A Study to Evaluate the Safety, Immune Response, and Efficacy of Gardasil (V501, qHPV) in Mid-Adult Women (V501-019)

NCT00090220 | Completed Phase 3 Results DMC

• 2 other identifiers: V501-0192004_013
• Study Type: interventional
• Target: 3,819
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study was conducted to assess the safety, immunogenicity, efficacy and long-term effectiveness of a vaccine being evaluated for the prevention of human papillomavirus (HPV) infection and disease in mid-adult women.

Conditions

Healthy Adult Female Participants; Prevention; Papillomavirus Infection; Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18

Outcome Measures

Primary Outcomes (26)

• Incidence Rate of HPV 6/11/16/18 Related Persistent Infection, Genital Warts, VIN, VaIN, Vulvar Cancer, Vaginal Cancer, Cervical Dysplasia, Cervical AIS, and Cervical Cancer

  The four HPV types were determined by polymerase chain reaction (PCR) testing. VIN = vulvar intraepithelial neoplasia; VaIN = vaginal intraepithelial neoplasia; AIS = adenocarcinoma in situ.

  Up to 48 months (4 years) after the first dose of qHPV vaccine in the Base Study

• Number of Participants With Vaccine- or Placebo-Related Serious Adverse Events (SAEs) in the Base Study

  An adverse event (AE) is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an adverse event. A serious adverse event (SAE) is an AE that results in death, is life threatening, results in persistent or significant disability or incapacity, results in or prolongs a hospitalization, is a congenital anomaly or birth defect, is a cancer, or is an overdose. Vaccine-related SAEs are those deemed by the investigator to be definitely, probably, or possibly related to study vaccine.

  Up to Month 48 (up to 42 months after the third dose of qHPV vaccine in the Base Study)

• Number of Participants With Vaccine-Related SAEs After Vaccine Administration

  An adverse event (AE) is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an adverse event. A serious adverse event (SAE) is an AE that results in death, is life threatening, results in persistent or significant disability or incapacity, results in or prolongs a hospitalization, is a congenital anomaly or birth defect, is a cancer, or is an overdose. Vaccine-related SAEs are those deemed by the investigator to be definitely, probably, or possibly related to study vaccine.

  qHPV in Base Study: Up to Month 120; Placebo in Base Study: approximately Month 60 up to Month 120

• Number of Participants With an SAE Resulting in Death After Vaccine Administration

  An adverse event (AE) is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an adverse event. A serious adverse event (SAE) is an AE that results in death, is life threatening, results in persistent or significant disability or incapacity, results in or prolongs a hospitalization, is a congenital anomaly or birth defect, is a cancer, or is an overdose.

  qHPV in Base Study: Up to Month 120; Placebo in Base Study: approximately Month 60 up to Month 120

• Cumulative Incidence of HPV 6/11/16/18-related Cervical Intraepithelial Neoplasia (CIN) or Condyloma: Day 1 to Year 4

  The four HPV types were determined by PCR testing. Cumulative incidence probability is the probability of becoming an endpoint case at any time from Day 1 to Year 4, conditional on having been event-free at Day 1.

  Up to Month 48 (up to 42 months after the third dose of qHPV vaccine in the Base Study)

• Cumulative Incidence of HPV 6/11/16/18-related CIN or Condyloma: Year 4 to 8

  The four HPV types were determined by PCR testing. Cumulative incidence probability is the probability of becoming an endpoint case at any time from Year 4 to Year 8, conditional on having been event-free from Day 1 to Year 4. The analysis windows were cut at the exact time points, e.g., Year 4. Visits and events which occurred after Year 4 due to visit window or follow-up investigations are included in the Year 4 to Year 8 time interval.

  From 48 to 96 months (4 to 8 years) after the first dose of qHPV vaccine in the Base Study

• Cumulative Incidence of HPV 6/11/16/18-related CIN or Condyloma: Year 6 to 10

  The four HPV types were determined by PCR testing. Cumulative incidence probability is the probability of becoming an endpoint case at any time from Year 6 to Year 10, conditional on having been event-free from Day 1 to Year 6.

