Immunogenicity of GlaxoSmithKline Biological's Human Papillomavirus (HPV) Vaccine (580299) Versus Merck's Gardasil® in Healthy Females 18-45 Years of Age

Study Overview
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Brief Summary
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HPV infection has been established as a necessary cause of cervical cancer. GSK Biologicals has developed an HPV-16/18 L1 VLP AS04 vaccine (Cervarix TM) which targets the 2 most common oncogenic HPV types (HPV-16 and HPV-18), found in > 70%, approximately, of all cervical cancers. Recently, Merck's HPV vaccine Gardasil® [quadrivalent human papillomavirus (HPV-6,11,16,18 L1 VLP) recombinant vaccine] has been approved by the FDA for prevention of genital tract cancers and pre-cancers and genital warts in females. Although the GSK HPV vaccine and Gardasil® have different compositions and are expected to have different efficacy profiles, each vaccine targets prevention of HPV-16 and 18 genital tract cancers and pre-cancers. Therefore, a comparison of the immunogenicity of the two vaccines is warranted. This Phase 3b study is designed to compare the immunogenicity of the GSK vaccine (HPV-16/18) to Gardasil® in healthy adult females 18-45 years of age. The Protocol Posting has been updated as the study will be extended by 3 additional years.

Detailed Description
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This Protocol Posting has been updated following Protocol Amendment 25, November 2010

Official Title
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Phase IIIb, Observer-blind Study to Compare Immunogenicity of GSK Biologicals' HPV-16/18 L1/AS04 Vaccine Versus Gardasil® [Quadrivalent Human Papillomavirus (HPV-6,11,16,18 L1 VLP) Recombinant Vaccine Merck & Co., Inc.]

Conditions
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Infections, Papillomavirus, Papillomavirus Vaccines

