Human Papillomavirus (HPV) Vaccine (Cervarix TM) Efficacy, Immunogenicity & Safety Trial in Adult Japanese Women With GSK Biologicals HPV-16/18 Vaccine

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. Indeed, certain oncogenic types of HPV can infect the cervix (part of the uterus or womb). This infection may go away by itself, but if it does not go away (this is called persistent infection), it can lead in women over a long period of time to cancer of the cervix. This study will evaluate the efficacy in prevention of persistent HPV-16 or HPV-18 cervical infection lasting at least 6 months, the immunogenicity and safety of GSK Biologicals HPV-16/18 vaccine (Cervarix TM ) over 24 months in Japanese adult women aged 20 - 25 years of age at study start. Approximately 1000 study subjects will either receive the HPV vaccine or a control vaccine (Hepatitis A vaccine) administered intramuscularly according to a 0-1-6 month schedule. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Detailed Description
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The Protocol Posting has been updated to reflect changes as a consequence of an amendment to the protocol. Sections impacted are Official Title of the study and Intervention name.

Official Title
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A Phase II Study to Assess the Efficacy, Immunogenicity and Safety of GSK Biologicals' HPV-16/18 L1 VLP AS04 (Cervarix TM) Vaccine Administered Intramuscularly According to a 0, 1, 6 Month Schedule in Healthy Japanese Female Subjects Aged 20 - 25 Years.

Conditions
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Infections, Papillomavirus

Intervention / Treatment
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* Biological: HPV-16/18 vaccine (Cervarix™)
* Biological: Aimmugen™


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Subjects who the investigator/co-investigator believes that they can and will comply with the requirements of the protocol should be enrolled in the study. A Japanese female subject between, and including, 20 and 25 years of age at the time of the first vaccination. Written informed consent obtained from the subject prior to enrolment. Healthy subjects as established by medical history and history-oriented clinical examination before entering into the study. Subjects must have a negative urine pregnancy test. Subjects must be of non-childbearing potential, she must be abstinent or have used adequate contraceptive precautions 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. Subject must have an intact cervix Exclusion criteria: 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 women. Women must be at least 3 months post-pregnancy and not breastfeeding to enter the study. A women planning to become pregnant, likely to become pregnant or planning to discontinue contraceptive precautions during the study period, up to 2 months after the last vaccine dose previous administration of components of the investigational vaccine 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 the first dose of vaccine. Routine vaccines may be allowed up to 8 days before the first dose of study vaccine. Previous vaccination against HPV. History of vaccination against hepatitis A or a known clinical history of hepatitis A disease Administration of immunoglobulin and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period. Any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination History of allergic disease or reactions likely to be exacerbated by any component of the study vaccines Hypersensitivity to latex Known acute or chronic, clinically significant pulmonary, cardiovascular, neurologic, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests. Cancer or autoimmune disease under treatment. History of having had colposcopy or has planned a colposcopy to evaluate an abnormal cervical cytology (Pap smear) test. Heavy bleeding or heavy vaginal discharge such that a pelvic examination can not be performed Acute disease at the time of enrolment. Oral temperature >= 37.5°C / axillary temperature > 37.5°C. 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).

