Evaluation of Immunogenicity and Safety of Human Papillomavirus (HPV) Vaccine Co-administered With Another Vaccine in Healthy Female Subjects

Immunogenicity and Safety Study of GlaxoSmithKline Biologicals' HPV Vaccine (580299) Co-administrated With a Commercially Available Vaccine in Healthy Female Adolescents

Infection with human papillomavirus (HPV) has been clearly established as the necessary cause of cervical cancer. Vaccination of pre-teens and adolescents, ideally before sexual debut and thus before exposure to oncogenic HPV, is a rational strategy for prevention of cervical cancer. Thus, HPV vaccination could complement the existing pre-adolescent/adolescent vaccination programs. This Phase IIIb study is designed to evaluate the immunogenicity and safety of co-administering a commercially available vaccine with GSK Biologicals' HPV-16/18 L1 VLP AS04 (Cervarix TM) vaccine as compared to the administration of either vaccine alone.

Study Overview

• Status: Completed
• Conditions: Infections, Papillomavirus
• Intervention / Treatment: Biological: HPV Vaccine (GSK580299) Cervarix TM; Biological: Engerix B

• Study Type: Interventional
• Enrollment (Actual): 744
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6525 GA
    • GSK Investigational Site
  • Rotterdam, Netherlands, 3011 EN
    • GSK Investigational Site
• Sweden
  • Linköping, Sweden, SE-581 85
    • GSK Investigational Site
  • Luleå, Sweden, SE-972 31
    • GSK Investigational Site
  • Malmö, Sweden, SE-211 52
    • GSK Investigational Site
  • Norrköping, Sweden, SE-601 82
    • GSK Investigational Site
  • Skene, Sweden, SE-511 62
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 9 years to 15 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Subjects who the investigator believes that they and/or their parents/legally acceptable representatives (LARs) can and will comply with the requirements of the protocol (e.g. completion of the diary cards, return for follow-up visits) should be enrolled in the study.
• A female between, and including, 9 and 15 years of age (has not attained her 16th birthday) at the time of the first vaccination.
• Written informed consent obtained from the subject's parent/LAR prior to the enrolment. In addition, written informed assent must be obtained from the subject.
• Healthy subjects as established by medical history and clinical examination before entering into the study.
• Subjects must not be pregnant. Absence of pregnancy should be verified with a urine pregnancy test.
• If the subject is female, she must be of non-childbearing potential, or if she is of childbearing potential, she must practice adequate contraception for at least 30 days prior to vaccination, have a negative pregnancy test and continue such precautions for two months after completion of the vaccination series. Subjects who reach menarche (begin menstruating) during the study, and therefore become of childbearing potential, must agree to follow the same precautions.

Exclusion Criteria:

• Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine 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.
• Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before and 30 days after each dose of vaccine. Administration of routine vaccines such as meningococcal, inactivated influenza, diphtheria/tetanus and/or diphtheria/tetanus-containing vaccines up to 8 days before the first dose of study vaccine is allowed.
• Concurrently participating in another clinical study, at any time during the study period (up to the Month 12 telephone contact), in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device).
• A subject planning to become pregnant, likely to become pregnant (as determined by the investigator) or planning to discontinue contraceptive precautions during the study period and up to two months after the last vaccine dose.
• Pregnant or breastfeeding women.
• 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.
• Previous vaccination against hepatitis B or planned administration of any hepatitis B vaccine other than that foreseen by the study protocol during the study period.
• History of hepatitis B infection.
• Known exposure to hepatitis B within the previous 6 weeks.
• Known acute or chronic, clinically significant neurologic, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests.
• Cancer or autoimmune disease under treatment.
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccines.
• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
• Acute disease at the time of enrolment.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cervarix & Engerix Group; Subjects received 3 doses of Cervarix™ (Human Papillomavirus [HPV] vaccine) co-administered with Engerix™ (Hepatitis B [HBV] vaccine) according to a 0, 1, 6-month schedule.	Biological: HPV Vaccine (GSK580299) Cervarix TM; IM administration; Biological: Engerix B; IM administration
Experimental: Cervarix Group; Subjects received 3 doses of Cervarix™ (Human Papillomavirus [HPV] vaccine) according to a 0, 1, 6-month schedule.	Biological: HPV Vaccine (GSK580299) Cervarix TM; IM administration
Active Comparator: Engerix Group; Subjects received 3 doses of Engerix™ (Hepatitis B [HBV] vaccine) according to a 0, 1, 6-month schedule.	Biological: Engerix B; IM administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Above the Cut-off Value for Seroprotection	Only groups which had received the HBV vaccine were included in the analysis. Subjects included were seronegative for anti-HBs (antibody titer < 3.3 milli International Units per milliliter (mIU/mL)) prior to vaccination. Anti-HBs antibody cut-off value for seroprotection assessed included 10 mIU/mL.	Month 7
Number of Subjects With Anti-human Papillomavirus 16 and 18 (Anti-HPV-16 and Anti-HPV-18) Antibody Concentrations Above the Cut-off Value for Seroconversion	Only groups which had received the HPV vaccine were included in the analysis. Anti-HPV-16 antibody cut-off value assessed included 8 Enzyme-linked Immunosorbent Assay (ELISA) units per milliliter (EL.U/mL) and anti-HPV-18 antibody cut-off value assessed included 7 EL.U/mL. Subjects included were seronegative for anti-HPV-16 (antibody titer < 8 EL.U/mL) and anti-HPV-18 (antibody titer < 7 EL.U/mL) prior to vaccination.	Month 7
Anti-HPV-16/18 Antibody Titres	Antibody titers for Anti-HPV-16 and Anti-HPV-18 are expressed as Geometric Mean Titers (GMTs). Only groups which had received the HPV vaccine were included in the analysis. Subjects included were seronegative for anti-HPV-16 (antibody titer < 8 EL.U/mL) and anti-HPV-18 (antibody titer < 7 EL.U/mL) prior to vaccination.	Month 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Anti-HBs Antibody Concentrations Above the Cut-off Value for Seroconversion	Only groups which had received the HBV vaccine were included in the analysis. Subjects included were seronegative for anti-HBs (antibody titer < 3.3 mIU/mL) prior to vaccination. Anti-HBs antibody cut-off value for seroconversion assessed included 3.3 mIU/mL.	Month 7
Anti-HBs Antibody Titres	Antibody titers for anti-HBs are given as Geometric Mean Titers (GMTs) in mIU/mL. Only groups which had received the HBV vaccine were included in the analysis. Subjects included were seronegative for anti-HBs (antibody titer < 3.3 mIU/mL) prior to vaccination.	Month 7
Number of Subjects With Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations Above the Cut-off Value for Seroconversion	Only groups which had received the HPV vaccine were included in the analysis. Anti-HPV-16 antibody cut-off value assessed included 8 Enzyme-linked Immunosorbent Assay (ELISA) units per milliliter (EL.U/mL) and anti-HPV-18 antibody cut-off value assessed included 7 EL.U/mL. Subjects included were seronegative for anti-HPV-16 (antibody titer < 8 EL.U/mL) and anti-HPV-18 (antibody titer < 7 EL.U/mL) prior to vaccination.	Month 2
Anti-HPV-16/18 Antibody Titres	Antibody titers for Anti-HPV-16 and Anti-HPV-18 are expressed as Geometric Mean Titers (GMTs). Only groups which had received the HPV vaccine were included in the analysis. Subjects included were seronegative for anti-HPV-16 (antibody titer < 8 EL.U/mL) and anti-HPV-18 (antibody titer < 7 EL.U/mL) prior to vaccination.	Month 2
Number of Subjects With Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Above the Cut-off Value for Seroconversion	Only groups which had received the HBV vaccine were included in the analysis. Subjects included were seronegative for anti-HBs (antibody titer < 3.3 mIU/mL) prior to vaccination. Anti-HBs antibody cut-off value for seroconversion assessed included 3.3 mIU/mL.	Month 2
Number of Subjects With Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Above the Cut-off Value for Seroprotection	Only groups which had received the HBV vaccine were included in the analysis. Subjects included were seronegative for anti-HBs (antibody titer < 3.3 milli International Units per milliliter (mIU/mL)) prior to vaccination vaccination. Anti-HBs antibody cut-off value for seroprotection assessed included 10 mIU/mL.	Month 2
Anti-HBs Antibody Titers	Anti-HBs antibody titers are given as GMTs in mIU/mL. Only groups which had received the HBV vaccine were included in the analysis. Subjects included were seronegative for anti-HBs (antibody titer < 3.3 mIU/mL) prior to vaccination.	Month 2
Number of Subjects Reporting Any Solicited Local Symptoms	Solicited local symptoms included injection site pain, redness and swelling. Any solicited local symptom is occurence of a symptom regardless of its intensity.	During the 7-day period (Days 0 - 6) following vaccination
Number of Subjects Reporting Grade 3 Solicited Local Symptoms	Solicited local symptoms include injection site pain, redness and swelling. Grade 3 pain is pain that prevented normal everyday activities. Grade 3 redness is redness that was > 50 mm. Grade 3 swelling is swelling that was > 50 mm.	During the 7-day period (Days 0-6) following vaccination
Number of Subjects Reporting Any Solicited General Symptoms	Solicited general symptoms included arthralgia, fatigue, gastrointestinal, headache, myalgia, rash, temperature in degrees celsius (axillary) and urticaria. Any solicited general symptom is the occurence of the symptom regardless of its intensity or relationship to study vaccination.	During the 7-day (Days 0-6) period following vaccination.
Number of Subjects Reporting Grade 3 Solicited General Symptoms	Solicited general symptoms included arthralgia, fatigue, gastrointestinal, headache, myalgia, rash, temperature in degrees celsius (axillary) and urticaria. Grade 3 arthralgia, fatigue, gastrointestinal, headache, myalgia and rash were symptoms that prevented normal activity. Grade 3 temperature was temperature > 39 degrees Celsius. Grade 3 urticaria was urticaria distributed on at least 4 body areas.	During the 7-day (Days 0-6) period following vaccination
Number of Subjects Reporting Related Solicited General Symptoms	Solicited general symptoms included arthralgia, fatigue, gastrointestinal, headache, myalgia, rash, temperature in degrees celsius (axillary) and urticaria. Related solicited general symptoms were those symptoms assessed by the investigators as related to the study vaccination.	During the 7-day period (Days 0 - 6) following vaccination
Number of Subjects Reporting Any, Grade 3 and Causally Related to Vaccination 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 was an AE that prevented normal activities. Related AE was an AE that was assessed by the investigator as related to the study vaccination.	During the 30-day period (Days 0 - 29) following any vaccination
Number of Subjects Reporting Any and Causally Related to Vaccination 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 SAEs were SAEs assessed by the investigators as related to the vaccination. * Grade 3 SAEs were not assessed.	Throughout the active phase of the study (up to Month 7).
Number of Subjects Reporting Any and Causally Related to Vaccination 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. * Grade 3 SAEs were not assessed.	Throughout the safety follow-up (month 7 up to Month 12).
Number of Subjects Reporting Medically Significant Conditions	Medically significant conditions (i.e., AEs prompting emergency room or physician visits that are not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that are not related to common diseases).	Throughout the active phase of the study (up to Month 7)
Number of Subjects Reporting Medically Significant Conditions	Medically significant conditions (i.e., AEs prompting emergency room or physician visits that are not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that are not related to common diseases).	Throughout the safety follow-up (month 7 up to Month 12)

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Schmeink C et al. Co-administration of AS04-adjuvanted human papillomavirus-16/18 vaccine with hepatitis B vaccine in healthy female subjects aged 9-15 years. Abstract presented at the 28th Annual Meeting of European Society for Paediatric Infectious Diseases (ESPID). Nice, France, 4-8 May 2010.
• Schmeink CE, Bekkers RL, Josefsson A, Richardus JH, Berndtsson Blom K, David MP, Dobbelaere K, Descamps D. Co-administration of human papillomavirus-16/18 AS04-adjuvanted vaccine with hepatitis B vaccine: randomized study in healthy girls. Vaccine. 2011 Nov 15;29(49):9276-83. doi: 10.1016/j.vaccine.2011.08.037. Epub 2011 Aug 19.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start: April 9, 2008
• Primary Completion (Actual): August 28, 2009
• Study Completion (Actual): January 8, 2010

Study Registration Dates

• First Submitted: March 27, 2008
• First Submitted That Met QC Criteria: April 1, 2008
• First Posted (Estimate): April 4, 2008

Study Record Updates

• Last Update Posted (Actual): August 17, 2018
• Last Update Submitted That Met QC Criteria: June 28, 2018
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Cervical cancer; HPV vaccine; Co-administration
• Other Study ID Numbers: 111507

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Informed Consent Form
   Information identifier: 111507
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Statistical Analysis Plan
   Information identifier: 111507
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Dataset Specification
   Information identifier: 111507
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Study Protocol
   Information identifier: 111507
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Annotated Case Report Form
   Information identifier: 111507
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Individual Participant Data Set
   Information identifier: 111507
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Clinical Study Report
   Information identifier: 111507
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register