Anogenital Human Papilloma Virus Infection, Condyloma Acuminata
Conditions
Brief summary
A study to evaluate the efficacy and tolerability of V501 (quadrivalent Human Papilloma Virus \[HPV\] \[Type 6, 11, 16 and 18\] L1 Virus-Like Particle vaccine, GARDASIL™) in healthy, 16- to 26-year old Japanese males. The hypotheses tested are: 1) V501 reduces the combined incidence of HPV 6-, 11-, 16-, or 18-related persistent infection compared with placebo, and 2) V501 reduces the combined incidence of HPV 6-, 11-, 16-, or 18-related persistent infection, condyloma acuminata, penile/perianal/perineal intraepithelial neoplasia, or penile, perianal, or perineal cancer compared with placebo.
Interventions
BIOLOGICALV501
Formulated with aluminum hydroxyphosphate sulfate (AAHS) adjuvant
BIOLOGICALPlacebo
Formulated with AAHS adjuvant
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
16 Years to 26 Years
Healthy volunteers
Yes
Inclusion criteria
* Japanese * No clinical evidence of gross genital lesion suggesting sexually-transmitted disease and no clinically present external genital warts * Other inclusion criteria will be discussed with the investigator during screening
Exclusion criteria
* History of known prior vaccination with an HPV vaccine or plans to receive one outside the study * History of external genital warts * History of severe allergic reaction that required medical intervention * Received immune globulin or blood-derived products in the past 6 months or plan to receive any before Month 7 of the study * History of splenectomy, is currently immunocompromised, or has been diagnosed with immunodeficiency, Human Immunodeficiency Virus (HIV), lymphoma, leukemia, systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease, or other autoimmune condition * Received immunosuppressive therapy in the past year, excluding inhaled, nasal, or topical corticosteroids and certain regimens of systemic corticosteroids * Known thrombocytopenia or coagulation disorder that would contraindicate intramuscular injections * Ongoing alcohol or drug abuse within the past 12 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Combined Incidence of HPV Type 6, 11, 16, or 18-related Persistent Infection | Up to Month 36 | Persistent infection was defined as 1) polymerase chain reaction (PCR) positive to HPV Type 6, 11, 16, or 18 in 2 consecutive anogenital or biopsy samples collected ≥4 months apart, or 2) Pathology Panel consensus diagnosis of condyloma acuminate, penile/perianal/perineal intraepithelial neoplasia (PIN), penile, perianal, or perineal cancer and PCR detection of HPV Type 6, 11, 16, or 18 in an adjacent section and PCR positive for the same HPV type at a separate adjacent visit. The combined incidence of HPV Type 6, 11, 16, or 18 persistent infection detected in samples from ≥2 consecutive visits ≥6 months apart was assessed. |
| Percentage of Participants With Maximum Temperature ≥37.5°C Reported on the Vaccination Report Card | Up to 5 days after any vaccination | Body temperature (oral or oral equivalent) was recorded on the Vaccination Report Card (VRC). The percentage of participants with a maximum temperature ≥37.5°C was summarized. |
| Percentage of Participants With an Injection-site Adverse Event Prompted on the Vaccination Report Card | Up to 5 days after any vaccination | An adverse event (AE) is defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with study drug. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug or a protocol-specified procedure, whether or not considered related to the study drug or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the study drug or protocol-specified procedure is also an AE. The percentage of participants with an injection-site AE prompted on the VRC (erythema, pain, and swelling) was summarized. |
| Percentage of Participants With a Systemic Adverse Event | Up to 15 days after any vaccination | An adverse event (AE) is defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with study drug. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug or a protocol-specified procedure, whether or not considered related to the study drug or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the study drug or protocol-specified procedure is also an AE. The percentage of participants with a systemic AE was summarized. |
