Evaluation of Immunogenicity and Safety of Two 2-dose Human Papillomavirus (HPV) Vaccine Schedules in 9-14 Year Old Girls

Study Overview
=================
Brief Summary
-----------------
This study has been designed to evaluate the immunogenicity and safety of GSK Biologicals' HPV-16/18 vaccine when administered according to alternative 2-dose schedules (0,6 months and 0,12 months) in healthy 9-14 year old females as compared to the standard 3-dose schedule (0,1,6 months) in 15-25 year old females.

Official Title
-----------------
Immunogenicity and Safety Study of GlaxoSmithKline Biologicals' HPV-16/18 L1 AS04 Vaccine When Administered According to Alternative 2-dose Schedules in 9 - 14 Year Old Females

Conditions
-----------------
Infections, Papillomavirus

Intervention / Treatment
-----------------
* Biological: GSK Biologicals' HPV vaccine 580299


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who the investigator believes can and will comply with the requirements of the protocol or/ and subjects who the investigator believes their parent(s)/Legally Acceptable Representative(s) [LAR(s)] can and will comply with the requirements of the protocol A female between, and including, 9 and 25 years of age at the time of the first vaccination Written informed consent obtained from the subject/from the parent(s)/LAR(s) of the subject prior to enrolment in the study. In addition, subjects below the legal age of consent should sign and personally date a written informed assent form Healthy subjects Female subjects of non-childbearing potential may be enrolled in the study Female subjects of childbearing potential may be enrolled in the study, if the subject: has practiced adequate contraception for 30 days prior to vaccination, and has a negative pregnancy test on the day of vaccination, and has agreed to continue adequate contraception during the entire vaccination period and up to two months after the last study vaccine dose Exclusion Criteria: Pregnant or breastfeeding A female planning to become pregnant, likely to become pregnant or planning to discontinue contraceptive precautions during the entire vaccination period and up to two months after the last study vaccine dose Previous vaccination against HPV or planned administration of another HPV vaccine during the study Child in care. A child in care is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. The definition of a child in care does not include a child who is adopted or has an appointed legal guardian. Use of any investigational or non-registered product 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. History of allergic disease, suspected allergy or reactions likely to be exacerbated by any component of the study vaccines Cancer or autoimmune disease under treatment Planned administration/administration of a vaccine/product not foreseen by the study protocol within 30 days before each dose of vaccine. Administration of routine meningococcal, hepatitis B, hepatitis A, inactivated influenza, diphtheria/tetanus and/or diphtheria/tetanus-containing vaccine up to 8 days before each dose of study vaccine is allowed. Enrolment will be deferred until the subject 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 Previous administration of MPL or AS04 adjuvant. Administration of immunoglobulins and/or any blood products within the 3 months preceding the first dose of study vaccine or planned administration during the study period Any confirmed or suspected immunosuppressive or immunodeficient condition Family history of congenital or hereditary immunodeficiency Major congenital defects or serious chronic illness Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests, which in the opinion of the investigator precludes administration of the study vaccine Acute disease and/or fever at the time of enrolment

Ages Eligible for Study
-----------------
Minimum Age: 9 Years
Maximum Age: 25 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cervarix 1 Group<br>Female subjects aged 9 to 14 years at the time of the first vaccination, who received 2 doses of the Cervarix vaccine at Day 0 and at Month 6, respectively. The vaccine was administered intramuscularly into the deltoid muscle of the non-dominant arm. | Biological: GSK Biologicals' HPV vaccine 580299<br>* Subjects received 2 or 3 doses of HPV vaccine administered intramuscularly.<br>* Other names: Cervarix;|
| Active Comparator: Cervarix 2 Group<br>Female subjects aged 15 to 25 years at the time of the first vaccination, who received 3 doses of the Cervarix vaccine at Day 0, at Month 1 and at Month 6, respectively. The vaccine was administered intramuscularly into the deltoid muscle of the non-dominant arm. | Biological: GSK Biologicals' HPV vaccine 580299<br>* Subjects received 2 or 3 doses of HPV vaccine administered intramuscularly.<br>* Other names: Cervarix;|
