| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of cervical, vulvar, and vaginal cancers and related precancers, external genital lesions, Pap test abnormalities, and persistent infection caused by Human Papillomavirus (HPV) 6, 11, 16, 18, 31, 33, 45, 52, and 58. |
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| E.1.1.1 | Medical condition in easily understood language |
| Prevention of Papillomavirus Infections |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10063001 |
| E.1.2 | Term | Human papilloma virus infection |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
BASE STUDY:
- To evaluate the tolerability of the V503.
Part A:
- To evaluate a formulation of V503 for use in the efficacy evaluation in Part B.
Part B:
- To demonstrate that administration of V503 will reduce the combined incidence of HPV 31-, 33-, 45-, 52-, and 58-related highgrade cervical abnormalities, Adenocarcinoma In Situ, invasive cervical carcinoma, high-grade Vulvar Intraepithelial Neoplasia, highgrade Vaginal Intraepithelial Neoplasia, vulvar cancer, or vaginal cancer, compared with GARDASIL in 16- to 26-year-old adolescent and young adult women who are seronegative at Day 1 and PCR negative Day 1 through Month 7 to the relevant HPV type.
- To demonstrate that V503 induces noninferior GMTs for anti-HPV 6, 11, 16, and 18 compared to GARDASIL™
EXTENSION:
To evaluate anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 responses generated at Days 7 and 28 following administration of a fourth dose of 9vHPV vaccine in young women who received a 3-dose regimen of V503.
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| E.2.2 | Secondary objectives of the trial |
BASE STUDY:
- To demonstrate that administration of 9-valent HPV L1 VLP vaccine will reduce the combined incidence of HPV 31-, 33-, 45-, 52-, and 58-related persistent infection detected in samples from two or more consecutive visits (±1 month visit windows) 6 months or longer apart compared with GARDASIL in 16- to 26-yearold adolescent and young adult women who are seronegative at Day 1 and PCR negative Day 1 through Month 7 to the relevant HPV type.
- To demonstrate that 9-valent HPV L1 VLP vaccine is immunogenic with respect to HPV types 31, 33, 45, 52, and 58.
- To demonstrate that the 9-valent HPV L1 VLP vaccine induces noninferior immune responses with respect to seroconversion percentages for HPV 6, 11, 16, and 18 compared to GARDASIL
See protocol for additional secondary objectives.
EXTENSION:
- To evaluate the tolerability of a fourth dose of 9vHPV vaccine in young women who received a 3-dose regimen of 9vHPV vaccine at 16 to 26 years of age
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
BASE STUDY:
1. Subject is female, between the ages of 16 years and 0 days and 26 years and 364 days on the day of randomization.
2. Subject has never had Pap testing or has only had normal Pap test results.
3. Subject (or, for minor subjects, parent/legal guardian and subject) fully understands study procedures, alternative treatments available, the risks involved with the study, and voluntarily agrees to participate by giving written informed consent.
4. Subject is able to read, understand, and complete the vaccination report card.
5. Subject is judged to be in good physical health on the basis of medical history, physical examination, and laboratory results.
6. The subject has the following lifetime sexual history at the time of enrollment:
a) Subject has had 1 to 4 male and/or female sexual partners; or
b) Subject has had 0 male and/or female sexual partners, is 18 years of age or older, and plans to become sexually active within the first 3 months of the study.
7. Subject has refrained from douching/vaginal cleansing and using vaginal medications or preparations for 2 calendar days prior to the Day 1 visit. Subject agrees to refrain from these activities for 2 calendar days prior to any future visit that includes collection of study specimens.
8. Subject has refrained from sexual activity for 2 calendar days prior to the Day 1 visit. Subject agrees to refrain from these sexual activities for 2 calendar days prior to any future visit that includes collection of study specimens.
9. Since the first day of the subject’s last menstrual period through Day 1, the subject has not had sex with males or has had sex with males and used effective contraception with no failures.
EXTENSION PART V503-001-04:
1. *Cohort 1: Subject was enrolled in Part B of the V503-001 base study between 16 and 26 years of age, was randomized to the 9vHPV vaccine cohort, and was in the Per-Protocol Immunogenicity population for at least one HPV type3.
*Cohort 2: Subject was enrolled in Part A or Part B of the V503-001 base study between 16 and 26 years of age, was randomized to the GARDASIL™ cohort, and received at least 1 dose of GARDASIL™.
2. Subject is judged to be in good physical health on the basis of medical history, physical examination, and laboratory results
3. Subject fully understands study procedures, alternative treatments available, the risks involved with the study, and voluntarily agrees to participate by giving written informed consent.
4. Subject is able to read, understand, and complete the vaccination report card.
5. Subject agrees to provide study personnel with a telephone number for follow-up purposes.
6. *Cohort1: Since the first day of the subject’s last menstrual period through Month 60, the subject has not had sex with males or has had sex with males and used effective contraception with no failures. The subject understands and agrees that during the: Month 60 through Month 61 period, Cohort 2: Month 60 through Month 67 period, she should not have sexual intercourse with males without effective contraception.
