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Immunogenicity and Safety Study of GlaxoSmithKline Biologicals' Human Papillomavirus (HPV) Vaccine (GSK-580299) and Merck's Gardasil Vaccine When Administered According to Alternative 2-dose Schedules in 9-14 Year Old Females

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01462357
Recruitment Status : Completed
First Posted : October 31, 2011
Results First Posted : March 28, 2016
Last Update Posted : November 15, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE October 27, 2011
First Posted Date  ICMJE October 31, 2011
Results First Submitted Date  ICMJE August 11, 2014
Results First Posted Date  ICMJE March 28, 2016
Last Update Posted Date November 15, 2019
Actual Study Start Date  ICMJE November 21, 2011
Actual Primary Completion Date October 27, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 30, 2019)
  • Number of Seroconverted Subjects for Anti-HPV-16/18 Antibodies as Assessed by Enzyme-Linked Immunosorbent Assay (ELISA) at Month 7 Based on the ATP Cohort for Immunogenicity [ Time Frame: At Month 7 (i.e. one month after the last dose of study vaccine) ]
    Seroconversion was defined as the appearance of antibodies (i.e. anti-HPV-16 and anti-HPV-18 antibody titers greater than or equal to (≥) 19 and 18 ELISA units per milliliter (EL.U/mL), respectively), in the serum of subjects seronegative before vaccination.
  • Anti-HPV-16/18 Antibody Titers as Assessed by ELISA at Month 7 Based on the ATP Cohort for Immunogenicity [ Time Frame: At Month 7 (i.e. one month after the last dose of study vaccine) ]
    Anti-HPV 16/18 antibody titers were presented as Geometric Mean Titers (GMTs) and expressed in EL.U/mL.
  • Anti-HPV-16/18 Antibody Titers as Assessed by ELISA at Month 7 Based on the Total Vaccinated Cohort (TVC) [ Time Frame: At Month 7 (i.e. one month after the last dose of study vaccine) ]
    Anti-HPV 16/18 antibody titers were presented as Geometric Mean Titers (GMTs) and expressed in EL.U/mL.
Original Primary Outcome Measures  ICMJE
 (submitted: October 27, 2011)
  • Anti-HPV-16/18 seroconversion rates assessed by ELISA [ Time Frame: One month after the last dose of study vaccine (Month 7) ]
  • Anti-HPV-16/18 antibody titres assessed by ELISA [ Time Frame: One month after the last dose of study vaccine (Month 7) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 30, 2019)
  • Anti-HPV-16/18 Seroconversion Rates as Assessed by ELISA [ Time Frame: At Day 0 and Months 12, 18, 24 and 36 ]
    Seroconversion was defined as the appearance of antibodies (i.e. anti-HPV-16 and anti-HPV-18 antibody titers ≥ 19 and 18 EL.U/mL, respectively) in the serum of subjects seronegative before vaccination.
  • Anti-HPV-16/18 Antibody Titers as Assessed by ELISA [ Time Frame: At Day 0 and Months 12, 18, 24 and 36 ]
    Anti-HPV 16/18 antibody titers were presented as GMTs and expressed in EL.U/mL based on ELISA.
  • Anti-HPV-16/18 Antibody Titers as Assessed by ELISA at Month 36 [ Time Frame: At Month 36 ]
    Data at Month 36 were also expressed as International Units per milliliter (IU/mL). Conversion factor from EU/mL to IU/mL was determined to be 1/6.1 for HPV-16 and 1/5.7 for HPV-18, using the WHO International Standards (NIBSC codes 05-134 and 10-140 for HPV-16 and HPV-18, respectively). The assay cut-offs were therefore 3.1 IU/mL and 3.2 IU/mL for anti-HPV-16 and anti-HPV-18 antibodies, respectively.
  • Anti-HPV-16/18 Seroconversion Rates as Assessed by Pseudovirion-based Neutralization Assay (PBNA) in a Subset of Subjects, Based on the Month 36 ATP Cohort for Immunogenicity [ Time Frame: At Day 0 and Months 7, 12, 18, 24 and 36 ]
    Seroconversion was defined as the appearance of antibodies (i.e. anti-HPV-16 and anti-HPV-18 antibody titers ≥40 ED50) in the serum of subjects seronegative before vaccination. The assay was performed on a subset of approximately 100 subjects per study group.
