Papillomavirus Infections
Conditions
Keywords
HPV infections
Brief summary
This is a China registration study. A randomized, double-blind, placebo-controlled immunogenicity and safety study in Chinese female participants aged 9 to 45 years and male participants aged 9 to 15 years. Approximately 600 participants will be randomized in a 1:1 ratio to receive either vaccine or aluminum-containing placebo. Each participant received one injection at each visit at Day 1, Month 2, and Month 6. Vaccine or placebo was given as a 0.5-mL intramuscular injection. Serum will be collected from all participants to evaluate immune response against anti-Human Papillomavirus (HPV) 6/11/16/18 with Luminex Assay. At Month 2, Month 6, Month 7, subjects will be evaluated for any new medical condition or health concerns and Serious Adverse Experiences throughout the study. The primary objective is to evaluate the vaccine-induced serum anti-HPV 6, 11, 16 and 18 antibody titers following 3-dose regimen of Gardasil® compared with placebo.
Interventions
BIOLOGICALQuadrivalent Human Papillomavirus (HPV, Types 6, 11, 16, 18) Recombinant Vaccine (Gardasil®)
Human Papillomavirus (Type 6, 11, 16, 18) Recombinant Vaccine (Gardasil®), 0.5mL, 3 Dose of intramuscular injection at Day 1, Month 2 and Month 6
BIOLOGICALComparator: Placebo
aluminum-contained, 0.5mL, 3 Dose of intramuscular injection at Day 1, Month 2 and Month 6
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
9 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy female participants aged 9-45 years old and male participants aged 9-15 years old * Participants agrees to provide study personnel with a primary telephone number as well as an alternate telephone number for follow-up purposes * Not pregnant now (as demonstrated by a negative urine beta-Human Chorionic Gonadotropin (beta-HCG) test) for post-pubertal female participants
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | Collect blood sample for anti-HPV 6, 11, 16, 18 titers testing at Day 1 prior to vaccination, and Month 7 | Measured GMT of anti-HPV 6, 11, 16 and 18 at Day 1 and Month 7 (1 month after completion of administration of a 6-month 3-dose regimen of vaccines). GMT at Day 1 was used to define per-protocol population. Antibody titers were tested with Luminex array. The numeric values for the Day 1 (Vaccine and Placebo groups) and the Month 7 (Placebo groups) are the threshold of detection for the Luminex array assays. The reported values are all below the lower limit of qualification, ((less than) \<7, \<8, \<11, \<10 respectively) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Were Seronegative at Baseline and Developed Seropositive at Month 7 | Collect blood sample for anti-HPV 6, 11, 16, 18 titers testing at Day 1 prior to vaccination and Month 7 | Anti-HPV 6, 11, 16, 18 Seroconversion Rate, i.e., the Number of participants who were seronegative at baseline and developed seropositive at Month 7. Seroconversion for HPV 6, 11, 16, and 18 is defined as achieving an anti-HPV cLIA level of at least 20, 16, 20 and 24 mMU/mL, respectively. Seroconversion rate = (number of participants with seronegative at baseline and developed seropositive at Month 7)/(number of participants with seronegative at baseline regardless relevant HPV serum status at Month 7). Measure serum anti-HPV 6, 11, 16, 18 titers at Day 1 prior to vaccination and at Month 7 |
| Serious Adverse Experiences and Systemic Adverse Experiences Occurring Within 14 Days After Each Vaccination, and Injection-site Complaints Occurring Day 1 Through Day 5 After Each Vaccination | For serious adverse experiences and systemic adverse experiences: 14 days follow-up after each dose of vaccination; For injection-site adverse experiences: 5 days follow-up after each dose of vaccination | All adverse experiences were collected through 14 days following each vaccination. All participants were requested to record injection-site adverse experiences and monitor the participant's temperature daily on the Vaccination Report Card for Day 1 thereafter for 4 additional calendar days, and record all systemic adverse experiences that occur during the 14-day period after each injection. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vaccine (Gardasil®) Group Human Papillomavirus (HPV) (Type 6, 11, 16, 18) Recombinant Vaccine (Gardasil®), 0.5mL, 3 Dose of intramuscular injection at Day 1, Month 2 and Month 6 | 302 |