  From 72 to 120 months (6 to 10 years) after the first dose of qHPV vaccine in the Base Study

• Incidence Rate of HPV 6/11/16/18-related CIN or Condyloma (Secondary Analysis): Day 1 to Year 4

  The four HPV types were determined by PCR testing.

  Up to Month 48 (up to 42 months after the third dose of qHPV vaccine in the Base Study)

• Incidence Rate of HPV 6/11/16/18-related CIN or Condyloma (Secondary Analysis): Year 4 to 8

  The four HPV types were determined by PCR testing. The analysis windows were cut at the exact time points, e.g., Year 4. Visits and events which occurred after Year 4 due to visit window or follow-up investigations are included in the Year 4 to Year 8 time interval.

  From 48 to 96 months (4 to 8 years) after the first dose of qHPV vaccine in the Base Study

• Incidence Rate of HPV 6/11/16/18-related CIN or Condyloma (Secondary Analysis): Year 6 to 10

  The four HPV types were determined by PCR testing.

  From 72 to 120 months (6 to 10 years) after the first dose of qHPV vaccine in the Base Study

• Geometric Mean Titer for Anti-HPV Type 6, 11, 16, and 18 Antibody at 1 Month Postdose 3 in the Base Study

  Serum antibodies to the HPV Types were determined by Competitive Luminex Immunoassay (cLIA). Geometric Mean Titers (GMT) are reported in milli-Merck Units/mL (mMU/mL). This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 7 (1 month after the third dose of qHPV vaccine in the Base Study)

• Geometric Mean Titer for Anti-HPV Type 6, 11, 16, and 18 Antibody at 6 Months Postdose 3 in the Base Study

  Serum antibodies to the HPV Types were determined by Competitive Luminex Immunoassay (cLIA). Geometric Mean Titers (GMT) are reported in milli-Merck Units/mL (mMU/mL). This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 12 (6 months after the third dose of qHPV vaccine in the Base Study)

• Geometric Mean Titer for Anti-HPV Type 6, 11, 16, and 18 Antibody at 18 Months Postdose 3 in the Base Study

  Serum antibodies to the HPV Types were determined by Competitive Luminex Immunoassay (cLIA). Geometric Mean Titers (GMT) are reported in milli-Merck Units/mL (mMU/mL). This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 24 (18 months after the third dose of qHPV vaccine in the Base Study)

• Geometric Mean Titer for Anti-HPV Type 6, 11, 16, and 18 Antibody at 30 Months Postdose 3 in the Base Study

  Serum antibodies to the HPV Types were determined by Competitive Luminex Immunoassay (cLIA). Geometric Mean Titers (GMT) are reported in milli-Merck Units/mL (mMU/mL). This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 36 (30 months after the third dose of qHPV vaccine in the Base Study)

• Geometric Mean Titer for Anti-HPV Type 6, 11, 16, and 18 Antibody at 42 Months Postdose 3 in the Base Study

  Serum antibodies to the HPV Types were determined by Competitive Luminex Immunoassay (cLIA). Geometric Mean Titers (GMT) are reported in milli-Merck Units/mL (mMU/mL). This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 48 (42 months after the third dose of qHPV vaccine in the Base Study)

• Geometric Mean Titer for Anti-HPV Type 6, 11, 16, and 18 Antibody at 66 Months Postdose 3 in the Base Study

  Serum antibodies to the HPV Types were determined by Competitive Luminex Immunoassay (cLIA). Geometric Mean Titers (GMT) are reported in milli-Merck Units/mL (mMU/mL). This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 72 (66 months after the third dose of qHPV vaccine in the Base Study)

• Geometric Mean Titer for Anti-HPV Type 6, 11, 16, and 18 Antibody at 90 Months Postdose 3 in the Base Study

  Serum antibodies to the HPV Types were determined by Competitive Luminex Immunoassay (cLIA). Geometric Mean Titers (GMT) are reported in milli-Merck Units/mL (mMU/mL). This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 96 (90 months after the third dose of qHPV vaccine in the Base Study)

• Geometric Mean Titer for Anti-HPV Type 6, 11, 16, and 18 Antibody at 114 Months Postdose 3 in the Base Study

