Safety and Immunogenicity of GSK Biologicals' HPV-16/18 L1 VLP AS04 Vaccine (GSK-580299) in Healthy Female Children 4-6 Years Old

Study Overview
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Brief Summary
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The current study evaluates the immunogenicity and safety in 4-6 years old female subjects (experimental group) receiving Cervarix according to a 2-dose schedule (Month 0, 6), as compared to 4-6 years old female subjects (control group) receiving sequentially Priorix (Month 0) and Infanrix (Month 6) vaccines.

Official Title
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Safety and Immunogenicity of GSK Biologicals' HPV-16/18 L1 VLP AS04 Vaccine (GSK-580299) in Healthy Female Children 4-6 Years Old

Conditions
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Infections, Papillomavirus

Intervention / Treatment
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* Biological: Cervarix
* Biological: Priorix
* Biological: Infanrix


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that parent(s)/Legally Acceptable Representative(s) [LAR(s)] can and will comply with the requirements of the protocol. A female between, and including, 4 and 6 years of age at the time of the first vaccination. Written informed consent obtained from the parent(s)/LAR(s) of the subject prior to enrolment in the study. Healthy subjects as established by medical history and clinical examination before entering into the study. Subjects who received four doses of DTP vaccine (i.e., three doses in the first year of life and a fourth dose in the second year of life) according to the schedule applicable in the participating countries. Subjects who received a first dose of MMR vaccine according to the schedule applicable in the participating countries. Exclusion Criteria: Child in care. Previous vaccination against HPV or planned administration of another HPV vaccine during the study other than that foreseen in the protocol. Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before the first dose of study vaccine(s). Administration of routine meningococcal, hepatitis B, hepatitis A, inactivated influenza and/or poliomyelitis vaccines up to 8 days before the first dose of study vaccine(s) is allowed. Enrolment will be deferred until the subject is outside of specified window. 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(s), or planned use during the study period. History of any reactions or hypersensitivity likely to be exacerbated by any component of the study vaccines, including latex and/or obvious allergic reactions to neomycin (a history of contact dermatitis to neomycin is not a contraindication), egg protein, etc. (e.g. hives, swelling of the mouth and throat, difficulty breathing, hypotension, or shock subsequent to egg ingestion). Cancer or autoimmune disease under treatment. 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). Previous administration of MPL or AS04 adjuvant. Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine(s) or planned administration during the study period. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required). Family history of congenital or hereditary immunodeficiency. Documented human immunodeficiency virus (HIV)-positive subject. Major congenital defects or serious chronic illness. History of seizures or serious neurological disorder, which, according to the judgment of the investigator, precludes administration of any of the study vaccines. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests, which in the opinion of the investigator precludes administration of the study vaccine(s). Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥ 37.5°C on oral, axillary or tympanic setting, or ≥ 38.0°C on rectal setting. Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may, be enrolled at the discretion of the investigator. Enrolment can be deferred until condition is resolved. Previous administration of the fifth dose of DTP vaccine and/or the second dose of MMR vaccine or planned administration of DTP vaccine and/or MMR vaccine outside the study (during the study period from Day 0 to Month 12). History of tetanus, diphtheria, pertussis, measles, mumps and/or rubella. Known exposure to diphtheria or household exposure to pertussis within 30 days prior to vaccination with DTPa. Known exposure to measles, mumps and/or rubella 30 days prior to vaccination with the MMR study vaccine. Confirmed or suspected tuberculosis. Severe allergic reactions (e.g. anaphylaxis or severe Arthus-type hypersensitivity reactions) following the administration of previous dose(s) of DTP or MMR vaccines. Hyperpyrexia (≥ 40.5°C) within 48 hours of administration of previous doses of DTP or MMR vaccines. Persistent, inconsolable crying lasting more than 3 hours, occurring within 48 hours of administration of previous doses of DTP vaccine. Collapse or shocking-like state (hypotonic-hyporesponsive episode) within 48 hours of administration of previous doses of DTP vaccine. Idiopathic thrombocytopenic purpura or bleeding disorders. Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose(s). (For corticosteroids, this will mean prednisone ≥ 0.5 mg/kg/day, or equivalent. Inhaled and topical steroids are allowed.)

