Broad Spectrum HPV (Human Papillomavirus) Vaccine Study in 16-to 26-Year-Old Women (V503-001)

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the safety, efficacy, and immunogenicity of V503 in comparison to GARDASIL. The primary hypotheses tested in the study were 1) V503 administered to 16- to 26-year-old adolescents and young women is generally well-tolerated, 2) V503 reduces combined incidence of Human Papillomavirus (HPV) Type 31/33/45/52/58-related disease compared with GARDASIL, and 3) V503 induces non-inferior geometric mean titers for HPV Type 6/11/16/18 antibodies compared with GARDASIL.

Detailed Description
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The study included a dose-finding evaluation of a 3-dose regimen of V503 and GARDASIL, a safety/efficacy evaluation of a 3-dose regimen of the selected V503 dose formulation and GARDASIL, and an extension consisting of 2 substudies: an evaluation of immune memory in participants receiving a fourth vaccination with V503 (Cohort 1), and an opportunity for participants who received GARDASIL in the Base Study to receive a 3-dose regimen of V503 (Cohort 2).

Official Title
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A Randomized, International, Double-Blinded (With In-House Blinding), Controlled With GARDASIL, Dose-Ranging, Tolerability, Immunogenicity, and Efficacy Study of a Multivalent Human Papillomavirus (HPV) L1 Virus-Like Particle (VLP) Vaccine Administered to 16- to 26- Year-Old Women

Conditions
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Cervical Cancer, Vulvar Cancer, Vaginal Cancer, Genital Warts, Human Papillomavirus Infection

Intervention / Treatment
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* Biological: Comparator: GARDASIL
* Biological: Experimental: V503


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female between 16- to 26-years-old Has never had Pap testing or has only had normal Pap (Papanicolaou) test results For the immune memory substudy in the extension (Cohort 1): was randomized to V503 in the base study and was in the per-protocol immunogenicity population for ≥1 HPV type For the 3-dose V503 vaccination substudy in the extension (Cohort 2): was randomized to GARDASIL in the base study and received ≥1 dose of GARDASIL Exclusion Criteria: History of an abnormal cervical biopsy result History of a positive test for HPV History of external genital/vaginal warts Currently a user of any illegal drugs or an alcohol abuser History of severe allergic reaction that required medical attention Are pregnant Received marketed HPV vaccine or participated in an HPV trial Currently enrolled in a clinical trial Currently has or has a history of certain medical conditions or is currently taking or has taken certain medications (details will be discussed at the time of consent.)