  Serum antibodies to the HPV Types were determined by Competitive Luminex Immunoassay (cLIA). Geometric Mean Titers (GMT) are reported in milli-Merck Units/mL (mMU/mL). This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 120 (114 months after the third dose of qHPV vaccine in the Base Study)

• Percentage of Participants Seropositive for Anti-HPV Antibody at 1 Month Postdose 3 in the Base Study

  Serum antibodies to HPV Types 6, 11, 16, and 18 were determined by Competitive Luminex Immunoassay (cLIA). The seropositive thresholds (in mMU/mL) were \>20 for Type 6, \>16 for Type 11, \>20 for Type 16, and \>24 for Type 18. This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 7 (1 month after the third dose of qHPV vaccine in the Base Study)

• Percentage of Participants Seropositive for Anti-HPV Antibody at 6 Months Postdose 3 in the Base Study

  Serum antibodies to HPV Types 6, 11, 16, and 18 were determined by Competitive Luminex Immunoassay (cLIA). The seropositive thresholds (in mMU/mL) were \>20 for Type 6, \>16 for Type 11, \>20 for Type 16, and \>24 for Type 18. This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 12 (6 months after the third dose of qHPV vaccine in the Base Study)

• Percentage of Participants Seropositive for Anti-HPV Antibody at 18 Months Postdose 3 in the Base Study

  Serum antibodies to HPV Types 6, 11, 16, and 18 were determined by Competitive Luminex Immunoassay (cLIA). The seropositive thresholds (in mMU/mL) were \>20 for Type 6, \>16 for Type 11, \>20 for Type 16, and \>24 for Type 18. This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 24 (18 months after the third dose of qHPV vaccine in the Base Study)

• Percentage of Participants Seropositive for Anti-HPV Antibody at 30 Months Postdose 3 in the Base Study

  Serum antibodies to HPV Types 6, 11, 16, and 18 were determined by Competitive Luminex Immunoassay (cLIA). The seropositive thresholds (in mMU/mL) were \>20 for Type 6, \>16 for Type 11, \>20 for Type 16, and \>24 for Type 18. This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 36 (30 months after the third dose of qHPV vaccine in the Base Study)

• Percentage of Participants Seropositive for Anti-HPV Antibody at 42 Months Postdose 3 in the Base Study

  Serum antibodies to HPV Types 6, 11, 16, and 18 were determined by Competitive Luminex Immunoassay (cLIA). The seropositive thresholds (in mMU/mL) were \>20 for Type 6, \>16 for Type 11, \>20 for Type 16, and \>24 for Type 18. This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 48 (42 months after the third dose of qHPV vaccine in the Base Study)

• Percentage of Participants Seropositive for Anti-HPV Antibody at 66 Months Postdose 3 in the Base Study

  Serum antibodies to HPV Types 6, 11, 16, and 18 were determined by Competitive Luminex Immunoassay (cLIA). The seropositive thresholds (in mMU/mL) were \>20 for Type 6, \>16 for Type 11, \>20 for Type 16, and \>24 for Type 18. This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 72 (66 months after the third dose of qHPV vaccine in the Base Study)

• Percentage of Participants Seropositive for Anti-HPV Antibody at 90 Months Postdose 3 in the Base Study

  Serum antibodies to HPV Types 6, 11, 16, and 18 were determined by Competitive Luminex Immunoassay (cLIA). The seropositive thresholds (in mMU/mL) were \>20 for Type 6, \>16 for Type 11, \>20 for Type 16, and \>24 for Type 18. This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 96 (96 months after the third dose of qHPV vaccine in the Base Study)

• Percentage of Participants Seropositive for Anti-HPV Antibody at 114 Months Postdose 3 in the Base Study

  Serum antibodies to HPV Types 6, 11, 16, and 18 were determined by Competitive Luminex Immunoassay (cLIA). The seropositive thresholds (in mMU/mL) were \>20 for Type 6, \>16 for Type 11, \>20 for Type 16, and \>24 for Type 18. This Outcome Measure evaluated age-specific immunogenicity responses, and applied only to participants who received qHPV in the Base Study.