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 6 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cervarix Group<br>Healthy female subjects aged between, and including, 4 and 6 years, who received two doses of Cervarix vaccine at Day 0 and Month 6, administered intramuscularly in the deltoid muscle of the left upper arm. | Biological: Cervarix<br>* 2 doses administered intramuscularly in the deltoid muscle of the left arm at Day 0 and Month 6.<br>* Other names: HPV;|
| Active Comparator: Priorix + Infanrix Group<br>Healthy female subjects aged between, and including, 4 and 6 years, who received one dose of Priorix vaccine at Day 0 and one dose of Infanrix vaccine at Month 6, administered intramuscularly in the deltoid muscle of the left upper arm. | Biological: Priorix<br>* 1 dose administered intramuscularly in the deltoid muscle of the left arm at Day 0.<br>* Other names: MMR;Biological: Infanrix<br>* 1 dose administered intramuscularly in the deltoid muscle of the left arm at Month 6.<br>* Other names: DTPa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = cried when limb was moved/spontaneously painful. Grade 3 redness/swelling = redness/swelling spreading beyond 20 millimeters (mm) of injection site. | During the 7-day follow-up period (i.e. from the day of vaccination up to 6 subsequent days) after each vaccine dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were arthralgia (only in joints which were distal from the injection site), drowsiness, fatigue, fever [defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)], gastrointestinal symptoms (nausea, vomiting, diarrhoea and/or abdominal pain), headache, irritability/fussiness, loss of appetite, myalgia, rash (not urticaria, not measels/rubella-like rash), 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. Grade 3 irritability/fussiness = crying that could not be comforted/prevented normal activity. Grade 3 loss of appetite = did not eat at all. Related = symptom assessed by the investigator as causally related to the study vaccination. | During the 7-day follow-up period (i.e. from the day of vaccination up to 6 subsequent days) after each vaccine dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs) Reported During the 43-day Period Following the Vaccination at Day 0 | An unsolicited AE is 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. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also included failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 AE = an AE which prevented normal, everyday activities. Related AE = AE assessed by the investigator as causally related to the study vaccination. | During the 43-day period (i.e. from the day of vaccination up to 42 subsequent days) following the vaccination at Day 0 | 
| Number of Subjects With Any, Grade 3 and Related Unsolicited AEs Reported During the 30-day Period Following the Vaccination at Month 6 | An unsolicited AE is 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. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also included failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 AE = an AE which prevented normal, everyday activities. Related AE = AE assessed by the investigator as causally related to the study vaccination. | During the 30-day period (i.e. from the day of vaccination up to 29 subsequent days) following the vaccination at Month 6 | 
| Number of Subjects With Clinically Relevant Abnormalities in Biochemical and Haematological Parameters at Day 42 by Baseline Ranges | The parameters assessed were both biochemical (alanine aminotransferase = ALAT, creatinine = CREA, blood urea nitrogen = BUN) and haematological (basophils = BAS, eosinophils = EOS, red blood cells = RBC, hematocrit = HCT, hemoglobin = HGB, leukocytes [white blood cells] = WBC, lymphocytes = LYM, monocytes = MONO, neutrophils = NEU and platelets = PLA). Abnormal laboratory values at Day 42 were Below, Within and Above normal ranges, as compared to the baseline status of the same parameter, at Day 0 (Unknown, Below, Within and Above normal ranges) [e.g. ALAT Below (baseline) - Within (Day 42) = ALAT with below normal value at baseline and within normal values at Day 42]. | At Day 42 (i.e. 42 days after the vaccination at Day 0) | 
| Number of Subjects With Clinically Relevant Abnormalities in Biochemical and Haematological Parameters at Month 7 by Baseline Ranges | The parameters assessed were both biochemical (alanine aminotransferase = ALAT, creatinine = CREA, blood urea nitrogen = BUN) and haematological (basophils = BAS, eosinophils = EOS, red blood cells = RBC, hematocrit = HCT, hemoglobin = HGB, leukocytes [white blood cells] = WBC, lymphocytes = LYM, monocytes = MONO, neutrophils = NEU and platelets = PLA). Abnormal laboratory values at Month 7 were Below, Within and Above normal ranges, as compared to the baseline status of the same parameter, at Day 0 (Unknown, Below, Within and Above normal ranges) [e.g. ALAT Below (baseline) - Within (Month 7) = ALAT with below normal value at baseline and within normal values at Month 7]. | At Month 7 (i.e. 30 days after the vaccination at Month 6) | 
