Papillomavirus Infections
Conditions
Keywords
Cervical cancer, vulvar cancer, vaginal cancer, genital warts, human papillomavirus
Brief summary
The study is designed to determine the safety, tolerability and immunogenicity of a 3-dose regimen of GARDASIL™ administered to healthy females between 9 and 26 years of age, in Sub-Saharan Africa. Data from the current study are needed in order to complement existing extensive safety data from the GARDASIL™ clinical trials program, and confirm that GARDASIL™ may be administered safely and will induce immune responses in populations from and living in Sub-Saharan Africa, as GARDASIL™ has not previously been studied in this region of the world.
Detailed description
In Phase A of the study, healthy females between 9 and 12 years of age will be randomized (4:1) to receive the 3-dose regimen of GARDASIL™ or placebo, and those between 13 and 26 years old will receive GARDASIL™. In Phase B of the study, participants who received placebo in Phase A will have the option to receive the 3-dose regimen of GARDASIL™.
Interventions
BIOLOGICALQuadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine (GARDASIL™)
BIOLOGICALPlacebo
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
9 Years to 26 Years
Healthy volunteers
Yes
Inclusion criteria
: * Healthy subjects who are native to and living in a participating Sub-Saharan African country. * Subject agrees to provide study personnel with a primary telephone number as well as an alternate telephone number for follow-up purposes. If potential subject does not have a telephone number, the subject must provide an address at which he or she may be contacted. * Post-pubertal female subjects must not be pregnant * Subjects who are sexually active must agree to use effective contraception or remain abstinent through Month 7 of the study. * Subjects who have not yet had sexual intercourse must either agree to remain abstinent through Month 7 of the study, or if they become sexually active during the vaccination phase of the study, to use effective contraception through Month 7. * Subjects who have had sexual intercourse in the two weeks prior to enrollment must have been using effective contraception as defined above. (Emergency contraception is not considered effective contraception for enrollment in the study.)
Exclusion criteria
: * Subject is pregnant as determined by a positive pregnancy test * Subject has had a temperature ≥ 37.8 °C or ≥ 100 °F within 24 hours prior to the first injection. * Subject is currently enrolled in another clinical study of an investigational agent or agents. * Subject has a history of known prior vaccination with a HPV vaccine, or was previously enrolled in an HPV vaccine study and received either active agent or placebo. * Subject has received any inactivated vaccine within 14 days prior to enrollment or any live vaccine within 21 days prior to enrollment. * Subject has a history of severe allergic reaction to any agent (e.g., swelling of the mouth and throat, difficulty breathing, hypotension, or shock) that required medical intervention. * Subject has known allergy to any vaccine component, including aluminum, yeast or BENZONASE™ (nuclease, Nycomed™ \[used to remove residual nucleic acids from this and other vaccines\]). * Subject has received any immune globulin preparation or blood-derived products within the 6 months prior to the first injection, or plans to receive any such products during the course of the study. * Subject has a history of splenectomy, known autoimmune disorder (e.g., systemic lupus erythematosus, rheumatoid arthritis), or is receiving immunosuppressives (e.g., substances or treatments known to diminish immune response such as radiation therapy, administration of antimetabolites, antilymphocytic sera, systemic corticosteroids). Individuals who have received periodic treatments with immunosuppressives, defined as at least 3 courses of systemic corticosteroids each lasting at least 1 week in duration for the year prior to enrollment, will be excluded. Subjects using topical steroids (i.e., inhaled or nasal) will be eligible for vaccination. * Subject is immunocompromised or has been diagnosed as having Human Immunodeficiency Virus (HIV) infection * Subject has known thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections. * Subject has known sickle cell anemia disease, active malaria or active tuberculosis. * Subject has any condition which in the opinion of the investigator might interfere with the evaluation of the study objectives. * Subject has a history of recent or ongoing alcohol or other drug abuse. * Female subject has a prior history of abnormal Pap test showing squamous intraepithelial lesion (SIL), atypical squamous cells of undetermined significance (ASC-US), atypical squamous cells, cannot rule out a high grade lesion (ASC-H), or biopsy showing cervical intraepithelial neoplasia (CIN) or worse. * Subject has any prior history (or at Day 1) of genital warts or treatment for genital warts. * Subject with \>4 lifetime sexual partners. * Subject has undergone hysterectomy with removal of the cervix. * Subject plans to permanently relocate from the area prior to the completion of the study or to leave for an extended period of time when study visits would need to be scheduled.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Experiences | From the time of informed consent is signed through the last study visit (up to 19 months) | A serious adverse experience is any adverse experience that results in death, is life threatening, results in persistent or significant disability/incapacity, results in or prolongs existing inpatient hospitalization, is a congenital anomaly/birth defect, is a cancer, is an overdose, or is another important medical event that may jeopardize the participant and may require medical or surgical intervention |