  • Anti-HPV-16/18 Antibody Titers as Assessed by PBNA in a Subset of Subjects, Based on the Month 36 ATP Cohort for Immunogenicity [ Time Frame: At Day 0 and Months 7, 12, 18, 24 and 36 ]
    Anti-HPV 16/18 antibody titers were presented as GMT and expressed in titers using the PBNA. The assay was performed on a subset of approximately 100 subjects per study group.
  • Anti-HPV-16/18 Seroconversion Rates as Assessed by PBNA in a Subset of Subjects, Based on the Month 36 TVC [ Time Frame: At Day 0 and Months 7, 12, 18, 24 and 36 ]
    Seroconversion was defined as the appearance of antibodies (i.e. anti-HPV-16 and anti-HPV-18 antibody titers ≥40 ED50) in the serum of subjects seronegative before vaccination. The assay was performed on a subset of approximately 100 subjects per study group.
  • Anti-HPV-16/18 Antibody Titers as Assessed by PBNA in a Subset of Subjects, Based on the Month 36 TVC [ Time Frame: At Day 0 and Months 7, 12, 18, 24 and 36 ]
    Anti-HPV 16/18 antibody titers were presented as GMT and expressed in titers using the PBNA. The assay was performed on a subset of approximately 100 subjects per study group.
  • T-cell-mediated Immune Responses in the Sub-cohort for Cell-Mediated Immunity (CMI) [ Time Frame: At Day 0 and Months 7, 12, 24 and 36 ]
    Among immune markers expressed were Interleukin-2 (IL-2), Interferon-gamma (IFN-γ), Tumour necrosis factor-alpha (TNF-α) and CD40-ligand (CD40-L). The assay was performed on a sub-cohort of approximately 100 subjects per study group.
  • B-cell-mediated Immune Responses in the Sub-cohort for CMI [ Time Frame: At Day 0 and Months 7, 12, 24 and 36 ]
    The frequency of B-cell Elispot response to HPV-16/18 by overall status was presented. The assay was performed on a sub-cohort of approximately 100 subjects per study group.
  • Number of Subjects With Any and Grade 3 Solicited Local Symptoms [ Time Frame: During the 7-day period (from the day of vaccination up to 6 subsequent days) following vaccination after each dose and across doses ]
    Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 50 millimetres (mm) of injection site.
  • Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms [ Time Frame: During the 7-day period (from the day of vaccination up to 6 subsequent days) following vaccination after each dose and across doses ]
    Assessed solicited general symptoms were arthralgia, fatigue, gastrointestinal symptoms, headache, myalgia, rash, temperature [defined as oral temperature equal to or above (≥) 37.5 degrees Celsius (°C)] and urticaria. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever above (>) 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination.
  • Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs) [ Time Frame: During the 30-day (from the day of vaccination up to 29 subsequent days) post-vaccination period ]
    An unsolicited AE covers 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 and 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. 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 assessed by the investigator as related to the vaccination.
  • Number of Subjects With Potentially Immune Mediated Diseases (pIMDs) [ Time Frame: From Day 0 up to Month 12 ]
    pIMDs were defined as a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.
  • Number of Subjects With Medically Significant Conditions (MSCs) [ Time Frame: From Day 0 up to Month 36 (throughout the study period) ]
    MSCs were defined as AEs prompting emergency room (ER) or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs not related to common diseases. Common diseases include: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities and injury.
  • Number of Subjects With Serious Adverse Events (SAEs) [ Time Frame: From Day 0 up to Month 36 (throughout the study period) ]
    SAEs assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity.
  • Number of Subjects With SAEs Related to the Investigational Product, to Study Participation, to GSK Concomitant Products or Any Fatal SAE [ Time Frame: From Day 0 up to Month 36 (throughout the study period) ]
    SAEs assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. Related = an event assessed by the investigator as causally related to the investigational product, to study participation or to GSK concomitant products.
  • Number of Subjects Reporting Pregnancies and Outcomes of Reported Pregnancies [ Time Frame: From Day 0 up to Month 36 (throughout the study period) ]
    Outcomes of pregnancies were Live infant NO apparent congenital anomaly (ACA), Live infant congenital anomaly (CA), Elective termination NO ACA, Elective termination CA, Ectopic pregnancy, Spontaneous abortion NO ACA, Stillbirth NO ACA, Stillbirth CA, Lost to follow up and Pregnancy ongoing.
