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

Cervical Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00543543
• Other study ID #: V503-001
• Secondary ID: 2007_538
• Status: Completed
• Phase: Phase 3
• Start date: September 24, 2007
• Est. completion date: July 7, 2016

Study information

• Verified date: October 2018
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14840
• Est. completion date: July 7, 2016
• Est. primary completion date: April 10, 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 16 Years to 26 Years

Eligibility

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.)

Related Conditions & MeSH terms

• Cervical Cancer
• Condylomata Acuminata
• Genital Warts
• Human Papillomavirus Infection
• Papillomavirus Infections
• Uterine Cervical Neoplasms
• Vaginal Cancer
• Vaginal Neoplasms
• Vulvar Cancer
• Vulvar Neoplasms

Intervention

Biological:
• Comparator: GARDASIL
GARDASIL (quadrivalent HPV [Types 6, 11, 16, and 18] L1 virus-like particle vaccine), 0.5 mL injection in 3 dose regimen
• Experimental: V503
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).

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

References & Publications (7)

Chen YH, Gesser R, Luxembourg A. A seamless phase IIB/III adaptive outcome trial: design rationale and implementation challenges. Clin Trials. 2015 Feb;12(1):84-90. doi: 10.1177/1740774514552110. Epub 2014 Oct 1. — View Citation

Huh WK, Joura EA, Giuliano AR, Iversen OE, de Andrade RP, Ault KA, Bartholomew D, Cestero RM, Fedrizzi EN, Hirschberg AL, Mayrand MH, Ruiz-Sternberg AM, Stapleton JT, Wiley DJ, Ferenczy A, Kurman R, Ronnett BM, Stoler MH, Cuzick J, Garland SM, Kjaer SK, B — View Citation

Joura EA, Giuliano AR, Iversen OE, Bouchard C, Mao C, Mehlsen J, Moreira ED Jr, Ngan Y, Petersen LK, Lazcano-Ponce E, Pitisuttithum P, Restrepo JA, Stuart G, Woelber L, Yang YC, Cuzick J, Garland SM, Huh W, Kjaer SK, Bautista OM, Chan IS, Chen J, Gesser R — View Citation

Luxembourg A, Bautista O, Moeller E, Ritter M, Chen J. Design of a large outcome trial for a multivalent human papillomavirus L1 virus-like particle vaccine. Contemp Clin Trials. 2015 May;42:18-25. doi: 10.1016/j.cct.2015.02.009. Epub 2015 Mar 3. — View Citation

Luxembourg A, Brown D, Bouchard C, Giuliano AR, Iversen OE, Joura EA, Penny ME, Restrepo JA, Romaguera J, Maansson R, Moeller E, Ritter M, Chen J. Phase II studies to select the formulation of a multivalent HPV L1 virus-like particle (VLP) vaccine. Hum Va — View Citation

Moreira ED Jr, Block SL, Ferris D, Giuliano AR, Iversen OE, Joura EA, Kosalaraksa P, Schilling A, Van Damme P, Bornstein J, Bosch FX, Pils S, Cuzick J, Garland SM, Huh W, Kjaer SK, Qi H, Hyatt D, Martin J, Moeller E, Ritter M, Baudin M, Luxembourg A. Safe — View Citation

Pitisuttithum P, Velicer C, Luxembourg A. 9-Valent HPV vaccine for cancers, pre-cancers and genital warts related to HPV. Expert Rev Vaccines. 2015;14(11):1405-19. doi: 10.1586/14760584.2015.1089174. Epub 2015 Sep 14. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Extension Study: Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Predose 4	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. This outcome measure applied to Cohort 1 participants only.	Month 60: predose 4 in the Extension Study (Cohort 1)
Other	Extension Study: Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Day 7 Postdose 4	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. This outcome measure applied to Cohort 1 participants only.	Month 60 + 1 week: Day 7 postdose 4 in the Extension Study (Cohort 1)
Other	Extension Study: Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Day 28 Postdose 4	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. This outcome measure applied to Cohort 1 participants only.	Month 61: 28 days postdose 4 in the Extension Study (Cohort 1)
Primary	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
Primary	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
Primary	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
Primary	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)
Primary	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
Primary	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
Primary	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)
Primary	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	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
Secondary	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