| Placebo Group Placebo aluminum-containing, 0.5mL, 3 Dose of intramuscular injection at Day 1, Month 2 and Month 6 | 298 |
| Total | 600 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Relocated | 0 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 4 |
Baseline characteristics
| Characteristic | Vaccine (Gardasil®) Group | Placebo Group | Total |
|---|---|---|---|
| Age, Continuous | 24.5 years STANDARD_DEVIATION 10.9 | 24.8 years STANDARD_DEVIATION 11 | 24.6 years STANDARD_DEVIATION 10.9 |
| Age, Customized 16-26 Years of Age | 76 Participants | 74 Participants | 150 Participants |
| Age, Customized 27-34 Years of Age | 63 Participants | 62 Participants | 125 Participants |
| Age, Customized 35-45 Years of Age | 62 Participants | 63 Participants | 125 Participants |
| Age, Customized 9-15 Years of Age | 101 Participants | 99 Participants | 200 Participants |
| Body Temperature | 36.5 Degrees Celsius STANDARD_DEVIATION 0.31 | 36.5 Degrees Celsius STANDARD_DEVIATION 0.31 | 36.5 Degrees Celsius STANDARD_DEVIATION 0.31 |
| Pulse | 74.4 Beats per minute (BPM) STANDARD_DEVIATION 11.9 | 74.6 Beats per minute (BPM) STANDARD_DEVIATION 11.2 | 74.5 Beats per minute (BPM) STANDARD_DEVIATION 11.2 |
| Sex: Female, Male Female | 251 Participants | 249 Participants | 500 Participants |
| Sex: Female, Male Male | 51 Participants | 49 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 260 / 302 | 215 / 298 |
| serious Total, serious adverse events | 0 / 302 | 1 / 298 |
Outcome results
Primary
Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines)
Measured GMT of anti-HPV 6, 11, 16 and 18 at Day 1 and Month 7 (1 month after completion of administration of a 6-month 3-dose regimen of vaccines). GMT at Day 1 was used to define per-protocol population. Antibody titers were tested with Luminex array. The numeric values for the Day 1 (Vaccine and Placebo groups) and the Month 7 (Placebo groups) are the threshold of detection for the Luminex array assays. The reported values are all below the lower limit of qualification, ((less than) \<7, \<8, \<11, \<10 respectively)
Time frame: Collect blood sample for anti-HPV 6, 11, 16, 18 titers testing at Day 1 prior to vaccination, and Month 7
Population: Per-protocol population, defined as all participants who received all 3 dose vaccinations within acceptable day ranges, had at least 1 valid serology result after the third injection, and adhered to protocol guidelines. To be included in the immunogenicity analysis for given HPV type, participants must be seronegative to that HPV type at baseline.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Vaccine (Gardasil®) Group (Day 1) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 6 | 7 mMU/mL |
| Vaccine (Gardasil®) Group (Day 1) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 11 | 8 mMU/mL |
| Vaccine (Gardasil®) Group (Day 1) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 16 | 11 mMU/mL |
| Vaccine (Gardasil®) Group (Day 1) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 18 | 10 mMU/mL |
| Placebo Group (Day 1) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 11 | 8 mMU/mL |
| Placebo Group (Day 1) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 16 | 11 mMU/mL |
| Placebo Group (Day 1) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 18 | 10 mMU/mL |
| Placebo Group (Day 1) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 6 | 7 mMU/mL |
| Vaccine (Gardasil®) Group (Month 7) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 16 | 2336.9 mMU/mL |
| Vaccine (Gardasil®) Group (Month 7) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 11 | 665.0 mMU/mL |
| Vaccine (Gardasil®) Group (Month 7) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 18 | 535.6 mMU/mL |
| Vaccine (Gardasil®) Group (Month 7) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 6 | 426.0 mMU/mL |
| Placebo Group (Month 7) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 18 | 10 mMU/mL |
| Placebo Group (Month 7) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 11 | 8 mMU/mL |
| Placebo Group (Month 7) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 6 | 7 mMU/mL |
| Placebo Group (Month 7) | Geometric Mean Titer (GMT) of Anti-HPV 6, 11, 16 , 18 at Day 1 and Month 7 (1 Month After Completion of Administration of a 6-month 3-dose Regimen of Vaccines) | anti-HPV 16 | 11 mMU/mL |