  • Number of Subjects Using a Concomitant Medication Throughout the Study Period [ Time Frame: From Day 0 up to Month 36 (throughout the study period) following vaccination after each dose and across doses ]
    The number of subjects who have used any concomitant medication, as well as any antipyretic, any prophylactic antipyretic and any antibiotic.
  • Number of Subjects Completing the Vaccination Schedule [ Time Frame: From Day 0 up to Month 36 (throughout the study period) ]
    The number of subjects who have completed the three-dose vaccination schedule in all groups.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 27, 2011)
  • Anti-HPV-16/18 Seroconversion Rates Assessed by ELISA [ Time Frame: At Day 0 and Months 12, 18, 24 and 36 ]
  • Anti-HPV-16/18 antibody titres assessed by ELISA [ Time Frame: At Day 0 and Months 12, 18, 24 and 36 ]
  • Anti-HPV-16/18 seroconversion rates assessed by PBNA in a subset of subjects [ Time Frame: At Day 0 and Months 7, 12, 18, 24 and 36 ]
  • Anti-HPV-16/18 Antibody Titers Assessed by PBNA in a Subset of Subjects [ Time Frame: At Day 0 and Months 7, 12, 18, 24 and 36 ]
  • T-cell and B-cell-mediated immune responses in the sub-cohort for CMI [ Time Frame: At Day 0 and Months 7, 12, 24 and 36 ]
  • The occurrence and intensity of solicited local symptoms in all groups [ Time Frame: During the 7-day period (Days 0-6) following each vaccination ]
  • The occurrence and intensity and causal relationship to vaccination of solicited general symptoms in all groups [ Time Frame: During the 7-day period (Days 0-6) following each vaccination ]
  • The occurrence, intensity and causal relationship to vaccination of unsolicited symptoms in all groups [ Time Frame: During the 30-day period (Days 0-29) following each vaccination ]
  • The occurrence of potential immune-mediated diseases (pIMDs) in all groups [ Time Frame: From first vaccination to six months after the last vaccine dose (from Day 0 up to Month 12) ]
  • The occurrence of medically significant conditions (MSCs) in all groups [ Time Frame: Throughout the study period (From Day 0 up to Month 36) ]
  • The occurrence of serious adverse events (SAEs) in all groups [ Time Frame: Throughout the study period (From Day 0 up to Month 36) ]
  • The occurrence of SAEs related to the investigational product, to study participation, to GSK concomitant products or any fatal SAE in all groups [ Time Frame: Throughout the study period (from Day 0 up to Month 36) ]
  • The occurrence of pregnancies and pregnancy outcomes in all groups [ Time Frame: Throughout the study period (From Day 0 up to Month 36) ]
  • Use of concomitant medication (e.g. prophylactic use of antibiotics or antipyretics) [ Time Frame: Throughout the study period (From Day 0 up to Month 36) ]
  • Number of Subjects Completing the Vaccination Schedule [ Time Frame: Throughout the study period (From Day 0 up to Month 36) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Immunogenicity and Safety Study of GlaxoSmithKline Biologicals' Human Papillomavirus (HPV) Vaccine (GSK-580299) and Merck's Gardasil Vaccine When Administered According to Alternative 2-dose Schedules in 9-14 Year Old Females
Official Title  ICMJE Immunogenicity and Safety Study of GlaxoSmithKline Biologicals' HPV-16/18 L1 AS04 Vaccine and Merck's Gardasil Vaccine When Administered According to Alternative 2-dose Schedules in 9-14 Year Old Females
Brief Summary The purpose of this study is to evaluate the immunogenicity and the safety of Cervarix administered according to a 2-dose schedule at 0, 6 months compared to Gardasil, administered according to a 2-dose schedule at 0, 6 months or the standard 3-dose schedule of 0, 2, 6 months in 9-14 years old healthy females.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Infections, Papillomavirus
Intervention  ICMJE
  • Biological: Cervarix
    2 doses of 0.5 mL supplied as a liquid in individual pre-filled syringes to be administered intramuscularly in the deltoid muscle of the non-dominant arm at Day 0 and Month 6.
