Immunogenicity of GlaxoSmithKline Biological's Human Papillomavirus (HPV) Vaccine (580299) Versus Merck's Gardasil® in Healthy Females 18-45 Years of Age - Full Text View

Sponsor:	GlaxoSmithKline
Information provided by:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT00423046

Purpose

HPV infection has been established as a necessary cause of cervical cancer. GSK Biologicals has developed an HPV-16/18 L1 VLP AS04 vaccine (Cervarix TM) which targets the 2 most common oncogenic HPV types (HPV-16 and HPV-18), found in > 70%, approximately, of all cervical cancers. Recently, Merck's HPV vaccine Gardasil® [quadrivalent human papillomavirus (HPV-6,11,16,18 L1 VLP) recombinant vaccine] has been approved by the FDA for prevention of genital tract cancers and pre-cancers and genital warts in females. Although the GSK HPV vaccine and Gardasil® have different compositions and are expected to have different efficacy profiles, each vaccine targets prevention of HPV-16 and 18 genital tract cancers and pre-cancers. Therefore, a comparison of the immunogenicity of the two vaccines is warranted. This Phase 3b study is designed to compare the immunogenicity of the GSK vaccine (HPV-16/18) to Gardasil® in healthy adult females 18-45 years of age.

The Protocol Posting has been updated as the study will be extended by 3 additional years.

Condition	Intervention	Phase
Cervical Cancer Papillomavirus Infection	Biological: GSK Biologicals HPV 16/18 vaccine 580299 (CervarixTM) Biological: Gardasil ® (Merck & Co. Inc) Biological: Placebo	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator, Outcomes Assessor) Primary Purpose: Prevention
Official Title:	Phase IIIb, Observer-blind Study to Compare Immunogenicity of GSK Biologicals' HPV-16/18 L1/AS04 Vaccine Versus Gardasil® [Quadrivalent Human Papillomavirus (HPV-6,11,16,18 L1 VLP) Recombinant Vaccine Merck & Co., Inc.]

Resource links provided by NLM:

MedlinePlus related topics: Cancer Cervical Cancer

U.S. FDA Resources

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:

Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Neutralizing Antibody Titers in Females 18-26 Years of Age [ Time Frame: At Month 7 ] [ Designated as safety issue: No ]
The data are displayed as Geometric Mean Titers (GMTs). The titer is the serum dilution giving a 50 percent reduction of the signal compared to a control without serum.

Secondary Outcome Measures:

Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Neutralizing Antibodies [ Time Frame: At Month 6, 7, 12, 18, 24, 36, 48 and 60 ] [ Designated as safety issue: No ]
The data table displays Geometric Mean Titers (GMTs). Titer is the serum dilution giving a 50 percent reduction of the signal compared to a control without serum.

Data for Month 7 on subjects aged 18 to 26 years are given above as primary outcome measure.

The study is still ongoing and data for subsequent time points will be added as soon as they become available.
Number of Subjects With Antibody Titers (Neutralizing Assay) Against Human Papilloma Virus 16 (Anti-HPV-16) and Human Papilloma Virus 18 (Anti-HPV-18) Greater Than or Equal to a Cut-off Value [ Time Frame: At Month 6, 7, 12, 18, 24, 36, 48 and 60 ] [ Designated as safety issue: No ]
The titer value (=serum dilution giving a 50 percent reduction of the signal compared to a control without serum) used as the cut-off for seroconversion was 40 for both HPV-16 and HPV-18.

