Follow-up Study to Evaluate the Safety and Immunogenicity of a HPV Vaccine (580299) in North America

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. This study will further evaluate induction of immune memory and anamnestic responses in women who previously took part in the primary study (580299/001) and follow-up study (580299/007). Subjects were aged 15-25 yrs at the time of entry into the primary study and participation in the follow-up study lasted approximately 6 years. In the primary and follow-up studies, subjects were protected against HPV-16 and HPV-18 endpoints and had sustained antibody responses to both vaccine types over at least 5.5 years of follow-up. All subjects from North American study sites that completed the follow-up study will be invited to take part in the current study. The study will evaluate the safety and immunogenicity of a dose of GSK Biologicals HPV vaccine (580299) in women who had been immunologically primed in the primary study. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Official Title
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Safety and Immunogenicity Study of an Additional Dose of HPV Vaccine (580299) in Young, Adult Women in North America.

Conditions
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Infections, Papillomavirus

Intervention / Treatment
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* Biological: Cervarix™


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A subject whom the investigator believes that she can and will comply with the requirements of the protocol Must have received three doses of study vaccine or placebo control in study 580299/001. Must have completed study 580299/007. Written informed consent must be obtained from the subject prior to enrollment in the study. Healthy subjects, as established by medical history and history-directed clinical examination before entering into the study. Subject must have a negative urine pregnancy test. Subject must be at least three months post-termination of a pregnancy. Subject must be of non-childbearing potential,or subjects are required to be abstinent or use adequate contraceptive precautions for 30 days prior to vaccination. Subjects are also required to agree to continue such precautions for two months after completion of the vaccination series. Exclusion Criteria: Pregnant or breastfeeding. A woman planning to become pregnant or planning to discontinue contraceptive precautions during the study until approximately 2 months after the last vaccination. 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 or planned administration during the study period. Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days of each dose of vaccine. Administration of some routine vaccines up to 8 days before each dose of study vaccine is allowed. 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 outside of protocol 580299/001. Any medically diagnosed or suspected immunosuppressive or 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 Acute or chronic, clinically significant pulmonary, cardiovascular, neurologic, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests. Cancer or autoimmune disease under treatment. Administration of immunoglobulins and/or any blood products within the three months (90 days) preceding enrollment or planned administration during the study period. Acute disease at the time of enrollment. All vaccines can be administered to persons with a minor illness Heavy bleeding or heavy vaginal discharge in which a pelvic exam cannot be performed.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 25 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™ 4-Dose Group<br>Subjects who had received 3 doses of Cervarix™ in study 580299/001 (NCT00689741), received a 4th dose of Cervarix™ on Day 0 in the current study. | Biological: Cervarix™<br>* Intramuscular injection, one or three doses<br>* Other names: GSK Biologicals' HPV Vaccine GSK580299;|
| Experimental: Cervarix™ 3-Dose Group<br>Subjects who had received 3 doses of placebo in study 580299/001 (NCT00689741), received 3 doses of Cervarix™ (Day 0, Month 1 and Month 6) in the current study. | Biological: Cervarix™<br>* Intramuscular injection, one or three doses<br>* Other names: GSK Biologicals' HPV Vaccine GSK580299;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anti-human Papilloma Virus-16 (Anti-HPV-16) and Anti-HPV-18 Antibody Titers Greater Than or Equal to Pre-defined Cut-off Values | 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. | At Day 7 and Month 1 (Day 30) | 
| Anti-HPV-16 and Anti-HPV-18 Antibody Titers | Titers are given as geometric mean titers (GMTs) calculated on all subjects. | At Day 7 and at Month 1 (Day 30) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anti-HPV-16 and Anti-HPV-18 Greater Than or Equal to Pre-defined Cut-off Values | Cut-off values assessed include 8 EL.U/mL for anti-HPV-16 antibodies and 7 EL.U/mL for anti-HPV-18 antibodies. | At Month 7 and Month 18 | 