| Number of Participants Who Seroconvert to HPV Type 16 | Month 7 (1 month postdose 3 in study Phase A) | Seroconversion was defined as achieving an anti-HPV Type 16 cLIA level of \>=20 milli Merck U/mL. The dilution-corrected limit of detection for the Type 16 cLIA was 9.7 milli Merck U/mL. |
| Number of Participants Who Seroconvert to HPV Type 18 | Month 7 (1 month postdose 3 in study Phase A) | Seroconversion was defined as achieving an anti-HPV Type 18 cLIA level of \>=24 milli Merck U/mL. The dilution-corrected limit of detection for the Type 18 cLIA was 5.8 milli Merck U/mL. |
| Number of Participants With Injection-site Adverse Experiences | Up to Day 5 after any vaccination in study Phase A | Participants were prompted to report injection-site experiences of pain, erythema, or swelling and were also asked to report any other injection-site adverse experiences |
| Number of Participants With Elevated Temperature (Oral Temperature >=100 °F) | Up to Day 5 after any vaccination in study Phase A | — |
| Number of Participants Who Seroconvert to Human Papillomavirus (HPV) Type 6 | Month 7 (1 month postdose 3 in study Phase A) | Seroconversion was defined as achieving an anti-HPV Type 6 competitive Luminex Immunoassay (cLIA) level of \>=20 milli Merck U/mL. The dilution-corrected limit of detection for the Type 6 cLIA was 4.2 milli Merck U/mL. |
| Number of Participants Who Seroconvert to HPV Type 11 | Month 7 (1 month postdose 3 in study Phase A) | Seroconversion was defined as achieving an anti-HPV Type 11 cLIA level of \>=16 milli Merck U/mL. The dilution-corrected limit of detection for the Type 11 cLIA was 3.9 milli Merck U/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| GMT of Anti-HPV Type 11 Antibody | Month 7 (1 month postdose 3 in study Phase A) | Anti-HPV Type 11 antibodies were measured by cLIA. The seropositive cut-off threshold for this assay is defined as 16 milli Merck U/mL. |
| GMT of Anti-HPV Type 16 Antibody | Month 7 (1 month postdose 3 in study Phase A) | Anti-HPV Type 16 antibodies were measured by cLIA. The seropositive cut-off threshold for this assay is defined as 20 milli Merck U/mL. |
| GMT of Anti-HPV Type 18 Antibody | Month 7 (1 month postdose 3 in study Phase A) | Anti-HPV Type 18 antibodies were measured by cLIA. The seropositive cut-off threshold for this assay is defined as 24 milli Merck U/mL. |
| Geometric Mean Titer (GMT) of Anti-HPV Type 6 Antibody | Month 7 (1 month postdose 3 in study Phase A) | Anti-HPV Type 6 antibodies were measured by cLIA. The seropositive cut-off threshold for this assay is defined as 20 milli Merck U/mL. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GARDASIL 9 to 12 Years Old GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B. | 80 |
| GARDASIL 13 to 15 Years Old GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B. | 30 |
| GARDASIL 16 to 26 Years Old GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A and safety evaluation continued to Month 12 (total study duration up to 12 months). Participants did not continue to study Phase B. | 120 |
| Placebo 9 to 12 Years Old Placebo to GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase A. Immunogenicity was assessed at Month 7 of study Phase A. After database lock and unblinding for study Phase A, participants had the option to receive GARDASIL™ 0.5 mL injection at the Day 1, Month 2, and Month 6 visits in study Phase B. Safety evaluation continued to Month 7 of study Phase B (total study duration up to 19 months) | 20 |
| Total | 250 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Study Phase A | Lost to Follow-up | 0 | 0 | 5 | 0 |
| Study Phase A | Other | 3 | 2 | 3 | 1 |
| Study Phase A | Protocol Violation | 6 | 3 | 2 | 2 |
Baseline characteristics
| Characteristic | Total | Placebo 9 to 12 Years Old | GARDASIL 16 to 26 Years Old | GARDASIL 13 to 15 Years Old | GARDASIL 9 to 12 Years Old |
|---|---|---|---|---|---|
| Age, Customized 13 to 15 years | 30 Participants | 0 Participants | 0 Participants | 30 Participants | 0 Participants |
| Age, Customized 16 to 26 years | 120 Participants | 0 Participants | 120 Participants | 0 Participants | 0 Participants |
| Age, Customized >26 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 9 to 12 years | 100 Participants | 20 Participants | 0 Participants | 0 Participants | 80 Participants |
| Age, Customized <9 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 249 Participants | 20 Participants | 119 Participants | 30 Participants | 80 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Island | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 250 Participants | 20 Participants | 120 Participants | 30 Participants | 80 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 61 / 79 | 22 / 29 | 103 / 119 | 15 / 19 |
| serious Total, serious adverse events | 0 / 79 | 0 / 29 | 1 / 119 | 0 / 19 |
Outcome results
Primary
Number of Participants Who Seroconvert to HPV Type 11
Seroconversion was defined as achieving an anti-HPV Type 11 cLIA level of \>=16 milli Merck U/mL. The dilution-corrected limit of detection for the Type 11 cLIA was 3.9 milli Merck U/mL.