| Percentage of Participants With a Vaccine-related Systemic Adverse Event | Up to 15 days after any vaccination | An adverse event (AE) is defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with study drug. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug or a protocol-specified procedure, whether or not considered related to the study drug or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the study drug or protocol-specified procedure is also an AE. Vaccine-related AEs are those that were deemed possibly, probably, or definitely related to vaccine administration by the investigator. The percentage of participants with a vaccine-related systemic AE was summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Combined Incidence of HPV Type 6, 11, 16, or 18-related Persistent Infection or Disease | Up to Month 36 | Persistent infection was defined as 1) polymerase chain reaction (PCR) positive to HPV Type 6, 11, 16, or 18 in 2 consecutive anogenital or biopsy samples collected ≥4 months apart, or 2) Pathology Panel consensus diagnosis of condyloma acuminate, penile/perianal/perineal intraepithelial neoplasia (PIN), penile, perianal, or perineal cancer and PCR detection of HPV Type 6, 11, 16, or 18 in an adjacent section and PCR positive for the same HPV type at a separate adjacent visit. The incidence of persistent infection detected in samples from ≥2 consecutive visits ≥6 months apart was assessed. Disease was defined as HPV Type 6, 11, 16, or 18-related condyloma acuminate, PIN, penile, perianal, or perineal cancer. The combined incidence of HPV Type 6, 11, 16, or 18 persistent infection or disease was assessed. |
Participant flow
Recruitment details
A total of 1129 participants were screened and 1124 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| V501 Participants received V501 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Follow-up was up to Month 36. | 562 |
| Placebo Participants received placebo 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Follow-up was up to Month 36. | 562 |
| Total | 1,124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 26 | 29 |
| Overall Study | Physician Decision | 5 | 3 |
| Overall Study | Randomized not treated | 1 | 0 |
| Overall Study | Withdrawal by Subject | 46 | 40 |
| Overall Study | Withdrawn by parent/guardian | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | V501 |
|---|---|---|---|
| Age, Continuous | 22.6 Years STANDARD_DEVIATION 2 | 22.6 Years STANDARD_DEVIATION 2 | 22.6 Years STANDARD_DEVIATION 2.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 562 Participants | 1124 Participants | 562 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 562 Participants | 1124 Participants | 562 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 554 | 1 / 559 |
| other Total, other adverse events | 329 / 554 | 303 / 559 |
| serious Total, serious adverse events | 0 / 554 | 1 / 559 |
Outcome results
Primary
Combined Incidence of HPV Type 6, 11, 16, or 18-related Persistent Infection
Persistent infection was defined as 1) polymerase chain reaction (PCR) positive to HPV Type 6, 11, 16, or 18 in 2 consecutive anogenital or biopsy samples collected ≥4 months apart, or 2) Pathology Panel consensus diagnosis of condyloma acuminate, penile/perianal/perineal intraepithelial neoplasia (PIN), penile, perianal, or perineal cancer and PCR detection of HPV Type 6, 11, 16, or 18 in an adjacent section and PCR positive for the same HPV type at a separate adjacent visit. The combined incidence of HPV Type 6, 11, 16, or 18 persistent infection detected in samples from ≥2 consecutive visits ≥6 months apart was assessed.
Time frame: Up to Month 36
Population: Participants who were seronegative at Day 1 and PCR negative from Day 1 through Month 7 to the relevant HPV type, received all 3 vaccinations, did not deviate from the study protocol in ways that might interfere with vaccine efficacy, and had ≥1 follow-up visit after Month 7.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V501 | Combined Incidence of HPV Type 6, 11, 16, or 18-related Persistent Infection | 0.3 Cases per 100 person-years of follow-up |
| Placebo | Combined Incidence of HPV Type 6, 11, 16, or 18-related Persistent Infection | 1.9 Cases per 100 person-years of follow-up |
p-value: <0.00195% CI: [52.7, 97.3]One-sided exact test
Primary
Percentage of Participants With an Injection-site Adverse Event Prompted on the Vaccination Report Card
An adverse event (AE) is defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with study drug. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug or a protocol-specified procedure, whether or not considered related to the study drug or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the study drug or protocol-specified procedure is also an AE. The percentage of participants with an injection-site AE prompted on the VRC (erythema, pain, and swelling) was summarized.
