Cervical Cancers, Genital Warts, Vaginal Cancers, Vulvar Cancers
Conditions
Keywords
Cervical cancer, Genital warts, Human papillomavirus vaccine, GARDASIL™
Brief summary
This study will evaluate whether V503 (9vHPV vaccine), is well tolerated in girls and women between 12 and 26 years old who have previously been vaccinated with GARDASIL™. Participants will receive vaccination with 9vHPV vaccine or placebo on Day 1, Month 2, and Month 6 of the Base Study. Participants who receive placebo in the Base Study will be eligible to receive vaccination with 9vHPV vaccine on Day 1, Month 2, and Month 6 of the Extension Study.
Interventions
BIOLOGICALV503
V503 (9vHPV) vaccine given as a 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6 of the Base Study or the Study Extension
BIOLOGICALPlacebo to V503
Placebo to V503 (saline) given as a 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6 of the Base Study
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
12 Years to 26 Years
Healthy volunteers
Yes
Inclusion criteria
Participants Age 12 to 15 Years: * Participant is in good health * Parent/legal guardian and participant agree to provide study personnel with a primary telephone number for follow-up * Participant received a 3-dose regimen of marketed GARDASIL™ within a 1 year period and the last dose of GARDASIL™ was at least 1 year from study day 1 * Participant has not received any other HPV vaccine * Participant is not yet sexually active Participants Age 16 to 26 Years: * Participant is in good health * Participant agrees to provide a primary telephone number for follow-up * Participant received a 3-dose regimen of marketed GARDASIL™ within a 1 year period and the last dose of GARDASIL™ was at least 1 year from study day 1 * Participant has not received any other HPV vaccine * Participant has never had Papanicolaou (Pap) testing or has only had normal results * Participant has a history of 0 to 4 lifetime sexual partners at enrollment
Exclusion criteria
All participants: * Participant has a history of severe allergic reaction that required medical intervention * Participant has any disorder that would contraindicate intramuscular injections * Participant is pregnant * Participant is immunocompromised or has an autoimmune condition * Participant has had a splenectomy * Participant has received any immune globulin product or blood-derived product * Participant has participated in a HPV vaccine clinical trial Participants Age 16 to 26 Only: * Participant expects to donate eggs during the study * Participant has a history of abnormal cervical biopsy result * Participant has a history of HPV-related external genital lesions, external genital cancer, HPV-related vaginal lesions, or vaginal cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experience a Severe Injection-site AE - Base Study | up to 5 days after any vaccination - Base Study | 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 vaccine. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. Participants were instructed to estimate the severity of AEs such as pain at injection site as mild (awareness of symptom, but easily tolerated), moderate (discomfort enough to cause interference with usual activities), or severe (incapacitating with inability to work or do usual activity). Additionally, participants were instructed to measure any swelling and/or erythema at its greatest width. Swelling or erythema with diameter \>2 inches (\>5 cm) was recorded as severe. All AEs associated with the injection site and reported as severe were summarized. |
| Percentage of Participants Who Experience a Serious Adverse Event (SAE) Within 15 Days of Any Vaccination - Base Study | up to 14 days after any vaccination - Base Study | An SAE is one that results in death, disability/incapacity, or hospitalization or is life threatening, a congenital anomaly or birth defect, cancer, an overdose, or otherwise jeopardizes the participant and may require medical intervention. |
| Percentage of Participants Who Experience a Vaccine-related SAE Any Time During Study- Base Study | Up to 7 months - Base Study | An SAE is one that results in death, disability/incapacity, or hospitalization or is life threatening, a congenital anomaly or birth defect, cancer, an overdose, or otherwise jeopardizes the participant and may require medical intervention. An SAE that is judged by the Investigator to be definitely related, probably related, or possibly related is defined as a vaccine-related SAE. |
| Percentage of Participants Who Experience an Injection-site Adverse Event (AE) - Base Study | up to 5 days after any vaccination - Base Study | 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 vaccine. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. The percentage of participants who reported an AE that was associated with the injection site such as redness, swelling, and pain/tenderness/soreness was summarized. |
| Percentage of Participants With Body Temperature ≥100.0°F (≥37.8ºC) - Base Study | up to 5 days after any vaccination - Base Study | Participants collected their oral body temperature in the evening of their vaccination day and at the same time each day thereafter for 4 days. The maximum body temperature obtained within 5 days of any of the 3 vaccinations was recorded. |
