Study to Evaluate the Immune Response and Safety of GSK Biologicals' HPV Vaccine in Healthy Women Aged 18-35 Years

NCT00345878CompletedPHASE3INTERVENTIONAL

Summary

Human papillomavirus infection has clearly been recognized as the cause of cervical cancer. The infection of the cervix by certain oncogenic types of HPV, if not cleared, can lead to cervical cancer in women. This study will evaluate the immunogenicity and safety of the HPV-16/18 L1 VLP AS04 vaccine. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Key Facts

Lead Sponsor

GlaxoSmithKline

Enrollment

271

Start Date

2006-09-25

Completion Date

2007-12-21

Study Type

INTERVENTIONAL

Official Title

Phase 3, Open, Age-stratified Study to Assess Immunogenicity and Safety of GSK Biologicals' HPV-16/18 Vaccine Administered Intramuscularly According to 3-dose Schedule (0,1,6 Months) in Healthy Female Subjects Aged 15 - 55 Years and Long Term Follow-up

Interventions

PlaceboHPV-16/18 L1 VLP AS04 (Cervarix TM)

Conditions

InfectionsPapillomavirus

Eligibility

Age Range

18 Years – 35 Years

Sex

FEMALE

Inclusion Criteria:

* Subjects who the investigator believes that they can and will comply with the requirements of the protocol should be enrolled in the study.
* A female from Malaysia between, and including, 18 and 35 years of age at the time of the first vaccination.
* Written informed consent obtained from the subject.
* Healthy subjects as established by medical history and clinical examination before entering into the study.
* Subjects must have a negative urine pregnancy test.
* Subjects of childbearing potential at the time of study entry must be abstinent or must be using an effective method of birth control for 30 days prior to vaccination and must agree to continue such precautions for two months after completion of the vaccination series.

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.
* Chronic administration (defined as more than 14 days) 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 the first dose of vaccine. Administration of routine vaccines up to 8 days before the first dose of study vaccine is allowed. Enrolment will be deferred until the subject is outside of specified window.
* previous administration of components of the investigational vaccine
* Previous vaccination against HPV or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period.
* Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
* History of allergic disease or reactions likely to be exacerbated by any component of the vaccine(s).
* Hypersensitivity to latex.
* Acute disease at the time of enrolment.
* Known acute or chronic, clinically significant neurologic, pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests.
* History of chronic condition(s) requiring treatment.
* Administration of immunoglobulins and/or any blood product within three months preceding the first dose of study vaccine(s) or planned administration during the study period. Enrolment will be deferred until the subject is outside of specified window.
* Pregnant or lactating female.
* Female planning to become pregnant or planning to discontinue contraceptive precautions.

Outcome Measures

Primary Outcomes

Number of Subjects Who Seroconverted for Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies

Seroconversion is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subjects seronegative before vaccination. Cut-off values assessed include 8 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL) for anti-HPV-16 antibodies and 7 EL.U/mL for anti-HPV-18 antibodies.

Time frame: At Month 7

Secondary Outcomes

Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Antibodies

Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL).

Time frame: At Month 0 and Month 7

Number of Subjects Reporting Solicited Symptoms

Solicited local symptoms assessed include pain, redness and swelling. Solicited general symptoms assessed include arthralgia, fatigue, fever, gastro-intestinal symptoms, headache, myalgia, rash and urticaria.

Time frame: During the 7 days after each vaccination

Number of Subjects Reporting Unsolicited Adverse Events (AEs)

Unsolicited adverse event = Any adverse event (AE) reported in addition to those solicited during the clinical study. Also any "solicited" symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited adverse event.

Time frame: Within 30 days after any vaccination

Number of Subjects Reporting Unsolicited Adverse Events as New Onset Chronic Diseases (NOCDs) and Other Medically Significant Adverse Events (AEs)

NOCDs assessed include e.g. autoimmune disorders, asthma, type I diabetes, allergies,... Medically significant AEs assessed include AEs prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or SAEs that are not related to common diseases.

Time frame: Throughout the study period (up to Month 7)

Number of Subjects Reporting Serious Adverse Events

Serious adverse events assessed include medical occurrences that results in death, is 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.

Time frame: Throughout the study period (up to Month 7)

Locations

GSK Investigational Site, Kerajaan Persekutuan Putrajaya, Malaysia

GSK Investigational Site, Kuala Lumpur, Malaysia

Linked Papers

2025-11-24

Human papillomavirus (HPV) vaccination for the prevention of cervical cancer and other HPV-related diseases: a network meta-analysis

