Evaluation of Safety and Immunogenicity of Co-administering Human Papillomavirus Vaccine With Another Vaccine in Healthy Female Subjects

Study Overview
=================
Brief Summary
-----------------
Infection with human papillomavirus (HPV) has been clearly established as the central cause of cervical cancer. Vaccination of pre-teens and adolescents, ideally before sexual debut and thus before exposure to oncogenic HPV, is a rational strategy for prevention of cervical cancer, and so HPV vaccination could complement the existing pre-adolescent/adolescent vaccination programs. Therefore, this Phase IIIb study is designed to evaluate the safety and immunogenicity of co-administering a commercially available vaccine with GSK Biologicals' HPV-16/18 L1 AS04 (Cervarix ®) vaccine as compared to the administration of either vaccine alone. This Protocol Posting has been updated in order to comply with the FDA AA, Sept 2007.

Official Title
-----------------
Immunogenicity and Safety Study of GSK Biologicals' HPV Vaccine (GSK-580299) Co-administered With a Commercially Available Vaccine in Healthy Female Adolescents

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

Intervention / Treatment
-----------------
* Biological: Cervarix™
* Biological: Twinrix ™ Paediatric


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who the investigator believes that they and/or their legally acceptable representatives (LARs) can and will comply with the requirements of the protocol should be enrolled in the study. A female between, and including, 9 and 15 years of age (has not attained her 16th birthday) 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 LAR, and written informed assent must be obtained from the subject. Healthy subjects as established by medical history and clinical examination before entering into the study. Subjects must not be pregnant. Subjects must be of non-childbearing potential, or if the subject is of childbearing potential, she must be abstinent or use adequate contraception 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 vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period (up to Month 12). Concurrently participating in another clinical study, at any time during the study period (up to the Month 12 telephone contact), in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device). 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 each dose of vaccine(s). Administration of routine vaccines may be allowed up to 8 days before the first dose A subject planning to become pregnant, likely to become pregnant or planning to discontinue contraceptive precautions during the study period and up to two months after the last vaccine dose. Pregnant or breastfeeding women. 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. Previous vaccination against hepatitis A or B planned administration of any hepatitis A or B vaccine other than that foreseen by the study protocol during the study period. History of hepatitis A or B infection. Known exposure to hepatitis A or B within the previous 6 weeks. Known acute or chronic, clinically significant neurologic, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests. Cancer or autoimmune disease under treatment. History of allergic disease or reactions likely to be exacerbated by any component of the vaccines Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination Acute disease at the time of enrolment. Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period.

