Infections, Papillomavirus
Conditions
Keywords
Double-blind, Human Papillomavirus, Phase IIIb, Controlled, Randomized, India
Brief summary
Human papillomavirus infection has clearly been recognized as the cause of cervical cancer. Indeed, the infection of the cervix by certain oncogenic types of HPV, if not cleared , can lead over time to cervical cancer in women . This study will evaluate the immune response induced by the HPV-16/18 L1/AS04 vaccine and the safety of the vaccine. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.
Interventions
BIOLOGICALPlacebo
Three doses of vaccine administered intramuscularly according to a 0, 1, 6-month schedule.
BIOLOGICALHPV-16/18 VLP/AS04 Vaccine (Cervarix TM)
Three doses of vaccine 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
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
All subjects must satisfy the following criteria at study entry: * Subjects who the investigator believes that they can and will comply with the requirements of the protocol should be enrolled in the study. * A female between, and including, 18 and 35 years of age at the time of the first vaccination. * Written informed consent obtained from 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
The following criteria should be checked at the time of study entry. If any apply, the subject must not be included in the study: * Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine/ control within 30 days preceding the first dose of study vaccine/ control, or planned use during the study period. * Pregnant or breastfeeding. * Planning to become pregnant or likely to become pregnant. * 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 (Days 1 to 30) before and 30 days (Day 0- Day 29) after the first dose of vaccine. Administration of routine meningococcal, hepatitis B, inactivated influenza, diphtheria/tetanus and/or diphtheria/tetanus-containing vaccine up to 8 days before the first dose of study vaccine is allowed. * Previous administration of components of the investigational vaccine. * Previous vaccination against HPV. * 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 neurologic, hepatic or renal functional pulmonary, cardiovascular 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 vaccine/ control or planned administration during the study period. Enrolment will be deferred until condition is resolved. * Acute disease at the time of enrolment. Acute disease is defined as the presence of a moderate or severe illness with or without fever.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | At Month 7 | Seroconversion is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subjects seronegative before vaccination. Cut-off values assessed include 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 |
|---|---|---|
| Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | At Months 0 and 7 | Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL). |
| Number of Subjects Reporting Solicited Symptoms | During the 7 days (Days 0 - 6) after each vaccination | Solicited local symptoms assessed include pain, redness and swelling. Solicited general symptoms assessed include arthralgia, fatigue, fever, gastro-intestinal symptoms, headache, myalgia, rash and urticaria. |
| Number of Subjects Reporting Unsolicited Adverse Events (AEs) | Within 30 days (Days 0 - 29) after 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. |
| Number of Subjects Reporting Unsolicited Adverse Events as New Onset Chronic Diseases (NOCDs) and Other Medically Significant Adverse Events (AEs) | Throughout the study period (up to Month 7) | NOCDs assessed include e.g. autoimmune disorders, asthma, type I diabetes. Medically significant AEs assessed include AEs prompting emergency room or physician visits that are not related to common diseases or SAEs that are not related to common diseases. |
| Number of Subjects Reporting Serious Adverse Events | Throughout the study period (up to Month 7) | Serious adverse events assessed include medical occurrences that results 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. |
Countries
India
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cervarix Subjects who received 3 doses of HPV-16/18 VLP/AS04 Vaccine (Cervarix TM) (at 0, 1, 6 months). | 176 |
| Placebo Subjects who received 3 doses of Placebo (at 0, 1, 6 months). | 178 |
| Total | 354 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 4 | 6 |
| Overall Study | Physician Decision | 4 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 2 |
Baseline characteristics
| Characteristic | Cervarix | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 28.5 Years STANDARD_DEVIATION 4.7 | 28.5 Years STANDARD_DEVIATION 4.97 | 28.5 Years STANDARD_DEVIATION 4.83 |
| Sex: Female, Male Female | 176 Participants | 178 Participants | 354 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 | 153 / 176 | 132 / 178 |
| serious Total, serious adverse events | 2 / 176 | 4 / 178 |
Outcome results
Primary
Number of Subjects Who 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 antibodies with titers greater than or equal to the predefined cut-off value in the serum of subjects seronegative before vaccination. Cut-off values assessed include 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: At Month 7
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 | Number of Subjects Who Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-16 | 124 Participants |
| Cervarix | Number of Subjects Who Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-18 | 117 Participants |
| Placebo | Number of Subjects Who Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-16 | 16 Participants |
| Placebo | Number of Subjects Who Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-18 | 4 Participants |
Secondary
Number of Subjects Reporting Serious Adverse Events
Serious adverse events assessed include medical occurrences that results 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: Throughout the study period (up to Month 7)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cervarix | Number of Subjects Reporting Serious Adverse Events | 2 Participants |
| Placebo | Number of Subjects Reporting Serious Adverse Events | 4 Participants |
Secondary
Number of Subjects Reporting Solicited Symptoms
Solicited local symptoms assessed include pain, redness and swelling. Solicited general symptoms assessed include arthralgia, fatigue, fever, gastro-intestinal symptoms, headache, myalgia, rash and urticaria.