| Number of Subjects With Serious Adverse Events (SAEs) From Day 0 up to Month 7 | SAEs assessed included medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity or was a congenital anomaly/birth defect in the offspring of a study subject. | From Day 0 up to Month 7 (i.e. from first vaccination at Day 0 up to 30 days after the second vaccination at Month 6) | 
| Number of Subjects With AEs and SAEs Leading to Withdrawal From Day 0 up to Month 7 | The number of subjects with AEs and SAEs leading to premature discontinuation of the study was assessed. | From Day 0 up to Month 7 (i.e. from first vaccination at Day 0 up to 30 days after the second vaccination at Month 6) | 
| Number of Subjects With Potential Immune-mediated Diseases (pIMDs) From Day 0 up to Month 7 | pIMDs were defined as a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which might or might not have an autoimmune aetiology. | From Day 0 up to Month 7 (i.e. from first vaccination at Day 0 up to 30 days after the second vaccination at Month 6) | 
| Number of Subjects With Medically Significant Conditions (MSCs) From Day 0 up to Month 7 | MSCs were defined as AEs prompting emergency room or physician visits that were not related to common diseases or were not routine visits for physical examination or vaccination and as SAEs that were not related to common diseases. Common diseases included: upper respiratory tract infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections and injury. | From Day 0 up to Month 7 (i.e. from first vaccination at Day 0 up to 30 days after the second vaccination at Month 6) | 
| Number of Seroconverted Subjects for HPV-16 and HPV-18 Antigens at Month 7 | Seroconversion was defined as a titer greater than or equal to the cut-off value in the serum of seronegative subjects, defined as subjects who had an antibody titer below the cut-off value before vaccination. Titers were measured by Enzyme Linked Immunosorbent Assay (ELISA) and the cut-offs were 19 ELISA Units per milliliter (EU/mL) for HPV-16 and 18 EU/mL for HPV-18. | At Month 7 (i.e. 30 days after the vaccination at Month 6) | 
| Anti-HPV-16/18 Antibody Concentrations at Month 7 | Antibody concentrations were assessed by ELISA and expressed as geometric mean concentrations (GMCs) in EU/mL. | At Month 7 (i.e. 30 days after the vaccination at Month 6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Seroconverted Subjects for HPV-16 and HPV-18 Antigens at Month 7, Month 12 (for Both Groups) and at Month 18, Month 24 and Month 36 (Only for Cervarix Group) | Seroconversion was defined as a titer greater than or equal to the cut-off value in the serum of seronegative subjects, defined as subjects who had an antibody titer below the cut-off value before vaccination. Titers were measured by ELISA and the cut-offs were 19 EU/mL for HPV-16 and 18 EU/mL for HPV-18. Note: Month 7 data are also reported in the Primary outcome measure. | At Month 7, Month 12 (for both groups) and at Month 18, Month 24 and Month 36 (only for Cervarix Group) | 
| Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations at Month 7, Month 12 (for Both Groups) and at Month 18, Month 24 and Month 36 (Only for Cervarix Group) | Antibody concentrations were assessed by ELISA and expressed as GMCs in EU/mL. Note: Month 7 data are also reported in the Primary outcome measure. | At Month 7, Month 12 (for both groups) and at Month 18, Month 24 and Month 36 (only for Cervarix Group) | 
| Number of Seropositive Subjects for Measles Antigen | A seropositive subject was defined as a subject whose anti-measles antibody titer was equal to or above (≥) 150 milli-International Units per milliliter (mIU/mL), as assessed by ELISA. | At Day 0 and Day 42 (i.e. 42 days after the vaccination at Day 0) | 
| Anti-measles Antibody Concentrations | Anti-measles antibody concentrations were measured by ELISA, expressed as GMCs, in mIU/mL. The cut-off of the assay was an anti-measles antibody concentration ≥ 150 mIU/mL. | At Day 0 and Day 42 (i.e. 42 days after the vaccination at Day 0) | 
| Number of Seropositive Subjects for Mumps Antigen | A seropositive subject was defined as a subject whose anti-mumps antibody titer was equal to or above (≥) 231 U/mL, as assessed by ELISA. | At Day 0 and Day 42 (i.e. 42 days after the vaccination at Day 0) | 
| Anti-mumps Antibody Concentrations | Anti-mumps antibody concentrations were measured by ELISA, expressed as GMCs, in U/mL. The cut-off of the assay was an anti-mumps antibody concentration ≥ 231 U/mL. | At Day 0 and Day 42 (i.e. 42 days after the vaccination at Day 0) | 
| Number of Seropositive Subjects for Rubella Antigen | A seropositive subject was defined as a subject whose anti-rubella antibody titer was ≥ 4 IU/mL, as assessed by ELISA. | At Day 0 and Day 42 (i.e. 42 days after the vaccination at Day 0) | 
| Anti-rubella Antibody Concentrations | Anti-rubella antibody concentrations were measured by ELISA, expressed as GMCs, in IU/mL. The cut-off of the assay was an anti-rubella antibody concentration ≥ 4 IU/mL. | At Day 0 and Day 42 (i.e. 42 days after the vaccination at Day 0) | 
