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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00652938

Enrollment

744

Registered

2008-04-04

Start date

2008-04-09

Completion date

2010-01-08

Last updated

2018-08-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Infections, Papillomavirus

Keywords

Co-administration, HPV vaccine, Cervical cancer

Brief summary

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.

Interventions

BIOLOGICALHPV Vaccine (GSK580299) Cervarix TM

IM administration

BIOLOGICALEngerix B

IM administration

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

9 Years to 15 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
Number of Subjects With Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Above the Cut-off Value for Seroprotection	Month 7	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.
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	Month 7	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.
Anti-HPV-16/18 Antibody Titres	Month 7	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.

Secondary

Measure	Time frame	Description
Anti-HPV-16/18 Antibody Titres	Month 2	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.
Number of Subjects With Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Above the Cut-off Value for Seroconversion	Month 2	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.
Number of Subjects With Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Above the Cut-off Value for Seroprotection	Month 2	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.
Anti-HBs Antibody Titers	Month 2	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.
Number of Subjects Reporting Any Solicited Local Symptoms	During the 7-day period (Days 0 - 6) following vaccination	Solicited local symptoms included injection site pain, redness and swelling. Any solicited local symptom is occurence of a symptom regardless of its intensity.
Number of Subjects Reporting Grade 3 Solicited Local Symptoms	During the 7-day period (Days 0-6) following vaccination	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.
Number of Subjects With Anti-HBs Antibody Concentrations Above the Cut-off Value for Seroconversion	Month 7	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.
Number of Subjects Reporting Grade 3 Solicited General Symptoms	During the 7-day (Days 0-6) period following vaccination	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.
Number of Subjects Reporting Related Solicited General Symptoms	During the 7-day period (Days 0 - 6) following vaccination	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.
Number of Subjects Reporting Any, Grade 3 and Causally Related to Vaccination Unsolicited Adverse Events (AEs)	During the 30-day period (Days 0 - 29) following any vaccination	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.
Number of Subjects Reporting Any and Causally Related to Vaccination Serious Adverse Events (SAEs)	Throughout the active phase of the study (up to Month 7).	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.
Number of Subjects Reporting Any and Causally Related to Vaccination SAEs	Throughout the safety follow-up (month 7 up to Month 12).	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.
Number of Subjects Reporting Medically Significant Conditions	Throughout the active phase of the study (up to Month 7)	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).
Number of Subjects Reporting Any Solicited General Symptoms	During the 7-day (Days 0-6) period following vaccination.	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.
Anti-HBs Antibody Titres	Month 7	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.
Number of Subjects With Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations Above the Cut-off Value for Seroconversion	Month 2	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.

Countries

Netherlands, Sweden

Participant flow

Pre-assignment details

While the total numbers of subjects enrolled in the study was 744, the total number of subjects that entered the study was 741. The remaining 3 subjects received a subject number but no vaccine dose and were therefore excluded from the analysis and group assignment.

Participants by arm

Arm	Count
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.	247
Cervarix Group Subjects received 3 doses of Cervarix™ (Human Papillomavirus \[HPV\] vaccine) according to a 0, 1, 6-month schedule.	247
Engerix Group Subjects received 3 doses of Engerix™ (Hepatitis B \[HBV\] vaccine) according to a 0, 1, 6-month schedule.	247
Total	741

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	1	0	2
Overall Study	fear of blood sampling	0	1	0
Overall Study	Lost to Follow-up	0	0	2
Overall Study	Withdrawal by Subject	0	6	1

Baseline characteristics

Characteristic	Cervarix&Engerix Group	Cervarix Group	Engerix Group	Total
Age, Continuous	11.4 years STANDARD_DEVIATION 2.17	11.3 years STANDARD_DEVIATION 2.14	11.4 years STANDARD_DEVIATION 2.17	11.4 years STANDARD_DEVIATION 2.16
Sex: Female, Male Female	247 Participants	247 Participants	247 Participants	741 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	246 / 247	239 / 247	222 / 247
serious Total, serious adverse events	3 / 247	2 / 247	1 / 247

Outcome results

Primary

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.

Time frame: Month 7

Population: The analysis was performed on the According-to-Protocol (ATP) Cohort for immunogenicity, which included all evaluable subjects for whom data concerning immunogenicity outcome measures were available.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Cervarix&Engerix Group	Anti-HPV-16/18 Antibody Titres	Anti-HPV-16	19819.8 EL.U/mL
Cervarix&Engerix Group	Anti-HPV-16/18 Antibody Titres	Anti-HPV-18	8835.1 EL.U/mL
Cervarix Group	Anti-HPV-16/18 Antibody Titres	Anti-HPV-16	21712.6 EL.U/mL
Cervarix Group	Anti-HPV-16/18 Antibody Titres	Anti-HPV-18	8838.6 EL.U/mL

Primary

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.

Time frame: Month 7

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cervarix&Engerix Group	Number of Subjects With Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Above the Cut-off Value for Seroprotection	190 Participants
Engerix Group	Number of Subjects With Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Above the Cut-off Value for Seroprotection	181 Participants

Primary

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.

Time frame: Month 7

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Cervarix&Engerix Group	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	Anti-HPV-16	205 Participants
Cervarix&Engerix Group	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	Anti-HPV-18	199 Participants
Cervarix Group	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	Anti-HPV-16	200 Participants
Cervarix Group	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	Anti-HPV-18	202 Participants

Secondary

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.

Time frame: Month 2

Arm	Measure	Value (GEOMETRIC_MEAN)
Cervarix&Engerix Group	Anti-HBs Antibody Titers	13.6 mIU/mL
Engerix Group	Anti-HBs Antibody Titers	26.9 mIU/mL

Secondary

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.

Time frame: Month 7

Arm	Measure	Value (GEOMETRIC_MEAN)
Cervarix&Engerix Group	Anti-HBs Antibody Titres	1280.9 mIU/mL
Engerix Group	Anti-HBs Antibody Titres	3107.7 mIU/mL

Secondary

Anti-HPV-16/18 Antibody Titres

Time frame: Month 2

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Cervarix&Engerix Group	Anti-HPV-16/18 Antibody Titres	Anti-HPV-16	4894.7 EL.U/mL
Cervarix&Engerix Group	Anti-HPV-16/18 Antibody Titres	Anti-HPV-18	4790.4 EL.U/mL
Cervarix Group	Anti-HPV-16/18 Antibody Titres	Anti-HPV-16	5069.2 EL.U/mL
Cervarix Group	Anti-HPV-16/18 Antibody Titres	Anti-HPV-18	4663.8 EL.U/mL

Secondary

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.

Time frame: Throughout the safety follow-up (month 7 up to Month 12).