Comparison: An Analysis of Covariance (ANCOVA) model was used for each HPV type, based on the pooled data from all age groups and genders. The natural-log-transformed titer was the response variable, and vaccination group, gender and age group were covariates. The null hypothesis was that the GMT ratio (Gardasil/Placebo) was equal to 1.p-value: <=0.0595% CI: [88.1, 117.2]ANCOVA
Secondary
Number of Participants Who Were Seronegative at Baseline and Developed Seropositive at Month 7
Anti-HPV 6, 11, 16, 18 Seroconversion Rate, i.e., the Number of participants who were seronegative at baseline and developed seropositive at Month 7. Seroconversion for HPV 6, 11, 16, and 18 is defined as achieving an anti-HPV cLIA level of at least 20, 16, 20 and 24 mMU/mL, respectively. Seroconversion rate = (number of participants with seronegative at baseline and developed seropositive at Month 7)/(number of participants with seronegative at baseline regardless relevant HPV serum status at Month 7). Measure serum anti-HPV 6, 11, 16, 18 titers at Day 1 prior to vaccination and at Month 7
Time frame: Collect blood sample for anti-HPV 6, 11, 16, 18 titers testing at Day 1 prior to vaccination and Month 7
Population: Per-protocol population, defined as all participants who received all 3 dose vaccinations within acceptable day ranges, had at least 1 valid serology result after the third injection, and adhered to protocol guidelines. To be included in the immunogenicity analysis for given HPV type, participants must be seronegative to that HPV type at baseline.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vaccine (Gardasil®) Group (Day 1) | Number of Participants Who Were Seronegative at Baseline and Developed Seropositive at Month 7 | anti-HPV 6 | 269 Participants |
| Vaccine (Gardasil®) Group (Day 1) | Number of Participants Who Were Seronegative at Baseline and Developed Seropositive at Month 7 | anti-HPV 11 | 279 Participants |
| Vaccine (Gardasil®) Group (Day 1) | Number of Participants Who Were Seronegative at Baseline and Developed Seropositive at Month 7 | anti-HPV 16 | 277 Participants |
| Vaccine (Gardasil®) Group (Day 1) | Number of Participants Who Were Seronegative at Baseline and Developed Seropositive at Month 7 | anti-HPV 18 | 287 Participants |
| Placebo Group (Day 1) | Number of Participants Who Were Seronegative at Baseline and Developed Seropositive at Month 7 | anti-HPV 18 | 3 Participants |
| Placebo Group (Day 1) | Number of Participants Who Were Seronegative at Baseline and Developed Seropositive at Month 7 | anti-HPV 6 | 2 Participants |
| Placebo Group (Day 1) | Number of Participants Who Were Seronegative at Baseline and Developed Seropositive at Month 7 | anti-HPV 16 | 0 Participants |
| Placebo Group (Day 1) | Number of Participants Who Were Seronegative at Baseline and Developed Seropositive at Month 7 | anti-HPV 11 | 2 Participants |
Comparison: The null hypothesis was that the seroconversion rate in the Gardasil® Group was less than 90% for each HPV type.p-value: <=0.0595% CI: [93.74, 98.46]Exact Binomial CI
Secondary
Serious Adverse Experiences and Systemic Adverse Experiences Occurring Within 14 Days After Each Vaccination, and Injection-site Complaints Occurring Day 1 Through Day 5 After Each Vaccination
All adverse experiences were collected through 14 days following each vaccination. All participants were requested to record injection-site adverse experiences and monitor the participant's temperature daily on the Vaccination Report Card for Day 1 thereafter for 4 additional calendar days, and record all systemic adverse experiences that occur during the 14-day period after each injection.
Time frame: For serious adverse experiences and systemic adverse experiences: 14 days follow-up after each dose of vaccination; For injection-site adverse experiences: 5 days follow-up after each dose of vaccination
Population: Safety population, defined as all participants who were vaccinated at least one dose and had safety follow-up data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine (Gardasil®) Group (Day 1) | Serious Adverse Experiences and Systemic Adverse Experiences Occurring Within 14 Days After Each Vaccination, and Injection-site Complaints Occurring Day 1 Through Day 5 After Each Vaccination | 153 Participants |
| Placebo Group (Day 1) | Serious Adverse Experiences and Systemic Adverse Experiences Occurring Within 14 Days After Each Vaccination, and Injection-site Complaints Occurring Day 1 Through Day 5 After Each Vaccination | 131 Participants |