Time frame: Up to 5 days after any vaccination
Population: Participants who received ≥1 study vaccination and had follow-up data available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| V501 | Percentage of Participants With an Injection-site Adverse Event Prompted on the Vaccination Report Card | Injection-site erythema | 24.5 Percentage of participants |
| V501 | Percentage of Participants With an Injection-site Adverse Event Prompted on the Vaccination Report Card | Injection-site pain | 54.9 Percentage of participants |
| V501 | Percentage of Participants With an Injection-site Adverse Event Prompted on the Vaccination Report Card | Injection-site swelling | 21.3 Percentage of participants |
| Placebo | Percentage of Participants With an Injection-site Adverse Event Prompted on the Vaccination Report Card | Injection-site erythema | 21.6 Percentage of participants |
| Placebo | Percentage of Participants With an Injection-site Adverse Event Prompted on the Vaccination Report Card | Injection-site pain | 48.5 Percentage of participants |
| Placebo | Percentage of Participants With an Injection-site Adverse Event Prompted on the Vaccination Report Card | Injection-site swelling | 14.5 Percentage of participants |
Comparison: Injection-site erythemap-value: 0.25195% CI: [-2.1, 7.9]Miettinen & Nurminen
Comparison: Injection-site painp-value: 0.03395% CI: [0.5, 12.2]Miettinen & Nurminen
Comparison: Injection-site swellingp-value: 0.00395% CI: [2.3, 11.3]Miettinen & Nurminen
Primary
Percentage of Participants With a Systemic Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with study drug. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug or a protocol-specified procedure, whether or not considered related to the study drug or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the study drug or protocol-specified procedure is also an AE. The percentage of participants with a systemic AE was summarized.
Time frame: Up to 15 days after any vaccination
Population: Participants who received ≥1 study vaccination and had follow-up data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V501 | Percentage of Participants With a Systemic Adverse Event | 14.4 Percentage of participants |
| Placebo | Percentage of Participants With a Systemic Adverse Event | 15.4 Percentage of participants |
95% CI: [-5.2, 3.3]
Primary
Percentage of Participants With a Vaccine-related Systemic Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with study drug. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug or a protocol-specified procedure, whether or not considered related to the study drug or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the study drug or protocol-specified procedure is also an AE. Vaccine-related AEs are those that were deemed possibly, probably, or definitely related to vaccine administration by the investigator. The percentage of participants with a vaccine-related systemic AE was summarized.
Time frame: Up to 15 days after any vaccination
Population: Participants who received ≥1 study vaccination and had follow-up data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V501 | Percentage of Participants With a Vaccine-related Systemic Adverse Event | 3.4 Percentage of participants |
| Placebo | Percentage of Participants With a Vaccine-related Systemic Adverse Event | 5.0 Percentage of participants |
95% CI: [-4.1, 0.8]
Primary
Percentage of Participants With Maximum Temperature ≥37.5°C Reported on the Vaccination Report Card
Body temperature (oral or oral equivalent) was recorded on the Vaccination Report Card (VRC). The percentage of participants with a maximum temperature ≥37.5°C was summarized.
Time frame: Up to 5 days after any vaccination
Population: Participants who received ≥1 study vaccination and had follow-up data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V501 | Percentage of Participants With Maximum Temperature ≥37.5°C Reported on the Vaccination Report Card | 2.7 Percentage of participants |
| Placebo | Percentage of Participants With Maximum Temperature ≥37.5°C Reported on the Vaccination Report Card | 3.9 Percentage of participants |
p-value: 0.25695% CI: [-3.5, 0.9]Miettinen & Nurminen
Secondary
Combined Incidence of HPV Type 6, 11, 16, or 18-related Persistent Infection or Disease
Persistent infection was defined as 1) polymerase chain reaction (PCR) positive to HPV Type 6, 11, 16, or 18 in 2 consecutive anogenital or biopsy samples collected ≥4 months apart, or 2) Pathology Panel consensus diagnosis of condyloma acuminate, penile/perianal/perineal intraepithelial neoplasia (PIN), penile, perianal, or perineal cancer and PCR detection of HPV Type 6, 11, 16, or 18 in an adjacent section and PCR positive for the same HPV type at a separate adjacent visit. The incidence of persistent infection detected in samples from ≥2 consecutive visits ≥6 months apart was assessed. Disease was defined as HPV Type 6, 11, 16, or 18-related condyloma acuminate, PIN, penile, perianal, or perineal cancer. The combined incidence of HPV Type 6, 11, 16, or 18 persistent infection or disease was assessed.
Time frame: Up to Month 36
Population: Participants who were seronegative at Day 1 and PCR negative from Day 1 through Month 7 to the relevant HPV type, received all 3 vaccinations, did not deviate from the study protocol in ways that might interfere with vaccine efficacy, and had ≥1 follow-up visit after Month 7.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V501 | Combined Incidence of HPV Type 6, 11, 16, or 18-related Persistent Infection or Disease | 0.3 Cases per 100 person-years at risk |
| Placebo | Combined Incidence of HPV Type 6, 11, 16, or 18-related Persistent Infection or Disease | 1.9 Cases per 100 person-years at risk |
p-value: <0.00195% CI: [55.2, 97.4]One-sided exact test