Time frame: Month 7 (1 month postdose 3 in study Phase A)
Population: Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GARDASIL 9 to 26 Years Old | Number of Participants Who Seroconvert to HPV Type 11 | 147 Participants |
| Placebo 9 to 12 Years Old | Number of Participants Who Seroconvert to HPV Type 11 | 1 Participants |
Primary
Number of Participants Who Seroconvert to HPV Type 16
Seroconversion was defined as achieving an anti-HPV Type 16 cLIA level of \>=20 milli Merck U/mL. The dilution-corrected limit of detection for the Type 16 cLIA was 9.7 milli Merck U/mL.
Time frame: Month 7 (1 month postdose 3 in study Phase A)
Population: Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GARDASIL 9 to 26 Years Old | Number of Participants Who Seroconvert to HPV Type 16 | 160 Participants |
| Placebo 9 to 12 Years Old | Number of Participants Who Seroconvert to HPV Type 16 | 0 Participants |
Primary
Number of Participants Who Seroconvert to HPV Type 18
Seroconversion was defined as achieving an anti-HPV Type 18 cLIA level of \>=24 milli Merck U/mL. The dilution-corrected limit of detection for the Type 18 cLIA was 5.8 milli Merck U/mL.
Time frame: Month 7 (1 month postdose 3 in study Phase A)
Population: Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GARDASIL 9 to 26 Years Old | Number of Participants Who Seroconvert to HPV Type 18 | 156 Participants |
| Placebo 9 to 12 Years Old | Number of Participants Who Seroconvert to HPV Type 18 | 0 Participants |
Primary
Number of Participants Who Seroconvert to Human Papillomavirus (HPV) Type 6
Seroconversion was defined as achieving an anti-HPV Type 6 competitive Luminex Immunoassay (cLIA) level of \>=20 milli Merck U/mL. The dilution-corrected limit of detection for the Type 6 cLIA was 4.2 milli Merck U/mL.