The study is still ongoing and data for subsequent time points will be added as soon as they become available.
Number of Subjects With Antibody Titers (Neutralizing Assay) Against Other Oncongenic HPV Types Greater Than or Equal to a Cut-off Value [ Time Frame: At Month 7 ] [ Designated as safety issue: No ]
Other oncogenic HPV types include HPV-31 and HPV-45. The titer value (=serum dilution giving a 50 percent reductino of the signal compared to a control without serum) used as the cut-off for seroconversion was 40 for both other oncogenic types HPV-31 and HPV-45.
Titers of Antibodies to Other Oncogenic HPV Types Measured by Neutralization Assay [ Time Frame: At Month 7 ] [ Designated as safety issue: No ]
Other Oncogenic Types include HPV-31 and HPV-45. Titers were measured by neutralization assay and are given as Geometric Mean Titers (GMTs). The titer is the serum dilution giving a 50 percent reduction of the signal compared to a control without serum
Number of Subjects With Anti-HPV-16 and Anti-HPV-18 Immunoglobulin G (IgG) Antibody Titers Above Cut-off Values, Measured by Enzyme-linked Immunosorbent Assay (ELISA) [ Time Frame: At Month 6, 7, 12, 18, 24, 36, 48 and 60 ] [ Designated as safety issue: No ]
Cut-off values assessed were greater than or equal to 8 ELISA units per milliliter (EL.U/mL) for HPV-16 and greater than or equal to 7 EL.U/mL for HPV-18.

The study is still ongoing and data for subsequent time points will be added as soon as they become available.
Titers of Anti-HPV-16 and Anti-HPV-18 Immunoglobulin G (IgG) Antibodies Measured by Enzyme-linked Immunosorbent Assay (ELISA) [ Time Frame: At Month 6, 7, 12, 18, 24, 36, 48 and 60 ] [ Designated as safety issue: No ]
Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL).

The study is still ongoing and data for subsequent time points will be added as soon as they become available.
Number of Subjects With Antibody Titers to Other Oncogenic HPV Types Greater Than or Equal to a Cut-off Value, Measured by Enzyme-linked Immunosorbent Assay (ELISA) [ Time Frame: At Month 6, 7, 12, 18, 24, 36 and 48 ] [ Designated as safety issue: No ]
Other oncogenic types include HPV-31 and HPV-45. Cut-off values assessed were greater than or equal 59 EL.U/mL in the sera of subjects seronegative before vaccination.

The study is still ongoing and data for subsequent time points will be added as soon as they become available.
Titers of Antibodies to Other Oncogenic HPV Types Measured by Enzyme-linked Immunosorbent Assay (ELISA) [ Time Frame: At Month 6, 7, 12, 18, 24, 36 and 48 ] [ Designated as safety issue: No ]
Other oncogenic types include HPV-31 and HPV-45. Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL).

The study is still ongoing and data for subsequent time points will be added as soon as they become available.
Number of HPV-16 and HVP-18 Specific CD4 Cells Producing at Least 2 Different Cytokines Per Million of CD4 T Cells [ Time Frame: At Month 7, 12, 18, 24, 36 and 48 ] [ Designated as safety issue: No ]
Number of cells were expressed as geometric mean, minimum and maximum values of specific CD4 cells producing at least 2 cytokines (CD40 Ligand, Interleukin-2, Tumor Necrosis Factor Alpha or Interferon-gamma) per million of CD4 T-cells.

The study is still ongoing and data for subsequent time points will be added as soon as they become available.
Number of HPV-16 and HVP-18 Specific CD8 Cells Producing at Least 2 Different Cytokines Per Million of CD8 T Cells [ Time Frame: At Month 7, 12 and 18 ] [ Designated as safety issue: No ]
Data were expressed as geometric mean, minimum and maximum values of specific CD4 cells producing at least 2 cytokines (CD40 Ligand, Interleukin-2, Tumor Necrosis Factor Alpha or Interferon-gamma) per million of CD4 T-cells.

Analyses for further time points were not performed.
Number of HPV-16 and HVP-18 Specific B-cells Per Million B Cells [ Time Frame: At Month 7, 12, 18, 24, 36 and 48 ] [ Designated as safety issue: No ]
HPV-16 and HPV-18 Specific Memory B Cells were measured by Enzyme-linked immunosorbent spot (ELISPOT) assay and expressed as geometric mean, minimum and maximum values of specific B-cells per million of cells.