Intervention / Treatment
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* Biological: GSK Biologicals HPV 16/18 vaccine 580299 (CervarixTM)
* Biological: Gardasil ® (Merck & Co. Inc)
* Biological: Placebo
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A woman whom the investigator believes that she or her legally acceptable representative (in the event that the subject is illiterate) can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits). A woman between and including 18 and 45 years of age at the time of the first vaccination. Written informed consent must be obtained from the subject prior to enrollment. Subject must be free of obvious health problems 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 of non-childbearing potential, or if she is of child bearing potential, she must practice adequate contraception for 30 days prior to vaccination, have a negative pregnancy test and continue such precautions for 2 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(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period up to Month 60. Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose or planned administration during the study period up to Month 60. Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before and 30 days after (i.e. days 0-29) each dose of vaccine. Administration of routine vaccines up to 8 days before each dose of study vaccine is allowed. Enrolment will be deferred until the subject is outside of specified window. Pregnant or breastfeeding. Women must be at least 3 months post-pregnancy and not breastfeeding to enter the study. A woman planning to become pregnant or planning to discontinue contraceptive precautions during approximately the first eight months of the study (Months 0-8). Previous administration of components of the investigational vaccine Previous or planned vaccination against HPV outside of this protocol. Any medically diagnosed or suspected 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. Known acute or chronic, clinically significant pulmonary, cardiovascular, neurologic, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests. History of significant medical conditions and currently under treatment. Received immunoglobulins and/or blood product within 90 days preceding enrolment or planned administration during the study period up to Month 60. Enrollment will be deferred until the subject is outside of specified window. Acute disease at the time of enrolment. Enrollment will be deferred until condition is resolved. All vaccines can be administered to persons with a minor illness Heavy bleeding (menstruation or other) or heavy vaginal discharge in which a pelvic exam cannot be performed. Enrollment will be deferred until condition is resolved according to investigator's medical judgement.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cervarix Group<br>Subjects received 3 doses of GSK Biologicals human papillomavirus [HPV]16/18 vaccine 580299 (CervarixTM) at Months 0, 1 and 6 and a dose of placebo at Month 2. All doses were administered by intramuscular injection in the deltoid muscle of the upper arm. | Biological: GSK Biologicals HPV 16/18 vaccine 580299 (CervarixTM)<br>* Three doses administered intramuscularly at months 0, 1 and 6<br>* Other names: Cervarix;Biological: Placebo<br>* One dose administered intramuscularly at month 2 to maintain blinding<br>|
| Active Comparator: Gardasil Group<br>Subjects received 3 doses of Gardasil® (Merck's human papillomavirus [HPV] vaccine) at Months 0, 2 and 6 and a dose of placebo at Month 1. All doses were administered by intramuscular injection in the deltoid muscle of the upper arm. | Biological: Gardasil ® (Merck & Co. Inc)<br>* Three doses administered intramuscularly at months 0, 2 and 6<br>Biological: Placebo<br>* One dose administered intramuscularly at month 1 to maintain blinding<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Neutralizing Antibodies | Titers are displayed as Geometric Mean Titers (GMTs). The titer is the serum dilution giving a 50 percent reduction of the signal compared to a control without serum. | At Month 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Neutralizing Antibodies | Titers are given as Geometric Mean Titers (GMTs). Titer is the serum dilution giving a 50 percent reduction of the signal compared to a control without serum. Data for Month 7 on subjects aged 18 to 26 years are given in the outcome above as a primary outcome measure. | At Month 6, 7, 12, 18, 24, 36, 48 and 60 | 
| Number of Subjects With Antibody Titers (Neutralizing Assay) Against Other Oncongenic HPV Types Greater Than or Equal to the Cut-off Value | Other oncogenic HPV types include HPV-31 and HPV-45. The titer value (=serum dilution giving a 50 percent reduction of the signal compared to a control without serum) used as the cut-off for seroconversion was 40 for both other oncogenic types HPV-31 and HPV-45. | At Month 7 | 
| Titers of Antibodies to Other Oncogenic HPV Types Measured by Neutralization Assay | Other Oncogenic Types include HPV-31 and HPV-45. Titers were measured by neutralization assay and are given as Geometric Mean Titers (GMTs). The titer is the serum dilution giving a 50 percent reduction of the signal compared to a control without serum | At Month 7 | 
| Number of Subjects With Antibody Titers (Neutralizing Assay) Against Human Papilloma Virus 16 (Anti-HPV-16) and Human Papilloma Virus 18 (Anti-HPV-18) Greater Than or Equal to the Cut-off Value | The titer value (=serum dilution giving a 50 percent reduction of the signal compared to a control without serum) used as the cut-off for seroconversion was 40 for both HPV-16 and HPV-18. | At Month 6, 7, 12, 18, 24, 36, 48 and 60 | 
| Number of Subjects With Anti-HPV-16 and Anti-HPV-18 Immunoglobulin G (IgG) Antibody Titers Above Cut-off Values, Measured by Enzyme-linked Immunosorbent Assay (ELISA) | Cut-off values assessed were greater than or equal to 8 ELISA units per milliliter (EL.U/mL) for HPV-16 and greater than or equal to 7 EL.U/mL for HPV-18. | At Month 6, 7, 12, 18, 24, 36, 48 and 60 | 
