Immunogenicity and Safety of GlaxoSmithKline (GSK) Biologicals' Human Papillomavirus (HPV) Vaccine (GSK580299) in Healthy Female Subjects 10-25 Years of Age.

Study Overview
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Brief Summary
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Cervical cancer is the second most common cancer among women worldwide. Approximately 500 000 new cases are reported each year worldwide, from which 83% occur in developing countries. The incidence of cervical cancer varies depending on the region of the world. Africa has some of the highest age-standardized incidence and mortality rates in the world (Eastern Africa 42.7 and 34.6 per 100 000; Southern Africa 38.2 and 22.6 per 100 000; Western Africa 29.3 and 23.8 per 100 000; Middle Africa 28.0 and 23.0 per 100 000). As in the majority of developing countries, organization of cervical cancer screening programs in Africa is difficult to manage, especially in rural areas. HPV prophylactic vaccination could therefore clearly and efficiently decrease the incidence of cervical cancer. The current study is designed to assess the immunogenicity and safety of GSK Biologicals' HPV-16/18 L1 AS04 vaccine in female subjects enrolled from multiple countries in Africa. Ideally, HPV vaccination should be performed before onset of sexual activity, since studies have shown that acquisition of high-risk HPV occurs soon after sexual debut. This study will therefore be performed in subjects aged 10 to 25 years of age.

Official Title
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Study to Assess the Immunogenicity and Safety of GlaxoSmithKline (GSK) Biologicals' HPV Vaccine GSK580299 in Healthy Female Subjects Aged 10-25 Years.

Conditions
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Human Papillomavirus (HPV) Infection