The study is still ongoing and data for subsequent time points will be added as soon as they become available.
Titers for HPV-16 IgG and HPV-18 IgG (by ELISA) in Cervico-vaginal Secretions (CVS) [ Time Frame: At Month 7, 12, 18, 24, 36 and 48 ] [ Designated as safety issue: No ]
Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL). The study is still ongoing and data for subsequent time points will be added as soon as they become available.
Number of Subjects Completing the 3-dose Vaccination Schedule [ Time Frame: Up to Month 7 ] [ Designated as safety issue: No ]
Number of Subjects Reporting Solicited Local Symptoms [ Time Frame: During the 7-day period (Day 0-6) following vaccination ] [ Designated as safety issue: No ]
Solicited local symptoms included pain, redness and swelling.
Number of Subjects Reporting Solicited General Symptoms [ Time Frame: During the 7-day period (Day 0-6) following vaccination ] [ Designated as safety issue: No ]
Solicited general symptoms included arthralgia, fatigue, fever, gastrointestinal discomfort, headache, myalgia, rash and urticaria.
Number of Subjects Reporting Unsolicited Adverse Events (AEs) [ Time Frame: During the 30-day period (Day 0-29) following vaccination ] [ Designated as safety issue: No ]
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.
Number of Subjects Reporting Serious Adverse Events (SAEs) [ Time Frame: Up to Month 48 ] [ Designated as safety issue: No ]
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.

Data were analyzed until Month 36. Results from later time points will be disclosed when available.
Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions (MSCs) [ Time Frame: Up to Month 48 ] [ Designated as safety issue: No ]
NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. MSCs include AEs prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury.

Data were analyzed until Month 36. Additional results will be disclosed when available.

Enrollment:	1106
Study Start Date:	January 2007
Estimated Study Completion Date:	May 2012
Estimated Primary Completion Date:	May 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Cervarix Group Subjects received 3 doses of GSK Biologicals HPV 16/18 vaccine 580299 (CervarixTM) at Months 0, 1 and 6 and a dose of placebo at Month 2.	Biological: GSK Biologicals HPV 16/18 vaccine 580299 (CervarixTM) Three doses administered intramuscularly at months 0, 1 and 6 Other Name: Cervarix Biological: Placebo One dose administered intramuscularly at month 2 to maintain blinding
Active Comparator: Gardasil Group Subjects received 3 doses of Gardasil® (Merck's human papillomavirus [HPV] vaccine) at Months 0, 2 and 6 and a dose of placebo at Month 1.	Biological: Gardasil ® (Merck & Co. Inc) Three doses administered intramuscularly at months 0, 2 and 6 Biological: Placebo One dose administered intramuscularly at month 1 to maintain blinding

Detailed Description:

This Protocol Posting has been updated following Protocol Amendment 25, November 2010

Eligibility

Ages Eligible for Study:	18 Years to 45 Years
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

A woman whom the investigator believes that she or her legally acceptable representative (in the event that the subject is illiterate) can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits).
A woman between and including 18 and 45 years of age at the time of the first vaccination.
Written informed consent must be obtained from the subject prior to enrollment.
Subject must be free of obvious health problems as established by medical history and history-directed clinical examination before entering into the study.
Subject must have a negative urine pregnancy test.
Subject must be of non-childbearing potential, or if she is of child bearing potential, she must practice adequate contraception for 30 days prior to vaccination, have a negative pregnancy test and continue such precautions for 2 months after completion of the vaccination series.
Subject must have an intact cervix.

Exclusion Criteria:

Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period up to Month 60.
Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose or planned administration during the study period up to Month 60.
Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before and 30 days after (i.e. days 0-29) each dose of vaccine. Administration of routine vaccines up to 8 days before each dose of study vaccine is allowed. Enrolment will be deferred until the subject is outside of specified window.
Pregnant or breastfeeding. Women must be at least 3 months post-pregnancy and not breastfeeding to enter the study.
A woman planning to become pregnant or planning to discontinue contraceptive precautions during approximately the first eight months of the study (Months 0-8).
Previous administration of components of the investigational vaccine
Previous or planned vaccination against HPV outside of this protocol.
Any medically diagnosed or suspected immunodeficient condition based on medical history and physical examination.
History of allergic disease, suspected allergy or reactions likely to be exacerbated by any component of the study vaccines.
Hypersensitivity to latex.
Known acute or chronic, clinically significant pulmonary, cardiovascular, neurologic, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests.
History of significant medical conditions and currently under treatment.
Received immunoglobulins and/or blood product within 90 days preceding enrolment or planned administration during the study period up to Month 60. Enrollment will be deferred until the subject is outside of specified window.
Acute disease at the time of enrolment. Enrollment will be deferred until condition is resolved. All vaccines can be administered to persons with a minor illness
Heavy bleeding (menstruation or other) or heavy vaginal discharge in which a pelvic exam cannot be performed. Enrollment will be deferred until condition is resolved according to investigator's medical judgement.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00423046