| Anti-HPV-16 and Anti-HPV-18 Antibody Titers | Titers are given as GMTs calculated on all subjects. | At Month 7 and Month 18 | 
| Number of Subjects With Antibody Titers Against Other Oncogenic HPV Types (HPV-31 & HPV-45) Greater Than or Equal to 59 EL.U/mL |  | Day 0, Month 1 (Day 30), Month 7 and Month 18 | 
| Anti-HPV-31 and Anti-HPV-45 Antibody Titers | Titers are given as geometric mean titers (GMTs) calculated on all subjects. | Day 7, Month 1 (Day 30), Month 7 and Month 18 | 
| Number of Subjects With Cluster of Differentiation 4 (CD4) T Cell-mediated Immune Responses Specific to Defined Oncogenic HPV Types | CD4 T cell-mediated immune responses against the antigens HPV-16, HPV-18, HPV-31 and HPV-45 were analyzed for cells expressing at least 2 of the following immune markers: CD40 Ligand, Interleukin-2, Tumor Necrosis Factor alpha or Interferon-gamma. An immune response is defined as 500 or more antigen-specific CD4 T-cells per million CD4 T-cells. | Day 0, Month 1 [Day 30], Month 7 and Month 18 | 
| Number of Subjects With Cluster of Differentiation 8 (CD8) T Cell-mediated Immune Responses Specific to Defined Oncogenic HPV Types | CD8 T cell-mediated immune responses against the antigens HPV-16, HPV-18, HPV-31 and HPV-45 were analyzed for cells expressing at least 2 of the following immune markers: CD40 Ligand, Interleukin-2, Tumor Necrosis Factor alpha or Interferon-gamma. An immune response is defined as 200 or more antigen-specific CD8 T-cells per million CD8 T-cells. | Day 0, Month 1 [Day 30], Month 7 and Month 18 | 
| Number of Subjects With B Cell-mediated Immune Responses Specific to Defined Oncogenic HPV Types | B-cell-mediated immune responses against the antigens HPV-16, HPV-18, HPV-31 and HPV-45 were measured by Enzyme-linked immunosorbent spot (ELISPOT) assay. A memory B-cell immune response was defined as presence of any antigen-specific memory B-cells per million B-cells. | Day 0, Month 1 [Day 30], Month 7 and Month 18 | 
| Number of Subjects Seropositive for Anti-HPV-16 and Anti-HPV-18 Antibodies in Cervico-vaginal Secretion Samples | Seropositivity was defined as the detection of antibody titers above the limit of quantification by Enzyme-Linked Immunosorbant Assay. Defining a cut-off is technically not possible for this assay. Analyses were done in all collected samples from the evaluable subjects who provided cervical samples, with < 200 erythrocytes per microliter. | Day 0, Month 1 (Day 30), Month 7 and Month 18 | 
| Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies in Cervico-vaginal Secretion Samples | Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL). Analyses were done in all collected samples from the evaluable subjects who provided cervical samples with < 200 erythrocytes per microliter. | Day 0, Month 1 (Day 30), Month 7 and Month 18 | 
| Number of Subjects Reporting Solicited Local Symptoms | Solicited local symptoms assessed include pain, redness and swelling at the injection site. Solicited symptoms reported after the 4th vaccine dose in the 4-dose Group and across the 3 doses administered during this study in the 3-dose Group are disclosed. | Within 7 days after vaccination | 
| Number of Subjects Reporting Solicited General Symptoms | Solicited general symptoms assessed include arthralgia, fatigue, fever, gastrointestinal discomfort, headache, myalgia, rash and urticaria. Solicited symptoms reported after the 4th vaccine dose in the 4-dose Group and across the 3 doses administered during this study in the 3-dose Group are disclosed. | Within 7 days of vaccination | 
| Number of Subjects Reporting Unsolicited Adverse Events (AE) | An unsolicited adverse event is defined as 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. AEs reported after the 4th vaccine dose in the 4-dose Group and after the 3 doses administered in this study in the 3-dose Group are disclosed. | Within 30 days of vaccination | 
| Outcome of Any Reported Pregnancies | Information on any subject who became pregnant while participating in this study was collected. The outcomes of the pregnancies are reported below. | From Day 0 up to Month 18 | 
| Number of Subjects With New Onset of Chronic Diseases (NOCDs), New Onset of Autoimmune Diseases (NOADs) and Medically Significant Conditions (MSCs) | NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. MSC 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 18 | 
| Number of Subjects Reporting Serious Adverse Events (SAEs) | 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. | From Day 0 up to Month 18 | 

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