Intervention / Treatment
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* Biological: Cervarix
* Drug: Placebo Al(OH)3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that they and/or their parents/legally acceptable representative can and will comply with the requirements of the protocol should be enrolled in the study. A female between, and including, 10 and 25 years of age at the time of the first vaccination. Written or oral, signed or thumb printed or witnessed informed consent obtained from the subject prior to enrolment. For subjects below legal age of consent, written or oral, signed or thumb printed or witnessed informed consent obtained from the subject's parent or legally acceptable representative. In addition, a written or oral, signed or thumb printed and witnessed informed assent must be obtained from the subject. Free of obvious health problems as established by medical history, clinical examination and laboratory testing before entering into the study. Subjects must have a negative urine pregnancy test at the screening visit and at Visit 1 (Day 0). Subjects must be seronegative for human immunodeficiency virus (HIV) at the screening visit. Subjects must be of non-childbearing potential, or, if of 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. Subjects who reach menarche during the study and therefore are of childbearing potential must agree to follow the same precautions. Subjects must have had no more than 6 sexual partners prior to enrolment. Subjects must be willing to undergo HIV voluntary counselling and testing and must be willing to be informed of their HIV status. Subjects below legal age of consent must also be willing to have their parent or legally acceptable representative informed of their HIV status. 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). 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. Administration of a vaccine not foreseen by the study protocol within 30 days before the first dose of vaccine. Enrolment will be deferred until the subject is outside of specified window. Planned administration of a vaccine not foreseen by the study protocol within 30 days before and 30 days after any dose of study vaccine. 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. Cancer or autoimmune disease under treatment. Any confirmed or suspected immunosuppressive or immunodeficient condition, including HIV infection based on laboratory testing performed during the screening visit. Hypersensitivity to latex. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine/control. Acute disease at the time of enrolment. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory testing performed at the screening visit. History of any neurologic disorders or seizures. 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. Pregnant or breastfeeding female. A women planning to become pregnant, likely to become pregnant or planning to discontinue contraceptive precautions during the study period, up to two months after the last vaccine dose. 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: 10 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cervarix Group<br>Healthy female subjects who received 3 doses of Cervarix at Months 0, 1 and 6, administered intramuscularly into the deltoid region of the non-dominant arm. For some analyses the group was stratified by age into a 10-14 years of age group and a 15-25 years of age group. | Biological: Cervarix<br>* The vaccine was administered according to a 0, 1, and 6-month schedule, intramuscularly into the deltoid region of the non-dominant arm.<br>* Other names: HPV-16/18 L1 AS04 vaccine;|
| Placebo Comparator: Placebo Group<br>Healthy female subjects who received 3 doses of placebo at Months 0, 1 and 6, administered intramuscularly into the deltoid region of the non-dominant arm. For some analyses the group was stratified by age into a 10-14 years of age group and a 15-25 years of age group. | Drug: Placebo Al(OH)3<br>* Placebo was administered according to a 0, 1 and 6-month schedule, intramuscularly into the deltoid region of the non-dominant arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Seroconverted Subjects for Anti-human Papillomavirus (HPV)-16 and 18 Antibodies | A seroconverted subject was a subject with antibody titers below 8 or 7 Enzyme-linked Immunosorbent Assay Units per milliliter (EL.U/mL) for anti-HPV-16 and 18, respectively, before vaccination and antibody titers ≥ 8 or 7 EL.U/mL for anti-HPV-16 and 18, respectively, after vaccination. The groups were stratified by age for the analysis. The age strata were 10-14 years and 15-25 years. | At Month 7 | 
| Geometric Mean Titers (GMTs) of Anti-HPV-16 and Anti-HPV-18 Antibodies | Titers were expressed as GMTs in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). The groups were stratified by age for the analysis. The age strata were 10-14 years and 15-25 years. | At Month 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Seroconverted Subjects for Anti-HPV-16 and Anti-HPV-18 Antibodies | A seroconverted subject was a subject with antibody titers below 8 or 7 Enzyme-linked Immunosorbent Assay Units per milliliter (EL.U/mL) for anti-HPV-16 and 18, respectively, before vaccination and antibody titers ≥ 8 or 7 EL.U/mL for anti-HPV-16 and 18, respectively, after vaccination. The groups were stratified by age for the analysis. The age strata were 10-14 years and 15-25 years. | At Month 2 and Month 12 | 
| GMTs for Anti-HPV-16 and Anti-HPV-18 Antibodies | Titers were expressed as GMTs in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). The groups were stratified by age for the analysis. The age strata were 10-14 years and 15-25 years. | At Month 2 and Month 12 | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Solicited local symptoms assessed were pain and swelling at the injection site. Any = occurrence of any solicited local symptom regardless of their intensity grade. Grade 3 swelling = swelling spreading beyond 50 millimeters (mm) of injection site. Grade 3 pain = pain that prevented normal activity. | Within 7 days (Day 0-6) after each dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Solicited general symptoms assessed were arthralgia (only joints that are distal from the injection site), fatigue, fever (defined as axillary temperature ≥ 37.5 degrees Celsius), gastrointestinal symptoms, headache, myalgia, rash and urticaria. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 urticaria = urticaria distributed on at least 4 body areas. Grade 3 fever = axillary temperature > 39.0 °C. Related = symptom assessed by the investigator as causally related to the study vaccination. | Within 7 days (Day 0-6) after each dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. Any = any unsolicited AE regardless of intensity and relationship to vaccination. Grade 3 = an unsolicited AE that prevented normal everyday activity. Related = unsolicited AE assessed by the investigator as causally related to the study vaccination. | Within 30 days (Day 0-29) after any vaccination | 
| Number of Subjects With NOCDs and Other MSCs | New onset of chronic diseases (NOCDs) assessed included autoimmune disorders, asthma, type I diabetes, allergies. Medically significant conditions (MSCs) assessed included AEs prompting emergency room or physician visits that were not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that were not related to common diseases. Common diseases included upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury. | From Day 0 up to Month 7 and from Month 7 up to Month 12 | 
| Number of Subjects With Serious Adverse Events (SAEs) | SAEs assessed included medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or were a congenital anomaly/birth defect in the offspring of a study subject. | From Day 0 up to Month 7 and from Month 7 up to Month 12 | 
| Number of Subjects With Pregnancies and Their Outcomes | Pregnancy outcomes were ectopic pregnancy, elective termination no apparent congenital anomaly, live infant no apparent congenital anomaly, premature live infant no apparent congenital anomaly, lost to follow-up and spontaneous abortion no apparent congenital anomaly. | From Day 0 up to Month 12 | 
| Number of Senegalese Subjects With Clinically Relevant Abnormalities in Parameters Assessed | Biochemical and haematological parameters assessed were: Alanine amino-transferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), hematocrit (HC), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC), white blood cells (WBC). Number of subjects were separated with respect to their results at pre-vaccination, i.e. whether their results were in, above or below the normal range. N for each category at pre-vaccination noted in category title. For each parameter and for each range it was assessed whether the values of the subjects were in, above or below the normal range. | At Month 7 | 
| Number of Tanzanian Subjects With Clinically Relevant Abnormalities in Parameters Assessed | Biochemical and haematological parameters assessed were: Alanine amino-transferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), hematocrit (HC), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC), white blood cells (WBC). Number of subjects were separated with respect to their results at pre-vaccination, i.e. whether their results were in, above or below the normal range. N for each category at pre-vaccination noted in category title. For each parameter and for each range it was assessed whether the values of the subjects were in, above or below the normal range. | At Month 7 | 
| Number of Senegalese Subjects With Clinically Relevant Abnormalities in Parameters Assessed | Biochemical and haematological parameters assessed were: Alanine amino-transferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), hematocrit (HC), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC), white blood cells (WBC). Number of subjects were separated with respect to their results at pre-vaccination, i.e. whether their results were in, above or below the normal range. N for each category at pre-vaccination noted in category title. For each parameter and for each range it was assessed whether the values of the subjects were in, above or below the normal range. | At Month 12 | 
| Number of Tanzanian Subjects With Clinically Relevant Abnormalities in Parameters Assessed | Biochemical and haematological parameters assessed were: Alanine amino-transferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), hematocrit (HC), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC), white blood cells (WBC). Number of subjects were separated with respect to their results at pre-vaccination, i.e. whether their results were in, above or below the normal range. N for each category at pre-vaccination noted in category title. For each parameter and for each range it was assessed whether the values of the subjects were in, above or below the normal range. | At Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Immunogenicity, Human Papillomavirus (HPV) vaccine