Evaluation of Safety and Immunogenicity of Co-administering Human Papillomavirus (HPV) Vaccine With Other Vaccines in Healthy Female Subjects

Study Overview
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Brief Summary
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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/adolescents platform. Therefore, this Phase IIIb study is designed to evaluate the safety and immunogenicity of co-administering Boostrix polio (dTpa-IPV) with GSK Biologicals' (580299)HPV-16/18 L1 AS04 vaccine (Cervarix TM) as compared to the administration of either vaccine alone. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Official Title
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A Multicentre Study to Evaluate the Immunogenicity and Safety of GSK Biologicals' HPV Vaccine (580299) Co-administered With Boostrix Polio (dTpa-IPV) in Healthy Female Subjects Aged 10-18 Years

Conditions
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Infections, Papillomavirus

Intervention / Treatment
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* Biological: Boostrix ® Polio
* Biological: GSK Biologicals' HPV-16/18 L1 AS04 vaccine (Cervarix TM)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that they and their parents/legally acceptable representatives can, and will, comply with the requirements of the protocol should be enrolled in the study. A female between, and including, 10 and 18 years of age at the time of the first vaccination. Written informed consent/assent obtained from the subject prior to enrolment. For subjects above the legal age of consent, written informed consent must be obtained from the subject. For subjects below legal age of consent, written informed consent obtained from the subject's parent/LAR, and written informed assent must be obtained from the subject. Healthy subjects, as established by medical history and history-directed physical examination, before entering into the study. Previously completed routine childhood vaccinations according to the recommended vaccination schedule at the time. Subjects must have a negative urine pregnancy test. Subject must be of non-childbearing potential, or if she is of childbearing potential, she must practice adequate contraception for 30 days prior to vaccination, have a negative pregnancy test and must agree to continue such precautions for two months after completion of the vaccination series. Subjects who reach menarche during the study, and therefore become of childbearing potential, must agree to follow the same precautions. Exclusion Criteria: Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period (up to Month 12/13). 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). 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 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. A woman 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 Administration of a diphtheria, tetanus, pertussis (DTP) vaccine, diphtheria-tetanus (Td) booster or dTpa vaccine within the previous five years. Administration of a pre-school booster of Oral Polio Vaccine (OPV) or Inactivated Polio Virus (IPV) vaccine (4 or 5th dose) within the previous five years. Hypersensitivity to latex. Known acute or chronic, clinically significant neurologic, hepatic or renal functional abnormality or thrombocytopenia, 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. History of encephalopathy within seven days of administration of a previous dose of pertussis vaccine that is not attributable to another identifiable cause. Temperature of >=40°C within 48 hours of receipt of a prior dose of DTP vaccine (DTPw and/or DTPa), not due to another identifiable cause. Collapse or shock-like state within 48 hours of receipt of a prior dose of DTP vaccine (DTPw and/or DTPa). Seizures with or without fever within three days of a prior dose of DTP vaccine (Diphtheria, Tetanus, whole cell Pertussis vaccine DTPw and/or Diphtheria, Tetanus, acellular Pertussis vaccine DTPa). Persistent, inconsolable crying lasting >=3 hours, occurring within 48 hours of a prior dose of DTP vaccine (DTPw and/or DTPa). Severe Arthus-type hypersensitivity reactions following a prior dose of tetanus toxoid within the previous 10 years. Known exposure to diphtheria or household exposure to pertussis within 30 days before (i.e., Day 0-29) vaccination with Diphtheria, Tetanus, acellular Pertussis and inactivated polio virus vaccine (dTpa-IPV). Diphtheria and/or tetanus and/or pertussis and/or polio diagnosed within 30 days before (i.e., Day 0-29) vaccination with dTpa-IPV. Presence of a contra-indication to vaccination according to the product leaflet of the commercially available dTpa-IPV vaccine. 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 3 months preceding the first dose of study vaccine or planned administration during the study period. Enrolment will be postponed until the subject is outside the specified window.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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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 Group<br>Subjects who received GSK Biologicals' HPV-16/18 L1 AS04 vaccine (Cervarix TM) at Month 0, 1 and 6. | Biological: GSK Biologicals' HPV-16/18 L1 AS04 vaccine (Cervarix TM)<br>* Three doses of vaccine administered intramuscularly, with the second and third dose give one month and six months after the first dose respectively<br>* Other names: HPV-16/18 L1 AS04 vaccine;|
| Experimental: Boostrix Polio → Cervarix Group<br>Subjects who received Boostrix™ Polio at Month 0 and GSK Biologicals' HPV-16/18 L1 AS04 vaccine (Cervarix TM) at Month 1, 2 and 7. | Biological: Boostrix ® Polio<br>* One dose of vaccine administered intramuscularly<br>* Other names: dTPa-IPV vaccine;Biological: GSK Biologicals' HPV-16/18 L1 AS04 vaccine (Cervarix TM)<br>* Three doses of vaccine administered intramuscularly, with the second and third dose give one month and six months after the first dose respectively<br>* Other names: HPV-16/18 L1 AS04 vaccine;|