| Titers of Anti-HPV-16 and Anti-HPV-18 Immunoglobulin G (IgG) Antibodies Measured by Enzyme-linked Immunosorbent Assay (ELISA) | Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL). | At Month 6, 7, 12, 18, 24, 36, 48 and 60 | 
| Number of Subjects With Antibody Titers to Other Oncogenic HPV Types Greater Than or Equal to a Cut-off Value, Measured by Enzyme-linked Immunosorbent Assay (ELISA) | Other oncogenic types include HPV-31 and HPV-45. Cut-off values assessed were greater than or equal 59 EL.U/mL in the sera of subjects seronegative before vaccination. | At Month 6, 7, 12, 18, 24, 36 and 48 | 
| Titers of Antibodies to Other Oncogenic HPV Types Measured by Enzyme-linked Immunosorbent Assay (ELISA) | Other oncogenic types include HPV-31 and HPV-45. Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL). | At Month 6, 7, 12, 18, 24, 36 and 48 | 
| Number of HPV-16 and HVP-18 Specific CD4 Cells Producing at Least 2 Different Cytokines Per Million of CD4 T Cells | Number of cells were expressed as geometric mean, minimum and maximum values of specific CD4 cells producing at least 2 cytokines (CD40 Ligand, Interleukin-2, Tumor Necrosis Factor Alpha or Interferon-gamma) per million of CD4 T-cells. | At Month 7, 12, 18, 24, 36 and 48 | 
| Number of HPV-16 and HVP-18 Specific CD8 Cells Producing at Least 2 Different Cytokines Per Million of CD8 T Cells | Data were expressed as geometric mean, minimum and maximum values of specific CD8 cells producing at least 2 cytokines (CD40 Ligand, Interleukin-2, Tumor Necrosis Factor Alpha or Interferon-gamma) per million of CD8 T-cells. Analyses for further time points were not performed, as there was no response at these time points. | At Month 7, 12 and 18 | 
| Number of HPV-16 and HVP-18 Specific B-cells Per Million B Cells | HPV-16 and HPV-18 Specific Memory B Cells were measured by Enzyme-linked immunosorbent spot (ELISPOT) assay and expressed as geometric mean, minimum and maximum values of specific B-cells per million of cells. | At Month 7, 12, 18, 24, 36 and 48 | 
| Titers of HPV-16 IgG and HPV-18 IgG (by ELISA) in Cervico-vaginal Secretions (CVS) | Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL). | At Month 7, 12, 18, 24, 36 and 48 | 
| Number of Subjects Completing the 3-dose Vaccination Schedule |  | Up to Month 7 | 
| Number of Subjects Reporting Any, Grade 3 and Related Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 50 millimeters (mm) of injection site. All solicited local symptoms were assessed as related to study vaccination. | During the 7-day period (Day 0-6) following vaccination | 
| Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were arthralgia, fatigue, fever [defined as axillary temperature equal to or above 37.5 degrees Celsius (°C)], gastrointestinal, headache, myalgia, rash and urticaria. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever > 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination. | During the 7-day period (Day 0-6) following vaccination | 
| Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs) | 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.Grade 3 AE = AE that prevented normal activity. Related AE = AE assessed by the investigator as causally related to the study vaccination. | During the 30-day period (Day 0-29) following vaccination | 
| Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions (MSCs) | NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. 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. | Up to Month 7 | 
| Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) 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. | Up To Month 12 | 
| Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) 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. | Up To Month 18 | 
| Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) 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. | Up To Month 24 | 
| Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) 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. | Up To Month 36 | 
| Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions (MSCs) | NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. 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. | Up to Month 48 | 
| Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions (MSCs) | NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. 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. Note: NOCD and MSC cases were unblinded at the Month 60 analysis. | Up to Month 60 | 
| Number of Subjects With Any, Grade 3 and Related 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. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAEs was not assessed. | Up to Month 7 | 
| Number of Subjects With Any, Grade 3 and Related 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. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAEs was not assessed. | Up to Month 12 | 
| Number of Subjects With Any, Grade 3 and Related 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. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAEs was not assessed. | Up to Month 18 | 
| Number of Subjects With Any, Grade 3 and Related 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. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAEs was not assessed. | Up to Month 24 | 
| Number of Subjects With Any, Grade 3 and Related 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. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAEs was not assessed. | Up to Month 36 | 
| Number of Subjects With Any, Grade 3 and Related 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. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAEs was not assessed. | Up to Month 48 | 
| Number of Subjects With Any, Grade 3 and Related 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. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAE(s) was not assessed. Note: SAEs were unblinded at the Month 60 analysis. | Up to Month 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vaccines, Cervical cancer, Immunogenicity, Humans, Safety, Viral infections, Human papillomavirus (HPV), Comparative study, Human papillomavirus vaccine, Adults