  Month 120 (114 months after the third dose of qHPV vaccine in the Base Study)

Secondary Outcomes (8)

• Incidence Rate of HPV 6/11 Related Persistent Infection, Genital Warts, VIN, VaIN, Vulvar Cancer, Vaginal Cancer, Cervical Dysplasia, Cervical AIS, and Cervical Cancer

  Up to Month 48 (up to 42 months after the third dose of qHPV vaccine in the Base Study)

• Cumulative Incidence of HPV 6/11-related Condyloma: Day 1 to Year 4

  Up to 48 months (4 years) after the first dose of qHPV vaccine or placebo in the Base Study

• Cumulative Incidence of HPV 6/11-related Condyloma: Year 4 to Year 8

  From 48 to 96 months (4 to 8 years) after the first dose of qHPV vaccine in the Base Study

• Cumulative Incidence of HPV 6/11-related Condyloma: Year 6 to Year 10

  From 72 to 120 months (6 to 10 years) after the first dose of qHPV vaccine in the Base Study

• Incidence Rate of HPV 6/11-related Condyloma (Secondary Analysis): Day 1 to Year 4

  Up to 48 months (4 years) after the first dose of qHPV vaccine or placebo in the Base Study

Other Outcomes (7)

• Incidence Rate of HPV 16/18 Related Persistent Infection, Genital Warts, VIN, VaIN, Vulvar Cancer, Vaginal Cancer, Cervical Dysplasia, Cervical AIS, and Cervical Cancer

  Up to Month 48 (up to 42 months after the third dose of qHPV vaccine in the Base Study)

• Cumulative Incidence of HPV 16/18-related CIN 2 or Worse: Day 1 to Year 4

  Up to Month 48 (up to 42 months after the third dose of qHPV vaccine in the Base Study)

• Cumulative Incidence of HPV 16/18-related CIN 2 or Worse: Year 4 to 8

  From 48 to 96 months (4 to 8 years) after the first dose of qHPV vaccine in the Base Study

Study Arms (2)

qHPV Vaccine in Base Study

EXPERIMENTAL

Participants received blinded qHPV vaccination at Day 1, Month 2, and Month 6 of the Base Study

Biological: Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine

Placebo in Base Study

PLACEBO COMPARATOR

Participants received blinded placebo at Day 1, Month 2, and Month 6 in the Base Study. They were eligible to receive open-label qHPV vaccine in Extension 1

Biological: Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine; Biological: Comparator: Placebo

Interventions

Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine BIOLOGICAL

qHPV intramuscular injection in three 0.5 mL doses over 6 months in the Base Study or EXT1

Placebo in Base Study; qHPV Vaccine in Base Study

Comparator: Placebo BIOLOGICAL

Placebo intramuscular injection in three 0.5 mL doses over 6 months.

Placebo in Base Study

Eligibility Criteria

• Age: 24 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• No history of genital warts, vulvar intraepithelial neoplasia (VIN), or vaginal intraepithelial neoplasia (VaIN)
• Not pregnant and agrees to use effective contraception through Month 7 of the study
• Additional criteria applied

You may not qualify if:

• Pregnant
• Concurrently enrolled in a clinical study involving collection of cervical specimens
• Previously received any HPV vaccine
• History of severe allergic reaction that required medical intervention
• Received any immune globulin or blood-derived products within 3 months prior to the first study injection
• History of splenectomy, known immune disorders, or receiving immunosuppressives
• Immunocompromised or diagnosed with human immunodeficiency virus (HIV) infection
• Known thrombocytopenia or any coagulation disorders that could contraindicate intramuscular injections
• History of recent or ongoing alcohol or drug abuse
• Prior treatment for genital warts, VIN, or VaIN
• History of cervical disease (ie, surgical treatment for cervical lesions)
• Hysterectomy

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (8)

• Munoz N, Manalastas R Jr, Pitisuttithum P, Tresukosol D, Monsonego J, Ault K, Clavel C, Luna J, Myers E, Hood S, Bautista O, Bryan J, Taddeo FJ, Esser MT, Vuocolo S, Haupt RM, Barr E, Saah A. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomised, double-blind trial. Lancet. 2009 Jun 6;373(9679):1949-57. doi: 10.1016/S0140-6736(09)60691-7. Epub 2009 Jun 1.