| Experimental: Cervarix + Boostrix Polio Group<br>Subjects who received GSK Biologicals' HPV-16/18 L1 AS04 vaccine (Cervarix TM) at Month 0, 1 and 6 with co-administration of Boostrix™ Polio at Month 0. | Biological: Boostrix ® Polio<br>* One dose of vaccine administered intramuscularly<br>* Other names: dTPa-IPV vaccine;Biological: GSK Biologicals' HPV-16/18 L1 AS04 vaccine (Cervarix TM)<br>* Three doses of vaccine administered intramuscularly, with the second and third dose give one month and six months after the first dose respectively<br>* Other names: HPV-16/18 L1 AS04 vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Seroprotected Against Diphtheria and Tetanus | Seroprotection against diphtheria and tetanus is defined as anti-diphtheria and anti-tetanus antibody titres greater than or equal to 0.1 International Units per Milliliter (≥ 0.1 IU/mL). | One month after vaccination with Boostrix Polio | 
| Titers of Anti-pertussis Toxoid (Anti-PT), Anti-pertactin Toxoid (Anti-PRN) and Anti-filamentous Hemagglutinin (Anti-FHA) Antibodies | Titers are given as geometric mean titers (GMTs) calculated on all subjects and expressed as Enzyme-linked Immunosorbent Assay Units per Milliliter (EL.U/mL). | One month after vaccination with Boostrix Polio | 
| Number of Subjects Seroprotected Against Poliovirus Type 1 (Polio 1), Polio 2 and Polio 3 | Seroprotection against polio 1, 2 and 3 is defined as anti-polio 1, 2 and 3 antibody titers greater than or equal to 8 Effective Dose 50% (≥ 8 ED50). | One month after vaccination with Boostrix Polio | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-HPV-18 Antibodies After Completing the Cervarix Vaccination Course | 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 post Cervarix Dose 3 (Month 7/8) | 
| Number of Subjects Seroconverted for Anti-HPV-16 and Anti-HPV-18 Antibodies After Incomplete Cervarix Vaccination Course | 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 post Dose 1 | 
| Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies After Completing the Cervarix Vaccination Course | Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL). | One month post Cervarix Dose 3 (Month 7/8)] | 
| Titers of Anti-diphtheria and Anti-tetanus Antibodies | Titers are given as Geometric Mean Titers (GMTs) and expressed as IU/mL. | One month after vaccination with Boostrix-Polio | 
| Number of Subjects With Anti-diphtheria and Anti-tetanus Antibody Titers Above 1.0 International Units Per Milliliter (IU/mL) | Anti-diphtheria and anti-tetanus antibodies cut-off value assessed include 1.0 IU/mL. | One month after vaccination with Boostrix Polio | 
| Anti-poliovirus Type 1 (Anti-polio 1), Anti-polio 2 and Anti-polio 3 Antibody Titers | Titers are given as Geometric Mean Titers (GMTs). The titer is a serum dilution giving 50 percent reduction of signal compared to control without serum. | One month after vaccination with Boostrix Polio | 
| Number of Subjects With Booster Response to Diphtheria and Tetanus | Booster responses to diphtheria and tetanus were defined as: For initially seronegative subjects (pre-vaccination titer below cut-off value of 0.1 International Units per Milliliter): antibody titers at least four times the cut-off (post-vaccination titer greater than or equal to 0.4 IU/mL), and For initially seropositive subjects (pre-vaccination titer greater than or equal to 0.1 IU/mL): an increase in antibody titers of at least four times the pre-vaccination titer. | One month after vaccination with Boostrix Polio | 
| Number of Subjects With Booster Response to Pertussis Toxoid (PT), Pertactin Toxoid (PRN) and Filamentous Hemagglutinin (FHA) | Booster response to PT, FHA and PRN were defined as: For initially seronegative subjects [pre-vaccination titer below cut-off value of 5 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL)]: antibody titers at least 4 times the cut-off, For initially seropositive subjects with pre-vaccination titer above 5 EL.U/mL and < 20 EL.U/mL: an increase in antibody titers of at least 4 times the pre-vaccination titer, For initially seropositive subjects with pre-vaccination titer above 20 EL.U/mL: an increase in antibody titers of at least 2 times the pre-vaccination titer. | One month after vaccination with Boostrix Polio | 
| Number of Subjects Reporting Solicited Symptoms | Solicited local symptoms assessed include pain, redness and swelling at the injection site. Solicited general symptoms assessed include arthralgia, fatigue, fever (above 37.5 degree Celsius), gastrointestinal symptoms, headache, myalgia, rash and urticaria. | During the 7-day period (Day 0-6) following each vaccination | 
| Number of Subjects Reporting Unsolicited Adverse Events | 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. | During the 30-day period (Day 0-29) following vaccination | 
| Number of Subjects Reporting Unsolicited Adverse Events as New Onset Chronic Diseases (NOCDs) and Other Medically Significant Adverse Events (MSAEs) | NOCDs assessed include e.g. autoimmune disorders, asthma, type I diabetes. MSAEs 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. | During the active phase of the study (up to Month 7/8) and during the safety follow-up (up to Month 12/13) | 
| Number of Subjects Reporting Serious Adverse Events (SAEs) | Serious adverse events assessed include medical occurrences that results 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. | During the active phase of the study (up to Month 7/8) and during the safety follow-up (up to Month 12/13) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Papillomavirus