| Percentage of Participants Who Experience a Systemic AE - Base Study | up to 14 days after any vaccination - Base Study | 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 vaccine. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | 4 weeks post-vaccination 3 (Month 7; End of Base Study) | Serum antibody titers for HPV virus-like particles (VLPs), Types 6, 11, 16, 18, 31, 33, 45, 52 and 58 were determined 4 weeks post-vaccination 3 using competitive luminex immunoassay (cLIA). 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 Type 33: ≥8, HPV Type 45: ≥8, HPV Type 52: ≥8, and HPV Type 58: ≥8. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experience an SAE- Extension Study | up to Month 7 - Extension Study | An SAE is one that results in death, disability/incapacity, or hospitalization or is life threatening, a congenital anomaly or birth defect, cancer, an overdose, or otherwise jeopardizes the participant and may require medical intervention. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 9vHPV Vaccine - Base Study Blinded 9vHPV vaccine (V503) 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6 of the Base Study. Participants will not continue to the Extension Study. | 618 |
| Placebo - Base Study Blinded 0.5 mL intramuscular injection of saline placebo at Day 1, Month 2, and Month 6 of the Base Study. After completion of the Base Study, participants will be eligible to receive open-label 9vHPV 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6 of the Extension Study. | 306 |
| Total | 924 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Base Study | Adverse Event | 3 | 0 | 0 |
| Base Study | Lost to Follow-up | 4 | 1 | 0 |
| Base Study | Protocol Violation | 3 | 1 | 0 |
| Base Study | Withdrawal by Subject | 12 | 4 | 0 |
| Extension | Lost to Follow-up | 0 | 0 | 5 |
| Extension | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | 9vHPV Vaccine - Base Study | Placebo - Base Study | Total |
|---|---|---|---|
| Age, Customized 12 to 15 years | 122 Participants | 60 Participants | 182 Participants |
| Age, Customized 16 to 26 years | 496 Participants | 246 Participants | 742 Participants |
| Sex: Female, Male Female | 618 Participants | 306 Participants | 924 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 566 / 608 | 197 / 305 | 0 / 99 |
| serious Total, serious adverse events | 3 / 608 | 3 / 305 | 2 / 99 |
Outcome results
Primary
Percentage of Participants Who Experience an Injection-site Adverse Event (AE) - Base Study
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 vaccine. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. The percentage of participants who reported an AE that was associated with the injection site such as redness, swelling, and pain/tenderness/soreness was summarized.
Time frame: up to 5 days after any vaccination - Base Study
Population: All participants who received at least 1 vaccination and had available follow-up data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Experience an Injection-site Adverse Event (AE) - Base Study | 91.1 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Experience an Injection-site Adverse Event (AE) - Base Study | 43.9 Percentage of Participants |
Primary
Percentage of Participants Who Experience a Serious Adverse Event (SAE) Within 15 Days of Any Vaccination - Base Study
An SAE is one that results in death, disability/incapacity, or hospitalization or is life threatening, a congenital anomaly or birth defect, cancer, an overdose, or otherwise jeopardizes the participant and may require medical intervention.
Time frame: up to 14 days after any vaccination - Base Study
Population: All participants who received at least 1 vaccination and had available follow-up data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Experience a Serious Adverse Event (SAE) Within 15 Days of Any Vaccination - Base Study | 0.3 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Experience a Serious Adverse Event (SAE) Within 15 Days of Any Vaccination - Base Study | 0.3 Percentage of Participants |
95% CI: [-1.5, 0.9]Miettinen & Nurminen
Primary
Percentage of Participants Who Experience a Severe Injection-site AE - Base Study
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 vaccine. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. Participants were instructed to estimate the severity of AEs such as pain at injection site as mild (awareness of symptom, but easily tolerated), moderate (discomfort enough to cause interference with usual activities), or severe (incapacitating with inability to work or do usual activity). Additionally, participants were instructed to measure any swelling and/or erythema at its greatest width. Swelling or erythema with diameter \>2 inches (\>5 cm) was recorded as severe. All AEs associated with the injection site and reported as severe were summarized.
Time frame: up to 5 days after any vaccination - Base Study
Population: All participants who received at least 1 vaccination and had available follow-up data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Experience a Severe Injection-site AE - Base Study | 11.2 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Experience a Severe Injection-site AE - Base Study | 1.0 Percentage of Participants |
95% CI: [7.5, 13.1]Miettinen & Nurminen
Primary
Percentage of Participants Who Experience a Systemic AE - Base Study
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 vaccine. 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.
