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

NCT01627561 | Completed Phase 3 Results

• 2 other identifiers: 1158872011-005604-15
• Study Type: interventional
• Target: 148
• Locations: 3 countries
• Sites: 4

Brief Summary

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.

Conditions

Infections, Papillomavirus

Keywords

Immune response; Human papillomavirus; HPV vaccine; Safety

Outcome Measures

Primary Outcomes (12)

• 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 Outcomes (18)

• 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)

  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)

  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

  At Day 0 and Day 42 (i.e. 42 days after the vaccination at Day 0)

• Anti-measles Antibody Concentrations

  At Day 0 and Day 42 (i.e. 42 days after the vaccination at Day 0)

• Number of Seropositive Subjects for Mumps Antigen

  At Day 0 and Day 42 (i.e. 42 days after the vaccination at Day 0)

Study Arms (2)

Cervarix Group

EXPERIMENTAL

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

Priorix + Infanrix Group

ACTIVE COMPARATOR

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; Biological: Infanrix

Interventions

Cervarix BIOLOGICAL

2 doses administered intramuscularly in the deltoid muscle of the left arm at Day 0 and Month 6.

Also known as: HPV

Cervarix Group

Priorix BIOLOGICAL

1 dose administered intramuscularly in the deltoid muscle of the left arm at Day 0.

Also known as: MMR

Priorix + Infanrix Group

Infanrix BIOLOGICAL

1 dose administered intramuscularly in the deltoid muscle of the left arm at Month 6.

Also known as: DTPa

Priorix + Infanrix Group

Eligibility Criteria

• Age: 4 Years - 6 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (4)

GSK Investigational Site

Bogotá, 38007, Colombia

Location

GSK Investigational Site

Yopal, Casanare, Colombia

Location

GSK Investigational Site

México, 04530, Mexico

Location

GSK Investigational Site

Panama City, Panama

Location

Related Publications (3)

• Lin L, Parra MM, Sierra VY, Cespedes AS, Granados MA, Luque A, Damaso S, Castrejon Alba MM, Romano-Mazzotti L, Struyf F. Safety and Immunogenicity of the HPV-16/18 AS04-adjuvanted Vaccine in 4-6-year-old Girls: Results to Month 12 From a Randomized Trial. Pediatr Infect Dis J. 2018 Apr;37(4):e93-e102. doi: 10.1097/INF.0000000000001871.

  PMID: 29424799 BACKGROUND

• Lin L, Macias Parra M, Sierra VY, Salas Cespedes A, Granados MA, Luque A, Karkada N, Castrejon Alba MM, Romano-Mazzotti L, Borys D, Struyf F. Long-term Immunogenicity and Safety of the AS04-adjuvanted Human Papillomavirus-16/18 Vaccine in Four- to Six-year-old Girls: Three-year Follow-up of a Randomized Phase III Trial. Pediatr Infect Dis J. 2019 Oct;38(10):1061-1067. doi: 10.1097/INF.0000000000002437.

  PMID: 31469776 BACKGROUND

• Bergman H, Henschke N, Arevalo-Rodriguez I, Buckley BS, Crosbie EJ, Davies JC, Dwan K, Golder SP, Loke YK, Probyn K, Petkovic J, Villanueva G, Morrison J. Human papillomavirus (HPV) vaccination for the prevention of cervical cancer and other HPV-related diseases: a network meta-analysis. Cochrane Database Syst Rev. 2025 Nov 24;11(11):CD015364. doi: 10.1002/14651858.CD015364.pub2.

  PMID: 41276263 DERIVED

MeSH Terms

Conditions

Papillomavirus Infections

Interventions

human papillomavirus vaccine, L1 type 16, 18; Measles-Mumps-Rubella Vaccine; Diphtheria-Tetanus-acellular Pertussis Vaccines; Pentetic Acid

Condition Hierarchy (Ancestors)

Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Communicable Diseases; Infections; DNA Virus Infections; Virus Diseases; Tumor Virus Infections; Genital Diseases; Urogenital Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Vaccines, Combined; Vaccines; Biological Products; Complex Mixtures; Measles Vaccine; Viral Vaccines; Mumps Vaccine; Rubella Vaccine; Pertussis Vaccine; Bacterial Vaccines; Diphtheria Toxoid; Toxoids; Tetanus Toxoid; Vaccines, Acellular; Vaccines, Subunit; Polyamines; Amines; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 14, 2012
• First Posted: June 26, 2012
• Study Start: October 15, 2012
• Primary Completion: April 23, 2014
• Study Completion: October 6, 2016
• Last Updated: April 10, 2020
• Results First Posted: May 8, 2015

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

PA (1); CO (2); ME (1)