Ages Eligible for Study
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Minimum Age: 20 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cervarix Group<br>Subjects received 3 doses of GSK Biologicals HPV-16/18 vaccine (Cervarix™) according to a 0, 1, 6-month schedule. | Biological: HPV-16/18 vaccine (Cervarix™)<br>* Intramuscular injection, 3 doses<br>|
| Active Comparator: Aimmugen Group<br>Subjects received 3 doses of Aimmugen™ (Hepatitis A [HAV] vaccine) according to a 0, 1, 6-month schedule. | Biological: Aimmugen™<br>* Intramuscular injection, 3 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Persistent Cervical Infection With Human Papillomavirus 16 (HPV-16) or Human Papillomavirus 18 (HPV-18) | Persistent HPV-16 or HPV-18 infection is defined as at least 2 positive Human Papillomavirus (HPV) deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) assays for the same viral genotype with no negative DNA sample between the 2 positive DNA samples, over an approximate interval of 6 months (> 150 days) [as assessed in women who were, for the corresponding HPV type, seronegative at Month 0 and HPV DNA negative (by PCR) at Month 0 and Month 6]. | Throughout the study period (up to Month 24) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Incident Cervical Infection With Human Papillomavirus 16 (HPV-16) or Human Papillomavirus 18 (HPV-18) | HPV-16 or HPV-18 incident infection is defined as at least one positive HPV-16 or HPV-18 deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) assay in women who were, for the corresponding HPV type, seronegative at Month 0 and HPV DNA negative (by PCR) at Month 0 and Month 6. | Up to Month 24 | 
| Number of Subjects With Cytologically-confirmed Abnormalities Concurrently Associated With Human Papillomavirus 16 (HPV-16) and/or Human Papillomavirus 18 (HPV-18) Cervical Infection | Cytologically-confirmed abnormalities assessed include atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), atypical squamous cells-can not exclude HSIL (ASC-H) and atypical glandular cells (AGC). These cytological abnormalities were assessed in women who were, for the corresponding Human Papillomavirus (HPV) type, seronegative at Month 0 and HPV deoxyribonucleic acid (DNA) negative (by polymerase chain reaction) at Month 0 and Month 6. | Up to Month 24 | 
| Number of Subjects With Histopathologically-confirmed Lesions Concurrently Associated With Human Papillomavirus 16 (HPV-16) and/or Human Papillomavirus (HPV-18) Cervical Infection | Histopathologically-confirmed lesions assessed include cervical intraepithelial neoplasia of grade 1 (CIN1), grade 2 (CIN2), grade 3 (CIN3) and adenocarcinoma. These lesions were assessed in women who were, for the corresponding Human Papillomavirus (HPV) type, seronegative at Month 0 and HPV deoxyribonucleic acid (DNA) negative (by polymerase chain reaction) at Month 0 and Month 6. | Up to Month 24 | 
| Number of Subjects With Incident Cervical Infection With Any Oncogenic Human Papillomavirus (HPV) Types | Incident infection for oncogenic HPV types is defined as at least one positive oncogenic HPV type deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) assay in women who were, for the corresponding HPV type, HPV DNA negative (by PCR) at Month 0 and Month 6. Oncogenic (high risk [HR]) HPV types assessed include HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68. | Up to Month 24 | 
| Number of Subjects With Persistent Cervical Infection With Any Oncogenic Human Papillomavirus (HPV) Types | Persistent infection for oncogenic HPV types is defined as at least 2 positive HPV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) assays for the same viral genotype with no negative DNA sample between the 2 positive DNA samples, over an approximate interval of 6 months (> 150 days) [as assessed in women who were, for the corresponding HPV type, HPV DNA negative (by PCR) at Month 0 and Month 6]. Oncogenic (high risk [HR]) HPV types assessed include HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68. | Up to Month 24 | 
| Number of Subjects With Cytologically-confirmed Abnormalities Concurrently Associated With Cervical Infection With Any Oncogenic Human Papillomavirus (HPV) Type | Cytologically-confirmed abnormalities assessed include ASC-US, LSIL, HSIL, ASC-H and AGC. These cytological abnormalities were assessed in women who were, for the corresponding HPV type (determined by PCR), HPV DNA negative (by PCR) at Month 0 and Month 6. Oncogenic (high risk [HR]) HPV types assessed include HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68. | Up to Month 24 | 
| Number of Subjects With Histopathologically Confirmed Lesions Concurrently Associated With Cervical Infection With Any Oncogenic Human Papillomavirus (HPV) Type | Histopathologically-confirmed lesions assessed include cervical intraepithelial neoplasia of grade 1 (CIN1), grade 2 (CIN2), grade 3 (CIN3) and adenocarcinoma. These lesions were assessed in women who were, for the corresponding HPV type (determined by polymerase chain reaction)), HPV deoxyribonucleic acid (DNA) negative at Month 0 and Month 6. Oncogenic (high risk [HR]) HPV types assessed include HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68. | Up to Month 24 | 
| Number of Subjects With Anti-human Papillomavirus 16 and 18 (Anti-HPV-16 and Anti-HPV-18) Antibody Titers Above the Cut-off Value | Anti-HPV-16 antibody cut-off value assessed include 8 ELISA units per milliliter (EL.U/mL) and anti-HPV-18 antibody cut-off value assessed include 7 EL.U/mL. | At Months 0 (pre-vaccination), 6, 7, 12, 18 and 24 | 
| 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). | At Months 0, 6, 7, 12, 18 and 24 | 
| Number of Subjects Reporting Solicited Local and General Symptoms | Solicited local symptoms assessed include pain, redness and swelling. Solicited general symptoms assessed include arthralgia, fatigue, fever (above 37.5 degree Celsius), gastrointestinal symptoms, headache, myalgia, rash and urticaria. | Within 7 days after each and any vaccination | 
| Number of Subjects Reporting Unsolicited Adverse Events (AE) | Unsolicited AE covers any AE 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. | Within 30 days after 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 period (up to Month 24) | 
| Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Other Medically Significant Conditions (MSCs) | NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. MSC 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 study period (up to Month 24) | 
| 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. | Throughout the study period (up to Month 24) | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Hematological Parameters | Hematological parameters assessed in blood samples include hemoglobin, haematocrit, mean corpuscular (MC) hemoglobin, mean corpuscular (MC) hemoglobin concentration, mean corpuscular (MC) volume, platelet count, red blood cell count, white blood cell count. Abnormalities reported include values outside the normal ranges: values higher than normal are designated as Above and values lower than normal as Below while Unknown stands for values not determined. | At Month 0 and Month 7 | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical Parameters | Biochemical parameters were assessed in blood samples. Abnormalities reported include values outside the normal ranges: values higher than normal are designated as Above and values lower than normal as Below while Unknown stands for values not determined. Abbreviations: aminotransferase (ALT), aspartate aminotransferase (ASP), C reactive protein (CRP), gamma-glutamyl-transferase (GGT) and lactate dehydrogenase (LDH). | At Month 0 and Month 7 | 
| Number of Subjects Reporting Abnormal Biochemical Parameters in Urine Samples | Abnormalities in concentrations (expressed as milligrams per deciliter [mg/dL]) are presented categorical as follows: Protein: <10 (-)*; 10-25 (+-)*; 25-85 (+); 85-250 (2+); 250-800 (3+). Glucose: <30 (-)*; 30-60 (+-)*; 60-125 (+); 125-250 (2+); 250-750 (3+). Urobilinogen: <1.5 (+-)*; 1.5-3.5 (+); 3.5-7 (2+); 7-14 (3+). Bilirubin: <0.35 (-)*; 0.35-1.5 (+); 1.5-5 (2+); 5-12 (3+). Occult blood: <0.015 (-)*; 0.015-0.045 (+-); 0.045-015 (+); 0.15-0.75 (2+); >0.75 (3+). Ketone body: <2.5 (-)*; 2.5-7.5 (+-); 7.5-30 (+); 30-70 (2+); 70-125 (3+). Normal ranges indicated by asterix*. | At Month 0 and Month 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPV Vaccine Efficacy