  PMID: 19493565 RESULT

• Velicer C, Zhu X, Vuocolo S, Liaw KL, Saah A. Prevalence and incidence of HPV genital infection in women. Sex Transm Dis. 2009 Nov;36(11):696-703. doi: 10.1097/OLQ.0b013e3181ad25ff.

  PMID: 19652630 RESULT

• Castellsague X, Munoz N, Pitisuttithum P, Ferris D, Monsonego J, Ault K, Luna J, Myers E, Mallary S, Bautista OM, Bryan J, Vuocolo S, Haupt RM, Saah A. End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24-45 years of age. Br J Cancer. 2011 Jun 28;105(1):28-37. doi: 10.1038/bjc.2011.185. Epub 2011 May 31.

  PMID: 21629249 RESULT

• Luna J, Plata M, Gonzalez M, Correa A, Maldonado I, Nossa C, Radley D, Vuocolo S, Haupt RM, Saah A. Long-term follow-up observation of the safety, immunogenicity, and effectiveness of Gardasil in adult women. PLoS One. 2013 Dec 31;8(12):e83431. doi: 10.1371/journal.pone.0083431. eCollection 2013.

  PMID: 24391768 RESULT

• Matys K, Mallary S, Bautista O, Vuocolo S, Manalastas R, Pitisuttithum P, Saah A. Mother-infant transfer of anti-human papillomavirus (HPV) antibodies following vaccination with the quadrivalent HPV (type 6/11/16/18) virus-like particle vaccine. Clin Vaccine Immunol. 2012 Jun;19(6):881-5. doi: 10.1128/CVI.00002-12. Epub 2012 Apr 18.

  PMID: 22518014 RESULT

• Garland SM, Ault KA, Gall SA, Paavonen J, Sings HL, Ciprero KL, Saah A, Marino D, Ryan D, Radley D, Zhou H, Haupt RM, Garner EIO; Quadrivalent Human Papillomavirus Vaccine Phase III Investigators. Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/16/18 vaccine: a combined analysis of five randomized controlled trials. Obstet Gynecol. 2009 Dec;114(6):1179-1188. doi: 10.1097/AOG.0b013e3181c2ca21.

  PMID: 19935017 RESULT

• Doshi P, Bourgeois F, Hong K, Jones M, Lee H, Shamseer L, Spence O, Jefferson T. Adjuvant-containing control arms in pivotal quadrivalent human papillomavirus vaccine trials: restoration of previously unpublished methodology. BMJ Evid Based Med. 2020 Dec;25(6):213-219. doi: 10.1136/bmjebm-2019-111331. Epub 2020 Mar 17.

  PMID: 32184277 DERIVED

• Castellsague X, Ault KA, Bosch FX, Brown D, Cuzick J, Ferris DG, Joura EA, Garland SM, Giuliano AR, Hernandez-Avila M, Huh W, Iversen OE, Kjaer SK, Luna J, Monsonego J, Munoz N, Myers E, Paavonen J, Pitisuttihum P, Steben M, Wheeler CM, Perez G, Saah A, Luxembourg A, Sings HL, Velicer C. Human papillomavirus detection in cervical neoplasia attributed to 12 high-risk human papillomavirus genotypes by region. Papillomavirus Res. 2016 Dec;2:61-69. doi: 10.1016/j.pvr.2016.03.002. Epub 2016 Mar 14.

  PMID: 29074187 DERIVED

MeSH Terms

Conditions

Papillomavirus Infections

Interventions

Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18

Condition Hierarchy (Ancestors)

Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Communicable Diseases; Infections; DNA Virus Infections; Virus Diseases; Tumor Virus Infections; Genital Diseases; Urogenital Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Vaccines, Combined; Vaccines; Biological Products; Complex Mixtures; Papillomavirus Vaccines; Viral Vaccines

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Monitor

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2004
• First Posted: August 27, 2004
• Study Start: June 16, 2004
• Primary Completion: May 21, 2009
• Study Completion: November 12, 2015
• Last Updated: April 21, 2017
• Results First Posted: February 1, 2010

Record last verified: 2017-03

Data Sharing

• IPD Sharing: Will share