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

Study Overview
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Brief Summary
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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.

Detailed Description
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The Base study vaccination period (V501-019) encompassed Day 1 through Month 7, during which time participants received randomly assigned, blinded Gardasil™ (V501, qHPV vaccine) or placebo at Day 1, Month 2 and Month 6. The Base study follow-up period continued through approximately Month 48. The base study was extended in protocol V501-019-10 (EXT1). Participants who received placebo and participants who received only 1 dose of qHPV vaccine in the Base Study were offered a complete, open-label, 3-dose qHPV vaccine regimen (administered at EXT1 Day 1, Month 2 and Month 6). Participants who received only 2 doses of qHPV vaccine in the base study were offered a single additional dose of qHPV vaccine (administered at EXT1 Day 1). Participants were followed to EXT1 Month 7. A Long Term Follow-Up (LTFU) extension study V501-019-21 (EXT2) was added to observe the long term safety, effectiveness, and immunogenicity of qHPV vaccine in approximately 1,600 women who participated in the Base Study at sites in Colombia. Data were collected over a period of 6-10 years following participant's enrollment in the original Base Study.

Official Title
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Safety, Immunogenicity, and Efficacy of Gardasil (V501 (Human Papilloma Virus [Types 6, 11, 16, 18] Recombinant Vaccine) in Mid-Adult Women - The FUTURE III (Females United to Unilaterally Reduce Endo/Ectocervical Cancer) Study

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

Intervention / Treatment
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* Biological: Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine
* Biological: Comparator: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 24 Years
Maximum Age: 45 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: qHPV Vaccine in Base Study<br>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<br>* qHPV intramuscular injection in three 0.5 mL doses over 6 months in the Base Study or EXT1<br>|
| Placebo Comparator: Placebo in Base Study<br>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<br>* qHPV intramuscular injection in three 0.5 mL doses over 6 months in the Base Study or EXT1<br>Biological: Comparator: Placebo<br>* Placebo intramuscular injection in three 0.5 mL doses over 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate of HPV 6/11 Related Persistent Infection, Genital Warts, VIN, VaIN, Vulvar Cancer, Vaginal Cancer, Cervical Dysplasia, Cervical AIS, and Cervical Cancer | HPV 6/11: The two types of HPV (types 6/11) were determined by PCR testing | 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 | 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 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 | 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-related Condyloma: Year 6 to Year 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-related Condyloma (Secondary Analysis): Day 1 to Year 4 | The four HPV types were determined by PCR testing. | Up to 48 months (4 years) after the first dose of qHPV vaccine or placebo in the Base Study | 
| Incidence Rate of HPV 6/11-related Condyloma (Secondary Analysis): Year 4 to Year 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-related Condyloma (Secondary Analysis): Year 6 to Year 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 31/33/35/52/58 Related Persistent Infection, Genital Warts, VIN, VaIN, Vulvar Cancer, Vaginal Cancer, Cervical Dysplasia, Cervical AIS, and Cervical Cancer | This outcome measure was not analyzed because of diminished interest by experts in composite efficacy endpoints associated with these HPV types | Up to Month 48 (up to 42 months after the third dose of qHPV vaccine in the Base Study) |