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 26 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low-dose V503<br>V503 (9-Valent Human Papillomavirus [HPV] Vaccine) low-dose 0.5 mL injection in a 3-dose regimen in the base study. | Biological: Experimental: V503<br>* V503 (9-valent HPV [Types 6, 11, 16, 18, 31, 33, 45, 52, and 58] L1 virus-like particle vaccine), 0.5 mL injection in 3 dose regimen (and a fourth injection for Cohort 1 only).<br>|
| Experimental: Mid-dose V503<br>V503 (9-Valent HPV Vaccine) mid-dose 0.5 mL injection in a 3-dose regimen in the base study. A subset of participants (Cohort 1) received a fourth V503 mid-dose vaccination in the extension study. | Biological: Experimental: V503<br>* V503 (9-valent HPV [Types 6, 11, 16, 18, 31, 33, 45, 52, and 58] L1 virus-like particle vaccine), 0.5 mL injection in 3 dose regimen (and a fourth injection for Cohort 1 only).<br>|
| Experimental: High-dose V503<br>V503 (9-Valent HPV Vaccine) high-dose 0.5 mL injection in a 3-dose regimen in the base study. | Biological: Experimental: V503<br>* V503 (9-valent HPV [Types 6, 11, 16, 18, 31, 33, 45, 52, and 58] L1 virus-like particle vaccine), 0.5 mL injection in 3 dose regimen (and a fourth injection for Cohort 1 only).<br>|
| Active Comparator: Gardasil<br>Gardasil (4-Valent HPV Vaccine) 0.5 mL injection in a 3-dose regimen in the base study. Participants (Cohort 2) were offered the V503 mid-dose 3-dose regimen in the extension study. | Biological: Comparator: GARDASIL<br>* GARDASIL (quadrivalent HPV [Types 6, 11, 16, and 18] L1 virus-like particle vaccine), 0.5 mL injection in 3 dose regimen<br>Biological: Experimental: V503<br>* V503 (9-valent HPV [Types 6, 11, 16, 18, 31, 33, 45, 52, and 58] L1 virus-like particle vaccine), 0.5 mL injection in 3 dose regimen (and a fourth injection for Cohort 1 only).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Disease (Test of Hypothesis) | HPV Type 31/33/45/52/58-related high-grade Cervical Intraepithelial Neoplasia (CIN 2/3), Adenocarcinoma in Situ (AIS), Invasive Cervical Carcinoma, high-grade Vulvar Intraepithelial Neoplasia (VIN 2/3), high-grade Vaginal Intraepithelial Neoplasia (VaIN 2/3), vulvar cancer, or vaginal cancer were determined by clinical/pathologic criteria and positive Polymerase Chain Reaction (PCR) assay for virus subtype. This outcome measure reports data based on the protocol-specified plan of conducting hypothesis testing when at least 30 cases had accumulated. The cutoff date for this analysis was 10 April 2013. Disease incidence was defined as the number of primary efficacy cases per 10,000 person-years of follow-up in a treatment arm. | From Day 1 until >=30 cases accumulate, up to Month 54 in the base study | 
| Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Disease (End-of-study Update) | HPV Type 31/33/45/52/58-related high-grade Cervical Intraepithelial Neoplasia (CIN 2/3), Adenocarcinoma in Situ (AIS), Invasive Cervical Carcinoma, high-grade Vulvar Intraepithelial Neoplasia (VIN 2/3), high-grade Vaginal Intraepithelial Neoplasia (VaIN 2/3), vulvar cancer, or vaginal cancer were determined by clinical/pathologic criteria and positive Polymerase Chain Reaction (PCR) assay for virus subtype. This outcome measure reports cumulative study data through 10 March 2014. Disease incidence was defined as the number of primary efficacy cases per 10,000 person-years of follow-up in a treatment arm. | Up to Month 54 in the base study | 
| Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58 | Serum antibodies to HPV types 6/11/16/18/31/33/45/52/58 were measured with a Competitive Luminex Immunoassay. Titers are reported in milli Merck Units/mL. Statistical analysis was performed only for HPV types contained in both vaccines. | 4 weeks postdose 3 in the base study | 
| Base Study: Percentage of Participants With One or More Adverse Event | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. | Up to Month 7 (low- and high-dose V503) or up to Month 54 (mid-dose V503 and Gardasil) | 
| Base Study: Percentage of Participants With One or More Injection-site Adverse Event | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. AEs such as redness, swelling, and pain/tenderness/soreness at the injection site were recorded. | Up to Day 5 after any vaccination | 
| Base Study: Percentage of Participants With One or More Non-injection-site (Systemic) Adverse Event | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. Systemic AEs were those not categorized as injection-site AEs. | Up to Day 15 after any vaccination | 
| Base Study: Percentage of Participants With One or More Vaccine-related Adverse Event | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. An AE that is judged by the investigator to be definitely related, probably related, or possibly related to the study drug is defined as a vaccine-related AE. | Up to Month 7 (low- and high-dose V503) or up to Month 54 (mid-dose V503 and Gardasil) | 
| Base Study: Percentage of Participants With Study Medication Withdrawn Due to an Adverse Event | An adverse event is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an adverse event. | Up to Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Persistent Infection | Combined Incidence of HPV Type 31/33/45/52/58-related persistent infection as determined by clinical/pathologic criteria and positive Polymerase Chain Reaction (PCR) assay for virus subtype. Persistent infection was defined as infection detected in samples from >=2 consecutive visits 6 months (+/-1 month visit window) or longer apart. Incidence was defined as the number of cases of persistent infection per 10,000 person-years of follow-up in a treatment arm. | Up to Month 54 in the base study | 
| Base Study: Percentage of Participants Who Are Seropositive for HPV Types 6/11/16/18/31/33/45/52/58 | Serum antibodies to HPV types were measured with a Competitive Luminex Immunoassay. The serostatus cutoffs (milli Merck U/mL) for HPV types were as follows: HPV Type 6: ≥30; HPV Type 11: ≥16; HPV Type 16: ≥20; HPV Type 18: ≥24; HPV Type 31: ≥10; HPV Types 33, 45, 52, and 58: ≥8. | 4 weeks postdose 3 |