Time frame: up to 14 days after any vaccination - Base Study
Population: All participants who received at least 1 vaccination and had available follow-up data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Experience a Systemic AE - Base Study | 59.7 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Experience a Systemic AE - Base Study | 55.7 Percentage of Participants |
95% CI: [-2.8, 10.8]Miettinen & Nurminen
Primary
Percentage of Participants Who Experience a Vaccine-related SAE Any Time During Study- Base Study
An SAE is one that results in death, disability/incapacity, or hospitalization or is life threatening, a congenital anomaly or birth defect, cancer, an overdose, or otherwise jeopardizes the participant and may require medical intervention. An SAE that is judged by the Investigator to be definitely related, probably related, or possibly related is defined as a vaccine-related SAE.
Time frame: Up to 7 months - Base Study
Population: All participants who received at least 1 vaccination and had available follow-up data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Experience a Vaccine-related SAE Any Time During Study- Base Study | 0.2 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Experience a Vaccine-related SAE Any Time During Study- Base Study | 0.3 Percentage of Participants |
95% CI: [-1.7, 0.6]Miettinen & Nurminen
Primary
Percentage of Participants With Body Temperature ≥100.0°F (≥37.8ºC) - Base Study
Participants collected their oral body temperature in the evening of their vaccination day and at the same time each day thereafter for 4 days. The maximum body temperature obtained within 5 days of any of the 3 vaccinations was recorded.
Time frame: up to 5 days after any vaccination - Base Study
Population: All participants who received at least 1 vaccination and had available temperature data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9vHPV Vaccine - Base Study | Percentage of Participants With Body Temperature ≥100.0°F (≥37.8ºC) - Base Study | 6.5 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants With Body Temperature ≥100.0°F (≥37.8ºC) - Base Study | 3.0 Percentage of Participants |
p-value: 0.02695% CI: [0.5, 6.2]Miettinen & Nurminen
Secondary
Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study
Serum antibody titers for HPV virus-like particles (VLPs), Types 6, 11, 16, 18, 31, 33, 45, 52 and 58 were determined 4 weeks post-vaccination 3 using competitive luminex immunoassay (cLIA). 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 Type 33: ≥8, HPV Type 45: ≥8, HPV Type 52: ≥8, and HPV Type 58: ≥8.
Time frame: 4 weeks post-vaccination 3 (Month 7; End of Base Study)
Population: Participants who received all 3 vaccinations within an acceptable day range, had Month 7 serology sample collected within an acceptable range and had no other protocol violations that could interfere with immunes response to the vaccine. Statistical testing performed only within the 9vHPV arm and only for HPV types 31, 33, 45, 52, and 58.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 11 (n=515; n=261) | 100.0 Percentage of Participants |
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 33 (n=515; n=261) | 99.8 Percentage of Participants |
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 18 (n=515; n=261) | 100.0 Percentage of Participants |
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 45 (n=515; n=261) | 98.3 Percentage of Participants |
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 16 (n=515; n=261) | 100.0 Percentage of Participants |
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 52 (n=515; n=261) | 99.6 Percentage of Participants |
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 31 (n=515; n=261) | 99.8 Percentage of Participants |
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 58 (n=515; n=261) | 99.8 Percentage of Participants |
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 6 (n=511; n=251) | 100.0 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 58 (n=515; n=261) | 9.2 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 6 (n=511; n=251) | 100.0 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 11 (n=515; n=261) | 99.6 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 16 (n=515; n=261) | 100.0 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 18 (n=515; n=261) | 85.4 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 31 (n=515; n=261) | 23.8 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 33 (n=515; n=261) | 8.0 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 45 (n=515; n=261) | 3.4 Percentage of Participants |
| Placebo - Base Study | Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine - Base Study | Anti-HPV 52 (n=515; n=261) | 3.8 Percentage of Participants |
Comparison: Anti-HPV 31p-value: <0.00195% CI: [98.9, 100]Clopper-Pearson
Comparison: Anti-HPV 33p-value: <0.00195% CI: [98.9, 100]Clopper-Pearson
Comparison: Anti-HPV 45p-value: <0.00195% CI: [96.7, 99.2]Clopper-Pearson
Comparison: Anti-HPV 52p-value: <0.00195% CI: [98.6, 100]Clopper-Pearson
Comparison: Anti-HPV 58p-value: <0.00195% CI: [98.9, 100]Clopper-Pearson
Other Pre-specified
Percentage of Participants Who Experience an SAE- Extension Study
An SAE is one that results in death, disability/incapacity, or hospitalization or is life threatening, a congenital anomaly or birth defect, cancer, an overdose, or otherwise jeopardizes the participant and may require medical intervention.
Time frame: up to Month 7 - Extension Study
Population: All participants who received at least 1 vaccination in Extension Study and had available follow-up data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9vHPV Vaccine - Base Study | Percentage of Participants Who Experience an SAE- Extension Study | 2.0 Percentage of Participants |