| Experimental: Cervarix 3 Group<br>Female subjects aged 9 to 14 years at the time of the first vaccination, who received 2 doses of the Cervarix vaccine at Day 0 and at Month 12, respectively. The vaccine was administered intramuscularly into the deltoid muscle of the non-dominant arm. | Biological: GSK Biologicals' HPV vaccine 580299<br>* Subjects received 2 or 3 doses of HPV vaccine administered intramuscularly.<br>* Other names: Cervarix;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Seroconverted Subjects for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies in Cervarix 1 Group and Cervarix 2 Group at Month 7 | Seroconversion was defined as the appearance of antibodies (anti-HPV-16 concentrations greater than or equal to (≥) 8 enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL) and anti-HPV-18 concentrations ≥ 7 EL.U/mL) in the serum of subjects seronegative before vaccination. A seronegative subject was a subject with anti-HPV-16/18 antibody concentration lower than (<) 8/7 EL.U/mL, respectively. | At Month 7 (i.e. one month after the last dose of study vaccine) | 
| Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations (by ELISA) in Cervarix 1 Group and Cervarix 2 Group at Month 7 | Antibody concentrations were assessed by ELISA and expressed as geometric mean concentrations (GMCs) in EL.U/mL. | At Month 7 (i.e. one month after the last dose of study vaccine) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Seroconverted Subjects for Anti-HPV-16 and Anti-HPV-18 Antibodies in Cervarix 1 Group and Cervarix 2 Group at Day 0 and at Months 7, 12, 18, 24 and 36 | Seroconversion was defined as the appearance of antibodies (anti-HPV-16 concentrations ≥ 8 EL.U/mL and anti-HPV-18 concentrations ≥ 7 EL.U/mL [applicable for Day 0, Month 7 and Month 12 time points] and anti-HPV-16 concentrations ≥ 19 EL.U/mL and anti-HPV-18 concentrations ≥ 18 EL.U/mL [applicable for Month 18, Month 24 and Month 36 time points]) in the serum of subjects seronegative before vaccination. A seronegative subject was a subject with an anti-HPV-16/18 antibody concentration below (<) the aforementioned cut-offs. Note: In order to increase the ELISA precision, the assay cut-off value was changed from 8 EL.U/mL to 19 EL.U/mL for HPV-16 and from 7 EL.U/mL to 18 EL.U/mL for HPV-18 from Month 18 onwards. | At Day 0 and at Months 7, 12, 18, 24 and 36 | 
| Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations (by ELISA) in Cervarix 1 Group and Cervarix 2 Group at Day 0 and at Months 7, 12, 18, 24 and 36 | Antibody concentrations were assessed by ELISA and expressed as geometric mean concentrations (GMCs) in EL.U/mL. | At Day 0 and at Months 7, 12, 18, 24 and 36 | 
| Number of Seroconverted Subjects for Anti-HPV-16 and Anti-HPV-18 Antibodies in Cervarix 3 Group | Seroconversion was defined as the appearance of antibodies (anti-HPV-16 concentrations ≥ 8 EL.U/mL and anti-HPV-18 concentrations ≥ 7 EL.U/mL [applicable for Day 0 and Month 13 time points] and anti-HPV-16 concentrations ≥ 19 EL.U/mL and anti-HPV-18 concentrations ≥ 18 EL.U/mL [applicable for Month 18, Month 24 and Month 36 time points]) in the serum of subjects seronegative before vaccination. A seronegative subject was a subject with an anti-HPV-16/18 antibody concentration below (<) the aforementioned cut-offs. Note: In order to increase the ELISA precision, the assay cut-off value was changed from 8 EL.U/mL to 19 EL.U/mL for HPV-16 and from 7 EL.U/mL to 18 EL.U/mL for HPV-18 from Month 18 onwards. | At Day 0 and at Months 13, 18, 24 and 36 | 
| Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations (by ELISA) in Cervarix 3 Group | Antibody concentrations were assessed by ELISA and expressed as geometric mean concentrations (GMCs) in EL.U/mL. | At Day 0 and at Months 13, 18, 24 and 36 | 
| Anti-HPV-16 and Anti-HPV-18 Antibody Titers [by Pseudovirion-Based Neutralisation Assay (PBNA)] in a Subset of Subjects From Cervarix 3 Group | Antibody titers were expressed as geometric mean titers (GMTs). The cut-off of the assay was 40 ED50 for both anti-HPV-16 and anti-HPV-18. The assay was performed on a subset of 100 subjects from Cervarix 3 Group. | At Day 0 and at Months 13, 18, 24 and 36 | 
| Anti-HPV-16 and Anti-HPV-18 Antibody Titers (by PBNA) in a Subset of Subjects From Cervarix 1 Group and Cervarix 2 Group | Antibody titers were expressed as GMTs. The cut-off of the assay was 40 ED50 for both anti-HPV-16 and anti-HPV-18. The assay was performed on a subset of 100 subjects per study group. | At Day 0 and at Months 7, 12, 18, 24 and 36 | 