Cervical cancer is the fourth most common cause of cancer-related death amongst females worldwide. Persistent infection with high-risk human papillomavirus (HPV) is the key factor in cervical cancer development. HPV vaccines aim to prevent cancer by generating antibodies against HPV infection. To evaluate the safety and efficacy of HPV vaccines, in females and males, to prevent cervical cancer and other HPV-related diseases, in standard (pairwise) and network meta-analysis (NMA) of randomised controlled trials. On 10 January 2022, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase. We searched Epistemonikos, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, the Health Technology Assessment database and vaccine manufacturer websites, and we checked reference lists from other relevant systematic reviews. We applied for Clinical Study Reports (CSRs) from the European Medicines Agency. An update search of electronic databases was done on 18 September 2024. We included randomised controlled trials (RCTs) regardless of language or publication status, assessing HPV vaccines pre-qualified by the World Health Organization (WHO) (Cervarix, Gardasil, Gardasil-9 and Cecolin). We used methods recommended by Cochrane. We primarily used CSRs to collect data, and we included outcome data irrespective of participants' baseline HPV infection or serostatus. We assessed risk of bias using the Cochrane tool (RoB 2). All outcomes were dichotomous, and we estimated risk ratios (RR) with 95% confidence intervals (CI). We used pairwise analysis for all outcomes. Where data were available, we carried out NMA for critical outcomes for networks in females and males in three age groups, ranking the vaccines using surface under the cumulative ranking curve (SUCRA) and mean ranks. We assessed the certainty of evidence using the GRADE approach. We included 60 individual studies with 157,414 participants ranging in follow-up from seven months to 11 years. Few participants were under 15. There were no studies for males under 15 years and males over 25 years. We obtained CSRs for 33 of the included studies. We assessed the risk of bias as low to 'some concerns' for the critical outcomes. Cancer and pre-cancer outcomes The studies were not of sufficient duration for cancers to develop. Four studies reported on cancer. No cancers were detected. Critical pre-cancer outcomes were reported in 15- to 25-year-old populations by 11 studies and in > 25-year-old females by three studies with up to seven years follow-up. None were reported in the under 15 years age group. In 15- to 25-year-old females, there was a reduction in CIN2+ irrespective of HPV type after six years (RR 0.70, 95% CI 0.56 to 0.88) (moderate-certainty) and a larger reduction in CIN2+ from vaccine-matched HPV types after six years (RR 0.40, 95% CI 0.30 to 0.54) (moderate-certainty). In females over 25 years old, there was little to no difference between Cervarix and Gardasil compared with control (moderate-certainty). There was no evidence on CIN2+ irrespective of HPV type from studies assessing Cecolin, or from studies assessing different dose schedules. In 15- to 25-year-old females, there was a slight reduction in vaccine-matched HPV-type high-grade vulval (VIN) or vaginal (VaIN) intraepithelial neoplasia following vaccination with Gardasil or Gardasil-9 (moderate-certainty). The NMA found a slight reduction of 1 case per 1000 following Gardasil (RR 0.21, 95% CI 0.1 to 0.45) and 0 cases per 1000 following Gardasil-9 (RR 0.16, 95% CI 0.05 to 0.51). Little to no difference was found in the NMA for Cervarix compared with control (RR 0.28, 95% CI 0.06 to 1.37), or for Cervarix, Gardasil and Gardasil-9 compared to each other. There was a reduction in high-grade anal intraepithelial neoplasia (AIN) irrespective of HPV type in the Gardasil group in one study in men who have sex with men (RR 0.75, 95% CI 0.53 to 1.07) (low-certainty). For both high-grade penile intraepithelial neoplasia (PeIN) irrespective of HPV type and vaccine-matched HPV-type high-grade PeIN, little to no difference per 1000 participants was reported in the Gardasil group in one study with 3880 participants at 36 months follow-up (RR 1.00, 95% CI 0.20 to 4.93) (low-certainty). Serious adverse events In a pairwise analysis of serious adverse events in 39 studies across all vaccine types with 97,272 participants, there was little to no difference in the HPV vaccine groups compared with the control group at up to 72 months follow-up (RR 0.99, 95% CI 0.94 to 1.04) (high-certainty). Treatment rates for HPV-related pre-invasive disease In pairwise analysis of five studies with 38,606 participants, there were 12 fewer people that needed to seek treatment per 1000 participants (95% CI 5 to 17 fewer per 1000) in the HPV vaccine groups compared with the control group rate at up to 84 months follow-up (RR 0.76, 95% CI 0.65 to 0.89) (moderate-certainty). Anogenital warts In pairwise analysis of three studies with 21,271 participants, there were 25 fewer cases of anogenital warts irrespective of HPV type per 1000 participants (95% CI 22 to 28 fewer per 1000) in the HPV vaccine groups compared with the control group rate at up to 48 months follow-up (RR 0.38, 95% CI 0.32 to 0.46) (high-certainty). In the NMA for females 15 to 25 years old, Gardasil-9 was most likely to reduce the risk of developing anogenital warts. The evidence in this network meta-analysis of HPV vaccines is based on extensive searches and analyses. There is evidence from randomised controlled trials that HPV vaccination reduces the risk of pre-cancerous outcomes such as CIN2+ and anogenital warts. No data were available for cervical cancer or other cancer outcomes, and no data on pre-cancer outcomes were available for vaccination under age 15 years. There were no safety concerns noted in the studies.

Linked Investigators

Hanna Bergman