Show 39 Study Locations

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director:

GSK Clinical Trials

GlaxoSmithKline

More Information

Publications:

Einstein MH, Baron M, Levin MJ, Chatterjee A, Edwards RP, Zepp F, Carletti I, Dessy FJ, Trofa AF, Schuind A, Dubin G; HPV-010 Study Group. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin. 2009 Oct;5(10):705-19. Epub 2009 Oct 14.

Verstraeten T, Descamps D, David MP, Zahaf T, Hardt K, Izurieta P, Dubin G, Breuer T. Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines. Vaccine. 2008 Dec 2;26(51):6630-8.

Einstein M et al. Comparative evaluation of immunogenicity of two prophylactic human papillomavirus vaccines. Abstract presented at the 25th International Papillomavirus Conference, Mälmo, Sweden, 8-14 May 2009.

Moris P et al. CervarixTM (HPV-16/18 AS04 adjuvanted vaccine) induces higher HPV-16/18-specific T Cell repsonses compared to GardasilR (human papillomavirus quadrivalent (types 6,11,16, 18) recombinant vaccine) in healthy women aged 18-45 years. Abstract presented at FIGO 2009 - 19th World Congress of Gynecology & Obstetrics. Cape Town, South Africa, 4-9 October 2009.

Einstein M et al. Comparative immunology of two prophylactic human papillomavirus cervidcal cancer vaccines: month 18 schedule. Abstract presented at IDSA. Philadelphia, USA, 29 October-1 November 2009.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Einstein MH, Baron M, Levin MJ, Chatterjee A, Fox B, Scholar S, Rosen J, Chakhtoura N, Meric D, Dessy FJ, Datta SK, Descamps D, Dubin G; HPV-010 Study Group. Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 vaccine and HPV-6/11/16/18 vaccine: follow-up from months 12-24 in a Phase III randomized study of healthy women aged 18-45 years. Hum Vaccin. 2011 Dec;7(12):1343-58. Epub 2011 Dec 1.

Einstein MH, Baron M, Levin MJ, Chatterjee A, Fox B, Scholar S, Rosen J, Chakhtoura N, Lebacq M, van der Most R, Moris P, Giannini SL, Schuind A, Datta SK, Descamps D; HPV-010 Study Group. Comparison of the immunogenicity of the human papillomavirus (HPV)-16/18 vaccine and the HPV-6/11/16/18 vaccine for oncogenic non-vaccine types HPV-31 and HPV-45 in healthy women aged 18-45 years. Hum Vaccin. 2011 Dec;7(12):1359-73. Epub 2011 Dec 1.

Responsible Party:	Cheri Hudson; Clinical Disclosure Advisor, GSK Clinical Disclosure
ClinicalTrials.gov Identifier:	NCT00423046 History of Changes
Other Study ID Numbers:	108933
Study First Received:	January 16, 2007
Results First Received:	November 12, 2009
Last Updated:	October 27, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:

Vaccines
Cervical cancer
Immunogenicity
Humans
Safety

Viral infections
Human papillomavirus (HPV)
Comparative study
Human papillomavirus vaccine
Adults

Additional relevant MeSH terms:

Uterine Cervical Neoplasms
Papillomavirus Infections
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms

Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
DNA Virus Infections
Virus Diseases
Tumor Virus Infections

ClinicalTrials.gov processed this record on February 12, 2012