| Cell-mediated Immunogenicity Related to Anti-HPV-16 Specific T Cell-mediated Immune Response (CMI) for Cervarix 1 Group and Cervarix 2 Group in a Sub-cohort of Subjects | The CMI response represents the measure of the cytokines production [i.e. interleukin-2 (IL-2), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α) and the cluster of differentiation 40 Ligand (CD40L)] by HPV-antigen specific T lymphocytes and measured by intracellular cytokine staining (ICS) assay for HPV-16. The frequency was presented as number of cytokine-positive cluster of differentiation (CD)4 i.e. CD4+/CD8+ cells per million CD4+/CD8+ cells. All doubles = T cell expressing at least 2 cytokines. Results were tabulated by the pre-vaccination status of the subjects, where S- = seronegative subjects (antibody concentration < cut-off value) prior to vaccination. S+ = seropositive subjects (antibody concentration ≥ cut-off value) prior to vaccination. The assay was performed on a subset of 100 subjects per study group. | At Day 0 and at Months 7, 12, 24 and 36 | 
| Cell-mediated Immunogenicity Related to Anti-HPV-18 Specific T CMI Response for Cervarix 1 Group and Cervarix 2 Group in a Sub-cohort of Subjects | The CMI response represents the measure of the cytokines production [IL-2, IFN-γ, TNF-α, and CD40L] by HPV-antigen specific T lymphocytes and measured by ICS assay for HPV-18. The frequency was presented as a number of cytokine-producing CD4+/CD8+ cells per million CD4+/CD8+ cells. All doubles = T cell expressing at least 2 cytokines. Results were tabulated by the pre-vaccination status of the subjects, where S- = seronegative subjects (antibody concentration < the cut-off value) prior to vaccination. S+ = seropositive subjects (antibody concentration ≥ cut-off value) prior to vaccination. The assay was performed on a subset of 100 subjects per study group. | At Day 0 and at Months 7, 12, 24 and 36 | 
| Cell-mediated Immunogenicity Related to Anti-HPV-16 Specific T CMI Response for Cervarix 3 Group in a Sub-cohort of Subjects | The CMI response represents the measure of the cytokines production (IL-2, IFN-γ, TNF-α, and CD40L) by HPV-antigen specific T lymphocytes and measured by ICS assay for HPV-16. The frequency was presented as a number of cytokine-positive cluster of differentiation (CD)4 i.e.CD4+/CD8+ cells per million CD4+/CD8+ cells. All doubles= T cell expressing at least 2 cytokines. Results were tabulated by the pre-vaccination status of the subjects, where S- = seronegative subjects (antibody concentration < cut-off value) prior to vaccination. S+ = seropositive subjects (antibody concentration ≥ cut-off value) prior to vaccination. The assay was performed on a subset of 100 subjects from Cervarix 3 Group. | At Day 0 and at Months 13, 18 and 36 | 
| Cell-mediated Immunogenicity Related to Anti-HPV-18 Specific T CMI Response for Cervarix 3 Group in a Sub-cohort of Subjects | The CMI response represents the measure of the cytokines production (i.e. IL-2, IFN-γ, TNF-α, and CD40L) by HPV-antigen specific T lymphocytes and measured by ICS assay for HPV-18. The frequency was presented as a number of cytokine-producing CD4+/CD8+ cells per million CD4+/CD8+ cells. All doubles = T cell expressing at least 2 cytokines. Results were tabulated by the pre-vaccination status of the subjects, where S- = seronegative subjects (antibody concentration < cut-off value) prior to vaccination. S+ = seropositive subjects (antibody concentration ≥ cut-off value) prior to vaccination. The assay was performed on a subset of 100 subjects from Cervarix 3 Group. | At Day 0 and at Months 13, 18 and 36 | 
| Cell-mediated Immunogenicity Related to Anti-HPV-16 Specific B CMI Response for Cervarix 1 Group and Cervarix 2 Group in a Sub-cohort of Subjects | The CMI response was assessed as being the frequency of B-cell memory of HPV-16 antigen-specific memory B-cells per million memory B-cells in subjects with detectable B-cells. The results are presented by pre-vaccination status, where S- = seronegative subjects (antibody concentration < cut-off value) prior to vaccination and S+ = seropositive subjects (antibody concentration ≥ cut-off value) prior to vaccination. The assay was performed on a subset of 100 subjects per study group. | At Day 0 and at Months 7, 12, 24 and 36 | 