Time frame: Month 7 (1 month postdose 3 in study Phase A)
Population: Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GARDASIL 9 to 26 Years Old | Number of Participants Who Seroconvert to Human Papillomavirus (HPV) Type 6 | 147 Participants |
| Placebo 9 to 12 Years Old | Number of Participants Who Seroconvert to Human Papillomavirus (HPV) Type 6 | 1 Participants |
Primary
Number of Participants With Elevated Temperature (Oral Temperature >=100 °F)
Time frame: Up to Day 5 after any vaccination in study Phase A
Population: The analysis included all participants receiving at least 1 vaccination in study Phase A and who had temperature data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GARDASIL 9 to 26 Years Old | Number of Participants With Elevated Temperature (Oral Temperature >=100 °F) | 9 Participants |
| Placebo 9 to 12 Years Old | Number of Participants With Elevated Temperature (Oral Temperature >=100 °F) | 6 Participants |
| GARDASIL 16 to 26 Years Old | Number of Participants With Elevated Temperature (Oral Temperature >=100 °F) | 7 Participants |
| Placebo 9 to 12 Years Old | Number of Participants With Elevated Temperature (Oral Temperature >=100 °F) | 5 Participants |
Primary
Number of Participants With Injection-site Adverse Experiences
Participants were prompted to report injection-site experiences of pain, erythema, or swelling and were also asked to report any other injection-site adverse experiences
Time frame: Up to Day 5 after any vaccination in study Phase A
Population: The analysis included all participants receiving at least 1 vaccination in study Phase A and who had postvaccination follow-up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GARDASIL 9 to 26 Years Old | Number of Participants With Injection-site Adverse Experiences | 54 Participants |
| Placebo 9 to 12 Years Old | Number of Participants With Injection-site Adverse Experiences | 21 Participants |
| GARDASIL 16 to 26 Years Old | Number of Participants With Injection-site Adverse Experiences | 88 Participants |
| Placebo 9 to 12 Years Old | Number of Participants With Injection-site Adverse Experiences | 9 Participants |
Primary
Number of Participants With Serious Adverse Experiences
A serious adverse experience is any adverse experience that results in death, is life threatening, results in persistent or significant disability/incapacity, results in or prolongs existing inpatient hospitalization, is a congenital anomaly/birth defect, is a cancer, is an overdose, or is another important medical event that may jeopardize the participant and may require medical or surgical intervention
Time frame: From the time of informed consent is signed through the last study visit (up to 19 months)
Population: The analysis included all participants receiving at least 1 vaccination in study Phase A or B and who had postvaccination follow-up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GARDASIL 9 to 26 Years Old | Number of Participants With Serious Adverse Experiences | 0 Participants |
| Placebo 9 to 12 Years Old | Number of Participants With Serious Adverse Experiences | 0 Participants |
| GARDASIL 16 to 26 Years Old | Number of Participants With Serious Adverse Experiences | 1 Participants |
| Placebo 9 to 12 Years Old | Number of Participants With Serious Adverse Experiences | 0 Participants |
Secondary
Geometric Mean Titer (GMT) of Anti-HPV Type 6 Antibody
Anti-HPV Type 6 antibodies were measured by cLIA. The seropositive cut-off threshold for this assay is defined as 20 milli Merck U/mL.
Time frame: Month 7 (1 month postdose 3 in study Phase A)
Population: Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| GARDASIL 9 to 26 Years Old | Geometric Mean Titer (GMT) of Anti-HPV Type 6 Antibody | 602 milli Merck U/mL |
| Placebo 9 to 12 Years Old | Geometric Mean Titer (GMT) of Anti-HPV Type 6 Antibody | NA milli Merck U/mL |
Secondary
GMT of Anti-HPV Type 11 Antibody
Anti-HPV Type 11 antibodies were measured by cLIA. The seropositive cut-off threshold for this assay is defined as 16 milli Merck U/mL.
Time frame: Month 7 (1 month postdose 3 in study Phase A)
Population: Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| GARDASIL 9 to 26 Years Old | GMT of Anti-HPV Type 11 Antibody | 626 milli Merck U/mL |
| Placebo 9 to 12 Years Old | GMT of Anti-HPV Type 11 Antibody | NA milli Merck U/mL |
Secondary
GMT of Anti-HPV Type 16 Antibody
Anti-HPV Type 16 antibodies were measured by cLIA. The seropositive cut-off threshold for this assay is defined as 20 milli Merck U/mL.
Time frame: Month 7 (1 month postdose 3 in study Phase A)
Population: Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| GARDASIL 9 to 26 Years Old | GMT of Anti-HPV Type 16 Antibody | 3786 milli Merck U/mL |
| Placebo 9 to 12 Years Old | GMT of Anti-HPV Type 16 Antibody | NA milli Merck U/mL |
Secondary
GMT of Anti-HPV Type 18 Antibody
Anti-HPV Type 18 antibodies were measured by cLIA. The seropositive cut-off threshold for this assay is defined as 24 milli Merck U/mL.
Time frame: Month 7 (1 month postdose 3 in study Phase A)
Population: Participants analyzed included those who received all 3 vaccinations in study Phase A and provided a sample for Month 7 serology testing. This analysis pooled results for participants receiving GARDASIL and compared these with results for participants receiving placebo.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| GARDASIL 9 to 26 Years Old | GMT of Anti-HPV Type 18 Antibody | 811 milli Merck U/mL |
| Placebo 9 to 12 Years Old | GMT of Anti-HPV Type 18 Antibody | NA milli Merck U/mL |