  • Biological: Gardasil
    2 or 3 doses of 0.5 mL supplied as a liquid in individual pre-filled syringes or vials to be administered intramuscularly in the deltoid muscle of the non-dominant arm at Day 0 and Month 6 (Gardasil 2 dose Group) or at Day 0, Month 2 and Month 6 (Gardasil 3 dose Group), respectively.
  • Drug: Placebo
    2 doses of 0.5 mL supplied as a liquid in individual pre-filled syringes to be administered intramuscularly in the deltoid muscle of the non-dominant arm at Month 2 to maintain blinding.
Study Arms  ICMJE
  • Experimental: Cervarix 2 dose Group
    Subjects who received 2 doses of Cervarix vaccine at Day 0 and Month 6 and 1 dose of placebo at Month 2. The vaccines were administered intramuscularly, in the deltoid muscle of the non-dominant upper arm.
    Interventions:
    • Biological: Cervarix
    • Drug: Placebo
  • Experimental: Gardasil 2 dose Group
    Subjects who received 2 doses of Gardasil vaccine at Day 0 and Month 6 and 1 dose of placebo at Month 2. The vaccines were administered intramuscularly, in the deltoid muscle of the non-dominant upper arm.
    Interventions:
    • Biological: Gardasil
    • Drug: Placebo
  • Experimental: Gardasil 3 dose Group
    Subjects who received 3 doses of Gardasil vaccine at Day 0 and at Months 2 and 6. The vaccines were administered intramuscularly, in the deltoid muscle of the non-dominant upper arm.
    Intervention: Biological: Gardasil
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 25, 2016)
1079
Original Estimated Enrollment  ICMJE
 (submitted: October 27, 2011)
1074
Actual Study Completion Date  ICMJE October 27, 2015
Actual Primary Completion Date October 27, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Subjects who the investigator believes can and will comply with the requirements of the protocol and subjects who the investigator believes their parent(s)/Legally Acceptable Representative(s) (LAR[s]) can and will comply with the requirements of the protocol.
  • A female between, and including, 9 and 14 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. In addition, if capable, the subject should sign and personally date a written informed assent.
  • Healthy subjects as established by medical history and clinical examination before entering into the study.
  • Female subjects of non-childbearing potential may be enrolled in the study.
  • Female subjects of childbearing potential may be enrolled in the study, if the subject:

    • has practiced adequate contraception for 30 days prior to vaccination, and
    • has a negative pregnancy test on the day of vaccination, and
    • has agreed to continue adequate contraception during the entire treatment period and for two months after completion of the vaccination series.

Exclusion Criteria:

  • Pregnant or breastfeeding.
  • A woman planning to become pregnant, likely to become pregnant (as determined by the investigator) or planning to discontinue contraceptive precautions during the vaccination phase of the study, i.e. up to two months after the last vaccine dose.
  • Previous vaccination against HPV or planned administration of another HPV vaccine during the study other than those foreseen in the protocol.
  • Child in care.
  • 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 36).
  • Chronic administration of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose.
  • History of allergic disease, suspected allergy or reactions likely to be exacerbated by any component of the study vaccines.
  • Cancer or autoimmune disease under treatment.
  • Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before each dose of vaccine. Administration of routine meningococcal, hepatitis B, hepatitis A, inactivated influenza, diphtheria/tetanus and/or diphtheria/tetanus-containing vaccine up to 8 days before each dose of study vaccine is allowed. Enrolment will be deferred until the subject is outside of specified window.
  • 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 vaccine components.
  • 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.
  • Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
  • Family history of congenital or hereditary immunodeficiency.
  • Major congenital defects or serious chronic illness.
  • 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.
  • Acute disease and/or fever at the time of enrolment.
  • Drug and/or alcohol abuse.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 9 Years to 14 Years   (Child)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   Hong Kong,   Singapore,   Sweden
Removed Location Countries Brazil
 
Administrative Information
NCT Number  ICMJE NCT01462357
Other Study ID Numbers  ICMJE 115411
2011-002035-26 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: IPD is available via the Clinical Study Data Request site (click on the link provided below).
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (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.
URL: https://www.clinicalstudydatarequest.com/Posting.aspx?ID=4513
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP