix-12 & Month 12 Cervarix-6. NOCDs assessed include eg. autoimmune disorders (NOADs), asthma, type I diabetes. MSCs assessed include AEs prompting emergency room visits and physician office visits not related to common illnesses. An SAE is any untoward medical occurrence that: results in death, is lifethreatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above. |
| Titer of Anti-HPV-16 and Anti-HPV-18 Antibodies | One month after the second vaccine dose | Titer given as GMT. |
Countries
Italy, Romania, Slovakia
Participant flow
Pre-assignment details
A total of 805 subjects were enrolled and 804 subjects were vaccinated and included in the analyses.
Participants by arm
| Arm | Count |
|---|---|
| Cervarix-12 Group Women received 3 doses of Cervarix™ (human papillomavirus \[HPV\] vaccine) administered according to a 0, 1, 12-month schedule. | 403 |
| Cervarix-6 Group Women received 3 doses of Cervarix™ (HPV vaccine) administered according to a 0, 1, 6-month schedule. | 401 |
| Total | 804 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 1 | 1 |
| Overall Study | Withdrawal by Subject | 12 | 1 |
Baseline characteristics
| Characteristic | Cervarix-12 Group | Cervarix-6 Group | Total |
|---|---|---|---|
| Age, Continuous | 18.6 years STANDARD_DEVIATION 2.98 | 18.7 years STANDARD_DEVIATION 3.13 | 18.6 years STANDARD_DEVIATION 3.05 |
| Sex: Female, Male Female | 403 Participants | 401 Participants | 804 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 | 388 / 403 | 389 / 401 |
| serious Total, serious adverse events | 12 / 403 | 9 / 401 |
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 after the third vaccine dose
Population: Analysis was performed on initially seronegative subjects from the According-to-Protocol (ATP) cohort for analysis of immunogenicity
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cervarix-12 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 | 337 Participants |
| Cervarix-12 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 | 345 Participants |
| Cervarix-6 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 | 342 Participants |
| Cervarix-6 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 | 346 Participants |
Primary
Titer of Anti-HPV-16 and Anti-HPV-18 Antibodies
Titer given as geometric mean titer (GMT).
Time frame: One month after the third vaccine dose
Population: Analysis was performed on initially seronegative subjects from the ATP cohort for analysis of immunogenicity
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Cervarix-12 Group | Titer of Anti-HPV-16 and Anti-HPV-18 Antibodies | Anti-HPV-16 | 11337.2 EL.U/mL |
| Cervarix-12 Group | Titer of Anti-HPV-16 and Anti-HPV-18 Antibodies | Anti-HPV-18 | 4526.7 EL.U/mL |
| Cervarix-6 Group | Titer of Anti-HPV-16 and Anti-HPV-18 Antibodies | Anti-HPV-16 | 10050.9 EL.U/mL |
| Cervarix-6 Group | Titer of Anti-HPV-16 and Anti-HPV-18 Antibodies | Anti-HPV-18 | 3879.9 EL.U/mL |
Secondary
Number of Subjects Completing the 3-dose Vaccination Schedule
Time frame: After the third vaccine dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cervarix-12 Group | Number of Subjects Completing the 3-dose Vaccination Schedule | 388 Participants |
| Cervarix-6 Group | Number of Subjects Completing the 3-dose Vaccination Schedule | 397 Participants |
Secondary
Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs), New Onset Autoimmune Diseases (NOADs), Serious Adverse Events (SAEs), and Medically Significant Conditions (MSCs)
Entire study period = up to Month 18 Cervarix-12 & Month 12 Cervarix-6. NOCDs assessed include eg. autoimmune disorders (NOADs), asthma, type I diabetes. MSCs assessed include AEs prompting emergency room visits and physician office visits not related to common illnesses. An SAE is any untoward medical occurrence that: results in death, is lifethreatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
Time frame: During the entire study period (up to Month 18 or up to Month 12)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cervarix-12 Group | Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs), New Onset Autoimmune Diseases (NOADs), Serious Adverse Events (SAEs), and Medically Significant Conditions (MSCs) | MSCs | 42 Participants |
| Cervarix-12 Group | Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs), New Onset Autoimmune Diseases (NOADs), Serious Adverse Events (SAEs), and Medically Significant Conditions (MSCs) | NOCDs | 0 Participants |
| Cervarix-12 Group | Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs), New Onset Autoimmune Diseases (NOADs), Serious Adverse Events (SAEs), and Medically Significant Conditions (MSCs) | NOADs | 0 Participants |
| Cervarix-12 Group | Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs), New Onset Autoimmune Diseases (NOADs), Serious Adverse Events (SAEs), and Medically Significant Conditions (MSCs) | SAEs | 12 Participants |
| Cervarix-6 Group | Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs), New Onset Autoimmune Diseases (NOADs), Serious Adverse Events (SAEs), and Medically Significant Conditions (MSCs) | SAEs | 9 Participants |
| Cervarix-6 Group | Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs), New Onset Autoimmune Diseases (NOADs), Serious Adverse Events (SAEs), and Medically Significant Conditions (MSCs) | MSCs | 44 Participants |
| Cervarix-6 Group | Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs), New Onset Autoimmune Diseases (NOADs), Serious Adverse Events (SAEs), and Medically Significant Conditions (MSCs) | NOADs | 2 Participants |
| Cervarix-6 Group | Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs), New Onset Autoimmune Diseases (NOADs), Serious Adverse Events (SAEs), and Medically Significant Conditions (MSCs) | NOCDs | 5 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 subjects with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cervarix-12 Group | Number of Subjects Reporting Solicited General Symptoms | Headache | 203 Participants |
| Cervarix-12 Group | Number of Subjects Reporting Solicited General Symptoms | Arthralgia | 85 Participants |
| Cervarix-12 Group | Number of Subjects Reporting Solicited General Symptoms | Myalgia | 167 Participants |
| Cervarix-12 Group | Number of Subjects Reporting Solicited General Symptoms | Temperature ≥ 37.5°C | 37 Participants |
| Cervarix-12 Group | Number of Subjects Reporting Solicited General Symptoms | Rash | 30 Participants |
| Cervarix-12 Group | Number of Subjects Reporting Solicited General Symptoms | Fatigue | 245 Participants |
| Cervarix-12 Group | Number of Subjects Reporting Solicited General Symptoms | Urticaria | 12 Participants |
| Cervarix-12 Group | Number of Subjects Reporting Solicited General Symptoms | Gastro-intestinal symptoms | 85 Participants |
| Cervarix-6 Group | Number of Subjects Reporting Solicited General Symptoms | Urticaria | 18 Participants |
| Cervarix-6 Group | Number of Subjects Reporting Solicited General Symptoms | Arthralgia | 78 Participants |
| Cervarix-6 Group | Number of Subjects Reporting Solicited General Symptoms | Fatigue | 237 Participants |
| Cervarix-6 Group | Number of Subjects Reporting Solicited General Symptoms | Temperature ≥ 37.5°C | 29 Participants |
| Cervarix-6 Group | Number of Subjects Reporting Solicited General Symptoms | Headache | 199 Participants |
| Cervarix-6 Group | Number of Subjects Reporting Solicited General Symptoms | Myalgia | 168 Participants |
| Cervarix-6 Group | Number of Subjects Reporting Solicited General Symptoms | Rash | 34 Participants |
| Cervarix-6 Group | Number of Subjects Reporting Solicited General Symptoms | Gastro-intestinal symptoms | 86 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 subjects with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cervarix-12 Group | Number of Subjects Reporting Solicited Local Symptoms | Pain | 385 Participants |
| Cervarix-12 Group | Number of Subjects Reporting Solicited Local Symptoms | Redness | 201 Participants |
| Cervarix-12 Group | Number of Subjects Reporting Solicited Local Symptoms | Swelling | 158 Participants |
| Cervarix-6 Group | Number of Subjects Reporting Solicited Local Symptoms | Pain | 386 Participants |
| Cervarix-6 Group | Number of Subjects Reporting Solicited Local Symptoms | Redness | 182 Participants |
| Cervarix-6 Group | Number of Subjects Reporting Solicited Local Symptoms | Swelling | 145 Participants |
Secondary
Number of Subjects Reporting Unsolicited Adverse Events (AE)
An AE is 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.
Time frame: During the 30-day (Days 0-29) period following each vaccination
Population: Analysis was performed on the Total Vaccinated Cohort, on subjects with available data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cervarix-12 Group | Number of Subjects Reporting Unsolicited Adverse Events (AE) | 117 Participants |
| Cervarix-6 Group | Number of Subjects Reporting Unsolicited Adverse Events (AE) | 129 Participants |
Secondary
Number of Subjects Seroconverted for Anti-HPV-16 and 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 after the second vaccine dose
Population: Analysis was performed on initially seronegative subjects from the ATP cohort for analysis of immunogenicity
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cervarix-12 Group | Number of Subjects Seroconverted for Anti-HPV-16 and Anti-HPV-18 Antibodies | Anti-HPV-16 | 337 Participants |
| Cervarix-12 Group | Number of Subjects Seroconverted for Anti-HPV-16 and Anti-HPV-18 Antibodies | Anti-HPV-18 | 346 Participants |
| Cervarix-6 Group | Number of Subjects Seroconverted for Anti-HPV-16 and Anti-HPV-18 Antibodies | Anti-HPV-16 | 342 Participants |
| Cervarix-6 Group | Number of Subjects Seroconverted for Anti-HPV-16 and Anti-HPV-18 Antibodies | Anti-HPV-18 | 346 Participants |
Secondary
Number of Subjects With Pregnancies and Their Outcomes
Entire study period = up to Month 18 Cervarix-12 & Month 12 Cervarix-6 Number of pregnancies and pregnancy outcomes.
Time frame: During the entire study period (up to Month 18 or Month 12)
Population: Analysis was performed on the Total vaccinated cohort, on pregnant subjects
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cervarix-12 Group | Number of Subjects With Pregnancies and Their Outcomes | Normal infant | 2 Participants |
| Cervarix-12 Group | Number of Subjects With Pregnancies and Their Outcomes | Ongoing | 1 Participants |
| Cervarix-12 Group | Number of Subjects With Pregnancies and Their Outcomes | Elective abortion | 0 Participants |
| Cervarix-12 Group | Number of Subjects With Pregnancies and Their Outcomes | Foetal distress syndrome | 1 Participants |
| Cervarix-12 Group | Number of Subjects With Pregnancies and Their Outcomes | Abortion threatened | 1 Participants |
| Cervarix-6 Group | Number of Subjects With Pregnancies and Their Outcomes | Foetal distress syndrome | 0 Participants |
| Cervarix-6 Group | Number of Subjects With Pregnancies and Their Outcomes | Normal infant | 1 Participants |
| Cervarix-6 Group | Number of Subjects With Pregnancies and Their Outcomes | Abortion threatened | 0 Participants |
| Cervarix-6 Group | Number of Subjects With Pregnancies and Their Outcomes | Ongoing | 0 Participants |
| Cervarix-6 Group | Number of Subjects With Pregnancies and Their Outcomes | Elective abortion | 2 Participants |
Secondary
Titer of Anti-HPV-16 and Anti-HPV-18 Antibodies
Titer given as GMT.
Time frame: One month after the second vaccine dose
Population: Analysis was performed on initially seronegative subjects from the ATP cohort for analysis of immunogenicity
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Cervarix-12 Group | Titer of Anti-HPV-16 and Anti-HPV-18 Antibodies | Anti-HPV-16 | 3307.0 EL.U/mL |
| Cervarix-12 Group | Titer of Anti-HPV-16 and Anti-HPV-18 Antibodies | Anti-HPV-18 | 2382.3 EL.U/mL |
| Cervarix-6 Group | Titer of Anti-HPV-16 and Anti-HPV-18 Antibodies | Anti-HPV-16 | 3184.1 EL.U/mL |
| Cervarix-6 Group | Titer of Anti-HPV-16 and Anti-HPV-18 Antibodies | Anti-HPV-18 | 2256.3 EL.U/mL |