| Cell-mediated Immunogenicity Related to Anti-HPV-18 Specific B CMI Response for Cervarix 1 Group and Cervarix 2 Group in a Sub-cohort of Subjects | The cell-mediated immune response was assessed as being the frequency of B-cell memory of HPV-18 antigen-specific memory B-cells per million memory B-cells in subjects with detectable B-cells. The results are presented by pre-vaccination status, where S- = seronegative subjects (antibody concentration < cut-off value) prior to vaccination and S+ = seropositive subjects (antibody concentration ≥ cut-off value) prior to vaccination. The assay was performed on a subset of 100 subjects per study group. | At Day 0 and at Months 7, 12, 24 and 36 | 
| Cell-mediated Immunogenicity Related to Anti-HPV-16 Specific B CMI Response for Cervarix 3 Group in a Sub-cohort of Subjects | The cell-mediated immune response was assessed as being the frequency of B-cell memory of HPV-16 antigen-specific memory B-cells per million memory B-cells in subjects with detectable B-cells. The results are presented by pre-vaccination status, where S- = seronegative subjects (antibody concentration < cut-off value) prior to vaccination and S+ = seropositive subjects (antibody concentration ≥ cut-off value) prior to vaccination. The assay was performed on a subset of 100 subjects from Cervarix 3 Group. | At Day 0 and at Months 13, 18 and 36 | 
| Cell-mediated Immunogenicity Related to Anti-HPV-18 Specific B CMI Response for Cervarix 3 Group in a Sub-cohort of Subjects | The cell-mediated immune response was assessed as being the frequency of B-cell memory of HPV-18 antigen-specific memory B-cells per million memory B-cells in subjects with detectable B-cells. The results are presented by pre-vaccination status, where S- = seronegative subjects (antibody concentration < cut-off value) prior to vaccination and S+ = seropositive subjects (antibody concentration ≥ cut off value) prior to vaccination. The assay was performed on a subset of 100 subjects from Cervarix 3 Group. | At Day 0 and at Months 13, 18 and 36 | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of any solicited local symptom regardless of their intensity grade. Grade 3 pain = significant pain at rest, that prevented normal every day activity. Grade 3 redness/swelling = redness/swelling above 50 millimeters (mm). | During the 7-day period (Days 0-6) after each vaccine dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were arthralgia, fatigue, gastrointestinal symptoms, headache, myalgia, rash, fever and urticaria. Any = occurrence of any solicited general symptom regardless of intensity grade or relationship to vaccination. Any fever = axillary temperature ≥ 37.5 degrees Celsius (°C). Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever greater than (>) 39.0 °C. Related = general symptom assessed by the investigator as causally related to the vaccination. | During the 7-day period (Days 0-6) after each vaccine dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs) | 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. Any = any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 = unsolicited AE preventing normal activity. Related = unsolicited AE assessed by the investigator as causally related to the study vaccination. | During the 30 day (Days 0-29) post-vaccination period | 
| Number of Subjects With Any Potential Immune-Mediated Diseases (pIMDs) | pIMDs are a subset of AEs that include both clearly autoimmune diseases and also other inflammatory and/or neurologic disorders which may or may not have an autoimmune etiology. | From Day 0 up to Month 13 (for Cervarix 1 Group and Cervarix 2 Group) and from Day 0 up to Month 18 (for Cervarix 3 Group) | 
| Number of Subjects With Medically Significant Conditions (MSCs) | MSCs include AEs prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury. | From Day 0 up to Month 36 (throughout the study period) | 
| Number of Subjects With Any, Related and Fatal Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity or were a congenital anomaly/birth defect in the offspring of a study subject. Any = any SAE regardless of intensity grade or relation to vaccination. Related = SAE assessed by the investigator as causally related to the study vaccination. | From Day 0 up to Month 36 (throughout the study period) | 
| Number of Subjects Reporting Pregnancies and Outcomes of Reported Pregnancies | Outcomes of reported pregnancies were: Ectopic pregnancy, Elective termination NO apparent congenital anomaly (ACA), Live Infant NO ACA, Stillbirth NO ACA. | From Day 0 up to Month 36 (throughout the study period) | 
| Number of Subjects Completing the Vaccination Course | The number of subjects completing the vaccination course was assessed as the number of subjects with at least one dose received during the study. | From Day 0 up to Month 13 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HPV infection, Human Papillomavirus, Cervical cancer, HPV-16, HPV-18, vaccine