Ages Eligible for Study
-----------------
Minimum Age: 9 Years
Maximum Age: 15 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™ & Twinrix™ Group<br>Subjects received 3 doses of Human Papilloma Virus (HPV) vaccine co-administered with combined Hepatitis A & Hepatitis B (HAB) vaccine (Months 0, 1 & 6). | Biological: Cervarix™<br>* Three doses of vaccine administered intramuscularly with the second and third dose given one month and six months after the first dose<br>* Other names: GSK Biologicals' HPV-16/18 L1 AS04;Biological: Twinrix ™ Paediatric<br>* Three doses of vaccine administered intramuscularly with the second and third dose given one month and six months after the first dose<br>|
| Experimental: Cervarix™ Group<br>Subjects received 3 doses of HPV vaccine (Months 0, 1 & 6). | Biological: Cervarix™<br>* Three doses of vaccine administered intramuscularly with the second and third dose given one month and six months after the first dose<br>* Other names: GSK Biologicals' HPV-16/18 L1 AS04;|
| Active Comparator: Twinrix™ Group<br>Subjects received 3 doses of HAB vaccine (Months 0, 1 & 6). | Biological: Twinrix ™ Paediatric<br>* Three doses of vaccine administered intramuscularly with the second and third dose given one month and six months after the first dose<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Seroconverted for Anti-hepatitis A (Anti-HAV) Antibodies | Seroconversion is defined as the appearance of anti-HAV antibodies [i.e., antibody titer greater than or equal to 15 milli-international units/milliliter (mIU/mL)] in the sera of subjects seronegative (antibody titer below 15 mIU/mL) before vaccination. | At Month 7 | 
| Anti-Heptatis A (HAV) Antibody Titers. | Titers are given as Geometric Mean Titers (GMTs) expressed as mIU/mL. | At Month 7 | 
| Number of Subjects Seroprotected for Anti-hepatitis B Surface Antigen (Anti-HBs) Antibodies | A subject seroprotected against HBs is a subject with antibody titers greater than or equal to 10 mIU/mL. | At Month 7 | 
| 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 antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off values = 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. | At Month 7 | 
| Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibody Titers | Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL). | At Month 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-HBs Antibody Titers | Titers are given as Geometric Mean Titers (GMTs)expressed as mIU/mL. | At Month 7 | 
| Number of Subjects Seroconverted for Anti-HBs Antibodies | Seroconversion is defined as the appearance of anti-HBs antibodies (i.e., antibody titer greater than or equal to 3.3 mIU/mL) in the sera of subjects seronegative (with antibody titers below 3.3 mIU/mL) before vaccination. | At month 7 | 
| Number of Subjects Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies in Vaccine Recipients Aged 9 Years | Seroconversion is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off values = 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. | At Month 7 | 
| Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibody Titers in Vaccine Recipients Aged 9 Years | Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL). | At Month 7 | 
| Number of Subjects Seroconverted for Anti-HAV Antibodies | Seroconversion is defined as the appearance of anti-HAV antibodies (i.e., antibody titer greater than or equal to 15 mIU/mL) in the sera of subjects seronegative (antibody titer below 15 mIU/mL) before vaccination. | One month after the second dose of vaccine | 
| Anti-HAV Antibody Titers | Titers are given as geometric mean titers (GMTs) expressed as mIU/mL. | One month after the second dose of vaccine | 
| Number of Subjects Seroconverted and Number of Subjects Seroprotected for Anti-HBs Antibodies | Seroconversion is defined as the appearance of anti-HBs antibodies (i.e., antibody titer greater than or equal to 3.3 mIU/mL) in the sera of subjects seronegative (with antibody titers below 3.3 mIU/mL) before vaccination. A seroprotected subject against HBs is a subject with antibody titers greater than or equal to 10 mIU/mL. | One month after the second dose of vaccine | 
| Anti-HBs Antibody Titers | Titers are given as geometric mean titers (GMTs) expressed as mIU/mL. | One month after the second dose of vaccine | 
| 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 antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject 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. | One month after the second dose of vaccine | 
| Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibody Titers | Titers are given as Geometric Mean Titers (GMTs) expressed as EL.U/mL. | One month after the second dose of vaccine | 
| Number of Subjects Reporting Solicited Local Symptoms | Solicited local symptoms assessed include injection site pain, redness and swelling. Data are presented across doses. | During the 7-day period (Day 0-6) following vaccination | 
| Number of Subjects Reporting Solicited General Symptoms | Solicited general symptoms assessed include arthralgia, fatigue, gastrointestinal symptoms, headache, myalgia, rash, temperature [axillary route, greater than or equal to 37.5 degree Celsius (°C)] and urticaria. | During the 7-day period following vaccination | 
| Number of Subjects Reporting Medically Significant Conditions | Medically significant conditions include adverse events (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. | Throughout the active phase of the study (up to Month 7) | 
| Number of Subjects Reporting Medically Significant Conditions | Medically significant conditions include adverse events (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. | Throughout the safety follow-up (from Month 7 up to Month 12) | 
| Number of Subjects Reporting Unsolicited Adverse Events | Unsolicited adverse events include any adverse event 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. | During the 30-day period following any vaccination | 
| Number of Subjects Reporting Serious Adverse Events (SAE) | SAEs assessed include medical occurrences that result in death, are 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. | Throughout the study (up to Month 12) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Human papillomavirus infection,, cervical cancer, HPV vaccine,