| Number of Seroprotected Subjects Against Diphtheria and Tetanus Antigens | A seroprotected subject against diphtheria antigen was defined as a subject with an anti-diphtheria (anti-D) antibody concentration ≥ the cut-off of 0.1 IU/mL, as measured by ELISA. A seroprotected subject against tetanus antigen was defined as a subject with an anti-tetanus (anti-T) antibody concentration ≥ the cut-off of 0.1 IU/mL, as measured by ELISA. | At Month 7 (i.e. 30 days after the vaccination at Month 6) | 
| Number of Subjects With pIMDs From Day 0 up to Month 12 | pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which might or might not have an autoimmune aetiology. | From Day 0 up to Month 12 (i.e. from first vaccination at Day 0 up to 6 months after the second vaccination at Month 6) | 
| Number of Subjects With MSCs From Day 0 up to Month 12 | MSCs were defined as AEs prompting emergency room or physician visits that were not related to common diseases or were not routine visits for physical examination or vaccination and as SAEs that were not related to common diseases. Common diseases included: upper respiratory tract infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections and injury. | From Day 0 up to Month 12 (i.e. from first vaccination at Day 0 up to 6 months after the second vaccination at Month 6) | 
| Number of Subjects With SAEs From Day 0 up to Month 12 | SAEs assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was a congenital anomaly/birth defect in the offspring of a study subject. | From Day 0 up to Month 12 (i.e. from first vaccination at Day 0 up to 6 months after the second vaccination at Month 6) | 
| Number of Subjects With SAEs Related to the Investigational Products or Any Fatal SAE | SAEs assessed included medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was a congenital anomaly/birth defect in the offspring of a study subject. | Throughout the study period (i.e. from Day 0 up to Month 12 for Priorix + Infanrix Group and from Day 0 up to Month 36 for Cervarix Group) | 
| Number of Subjects With AEs/SAEs Leading to Withdrawal Throughout the Study Period | The number of subjects with AEs and SAEs leading to premature discontinuation of study was assessed. | Throughout the study period (i.e from Day 0 up to Month 12 for Priorix + Infanrix Group and from Day 0 up to Month 36 for Cervarix Group) | 
| Number of Subjects Reporting the Intake of Concomitant Medication During the 43-day Period Following the Vaccination at Day 0 | Concomitant medication taken at least once during the 43-day period (i.e. from the day of vaccination up to 42 subsequent days) following the vaccination at Day 0 included: any type of medicines, antipyretics, prophylactic antipyretics and antibiotics. | During the 43-day period (i.e. from the day of vaccination up to 42 subsequent days) following the vaccination at Day 0 | 
| Number of Subjects Reporting the Intake of Concomitant Medication During the 30-day Period Following the Vaccination at Month 6 | Concomitant medication taken at least once during the 30-day period (i.e. from the day of vaccination up to 29 subsequent days) following the vaccination at Month 6 included: any type of medicines, antipyretics, prophylactic antipyretics and antibiotics. | During the 30-day period (i.e. from the day of vaccination up to 29 subsequent days) following the vaccination at Month 6 | 
| Percentage of Subjects Completing the Vaccination Schedule in Both Groups | The percentage of subjects who received the specified total number of doses (dose 1, dose 2, any dose) is reported. | From Day 0 up to Month 6 (i.e. from first vaccination at Day 0 up to the second vaccination at Month 6) | 
| Number of Subjects With Any, Grade 3 and Related to Vaccination Solicited Fever, Measles/Rubella-like Rash, Parotid Gland Swelling and Signs of Meningism Including Febrile Convulsion | Measles/Rubella-like rash: presence of macules, discoloured small patches or spots of the skin, neither elevated nor depressed below the skin's surface and/or papules, raised bumps on the skin usually below (<) 1 cm in diameter. Parotid/salivary gland swelling: swelling/tenderness in the mandibular/submandibular region. Suspected signs of meningism including febrile convulsions: febrile convulsions or any other neurological signs or symptoms indicative of meningism. Any = occurrence of any solicited symptom regardless of their intensity grade or relationship to vaccination. Any fever = axillary temperature equal to or above (≥) 37.5°C. Grade 3 AE = AE which prevented normal, everyday activities. Grade 3 measles/rubella-like rash = more than 150 lesions. Grade 3 parotid gland swelling = swelling with accompanying general symptoms. Grade 3 fever = axillary temperature above (>) 39.0°C. Related = any symptom assessed by the investigator as causally related to the vaccination. | During the 43-day period (i.e. from the day of vaccination up to 42 subsequent days) following the vaccination at Day 0 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immune response, Human papillomavirus, HPV vaccine, Safety