Time frame: During the 7 days (Days 0 - 6) after each vaccination
Population: Analysis was performed on the Total Vaccinated Cohort, on subjects with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cervarix | Number of Subjects Reporting Solicited Symptoms | Arthralgia | 19 Participants |
| Cervarix | Number of Subjects Reporting Solicited Symptoms | Gastro-intestinal symptoms | 25 Participants |
| Cervarix | Number of Subjects Reporting Solicited Symptoms | Swelling | 69 Participants |
| Cervarix | Number of Subjects Reporting Solicited Symptoms | Headache | 72 Participants |
| Cervarix | Number of Subjects Reporting Solicited Symptoms | Fatigue | 84 Participants |
| Cervarix | Number of Subjects Reporting Solicited Symptoms | Myalgia | 10 Participants |
| Cervarix | Number of Subjects Reporting Solicited Symptoms | Redness | 56 Participants |
| Cervarix | Number of Subjects Reporting Solicited Symptoms | Rash | 5 Participants |
| Cervarix | Number of Subjects Reporting Solicited Symptoms | Fever (above 37.5 degree Celsius) | 51 Participants |
| Cervarix | Number of Subjects Reporting Solicited Symptoms | Urticaria | 4 Participants |
| Cervarix | Number of Subjects Reporting Solicited Symptoms | Pain | 137 Participants |
| Placebo | Number of Subjects Reporting Solicited Symptoms | Urticaria | 6 Participants |
| Placebo | Number of Subjects Reporting Solicited Symptoms | Pain | 105 Participants |
| Placebo | Number of Subjects Reporting Solicited Symptoms | Redness | 24 Participants |
| Placebo | Number of Subjects Reporting Solicited Symptoms | Swelling | 35 Participants |
| Placebo | Number of Subjects Reporting Solicited Symptoms | Arthralgia | 16 Participants |
| Placebo | Number of Subjects Reporting Solicited Symptoms | Fatigue | 83 Participants |
| Placebo | Number of Subjects Reporting Solicited Symptoms | Fever (above 37.5 degree Celsius) | 48 Participants |
| Placebo | Number of Subjects Reporting Solicited Symptoms | Gastro-intestinal symptoms | 28 Participants |
| Placebo | Number of Subjects Reporting Solicited Symptoms | Headache | 71 Participants |
| Placebo | Number of Subjects Reporting Solicited Symptoms | Myalgia | 11 Participants |
| Placebo | Number of Subjects Reporting Solicited Symptoms | Rash | 8 Participants |
Secondary
Number of Subjects Reporting Unsolicited Adverse Events (AEs)
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: Within 30 days (Days 0 - 29) after each vaccination
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cervarix | Number of Subjects Reporting Unsolicited Adverse Events (AEs) | 20 Participants |
| Placebo | Number of Subjects Reporting Unsolicited Adverse Events (AEs) | 26 Participants |
Secondary
Number of Subjects Reporting Unsolicited Adverse Events as New Onset Chronic Diseases (NOCDs) and Other Medically Significant Adverse Events (AEs)
NOCDs assessed include e.g. autoimmune disorders, asthma, type I diabetes. Medically significant AEs assessed include AEs prompting emergency room or physician visits that are not related to common diseases or SAEs that are not related to common diseases.
Time frame: Throughout the study period (up to Month 7)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cervarix | Number of Subjects Reporting Unsolicited Adverse Events as New Onset Chronic Diseases (NOCDs) and Other Medically Significant Adverse Events (AEs) | NOCDs | 0 Participants |
| Cervarix | Number of Subjects Reporting Unsolicited Adverse Events as New Onset Chronic Diseases (NOCDs) and Other Medically Significant Adverse Events (AEs) | Medically Significant AEs | 13 Participants |
| Placebo | Number of Subjects Reporting Unsolicited Adverse Events as New Onset Chronic Diseases (NOCDs) and Other Medically Significant Adverse Events (AEs) | NOCDs | 2 Participants |
| Placebo | Number of Subjects Reporting Unsolicited Adverse Events as New Onset Chronic Diseases (NOCDs) and Other Medically Significant Adverse Events (AEs) | Medically Significant AEs | 24 Participants |
Secondary
Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies
Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL).
Time frame: At Months 0 and 7
Population: Analysis was performed on the According-to-Protocol (ATP) cohort for analysis of immunogenicity.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Cervarix | Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-16 (Month 0) | 5.4 EL.U/mL |
| Cervarix | Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-16 (Month 7) | 9813.8 EL.U/mL |
| Cervarix | Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-18 (Month 0) | 4.7 EL.U/mL |
| Cervarix | Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-18 (Month 7) | 4030.1 EL.U/mL |
| Placebo | Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-18 (Month 7) | 4.9 EL.U/mL |
| Placebo | Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-16 (Month 0) | 4.9 EL.U/mL |
| Placebo | Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-18 (Month 0) | 4.6 EL.U/mL |
| Placebo | Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies | Anti-HPV-16 (Month 7) | 6.0 EL.U/mL |