*Cohort2: Since the first day of the subject’s last menstrual period through Month 60, the subject has not had sex with males or has had sex with males and used effective contraception with no failures. The subject understands and agrees that during the: Month 60 through Month 67 period, she should not have sexual intercourse with males without effective contraception.
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| E.4 | Principal exclusion criteria |
BASE STUDY:
1. Subject has a history of an abnormal cervical biopsy result (showing cervical intraepithelial neoplasia [CIN] or worse).
2. Subject has a history of a positive test for HPV.
3. Subject is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence.
4. Subject has a history of severe allergic reaction that required medical intervention.
5. Subject has known allergy to any vaccine component.
6. Subject is currently immunocompromised or has been diagnosed as having a congenital or acquired immunodeficiency, HIV infection, lymphoma, leukemia, systemic lupus erythematosus (SLE), rheumatoid arthritis, juvenile rheumatoid arthritis (JRA), inflammatory bowel disease, or other autoimmune condition.
7. Subject has had a splenectomy.
8. Subject is receiving or has received in the year prior to enrollment immunosuppressive therapies prohibited by the protocol.
9. Subject has received any immune globulin product or blood-derived product within the 3 months prior to the Day1 vaccination, or plans to receive any such product during Day 1 through Month 7 of the study.
10. Subject has received non-replicating (inactivated) vaccines within 14 days prior to the Day 1 vaccination or has received replicating (live) vaccines within 21 days prior to the Day 1 vaccination.
11. Subject has thrombocytopenia or other coagulation disorder that would contraindicate intramuscular injections.
12. Subject has donated blood within 1 week prior to the Day 1 vaccination or intends to donate during Day 1 through Month 7 of the study.
13. Subject is expecting to donate eggs during Day 1 through Month 7 of the study.
14. Subject is concurrently enrolled in clinical studies of investigational agents or studies involving collection of cervical specimens.
15. Subject has received a marketed HPV vaccine, or has participated in an HPV vaccine clinical trial and has received either active agent or placebo.
16. Subject has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might confound the results of the study, or interfere with the subject’s participation for the full duration of the study, such that it is not in the best interest of the subject to participate.
17. Subject is unlikely to adhere to the study procedures..
18. Subject has had a fever within the 24-hour period prior to the Day 1 vaccination.
19. Subject is pregnant.
20. Subject has clinical evidence of gross purulent cervicitis.
21. Subject is having menses.
22. Subject has a history of or clinical evidence at the Day 1 pelvic examination of HPVrelated external genital lesions or external genital cancer, HPV-related vaginal lesions or vaginal cancer.
EXTENSION PART V503-001-04:
Base study exclusion criteria 3-8, 10, 11, 16-19, and
- Subject is concurrently enrolled in clinical studies of investigational agents.
- Subject has received an HPV vaccine outside of the context of the V503-001 study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
BASE STUDY:
1. Combined Incidence of HPV Type 31/33/45/52/58-related Disease (Test of Hypothesis)
2. Combined Incidence of HPV Type 31/33/45/52/58-related Disease (End-of-study Update)
3. Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58
4. Percentage of Participants With One or More Adverse Event
5. Percentage of Participants With One or More Injection-site Adverse Event
6. Percentage of Participants With One or More Non-injection-site (Systemic) Adverse Event
7. Percentage of Participants With One or More Vaccine-related Adverse Event
8. Percentage of Participants With Study Medication Withdrawn Due to an Adverse Event |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
BASE STUDY:
1. From Day 1 until >=30 cases accumulate, up to Month 54 in the base study
2. Up to Month 54 in the base study
3. 4 weeks postdose 3 in the base study
4. Up to Month 7 (low- and high-dose V503) or up to Month 54 (mid-dose V503 and Gardasil)
5. Up to Day 5 after any vaccination
6. Up to Day 15 after any vaccination
7. Up to Month 7 (low- and high-dose V503) or up to Month 54 (mid-dose V503 and Gardasil)
8. Time Frame: Up to Month 6 |
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| E.5.2 | Secondary end point(s) |
BASE STUDY:
1. Combined Incidence of HPV Type 31/33/45/52/58-related Persistent Infection
2. Percentage of Participants Who Are Seropositive for HPV Types 6/11/16/18/31/33/45/52/58
EXTENSION:
1. Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Predose 4
2. Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Day 7 Postdose 4
3. Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Day 28 Postdose 4 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
BASE STUDY:
1. Up to Month 54 in the base study
2. 4 weeks postdose 3
EXTENSION:
1. Month 60: predose 4 in the Extension Study (Cohort 1)
2. Month 60 + 1 week: Day 7 postdose 4 in the Extension Study (Cohort 1)
3. Month 61: 28 days postdose 4 in the Extension Study (Cohort 1) |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Hong Kong |
| Japan |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Peru |
| Philippines |
| Puerto Rico |
| Taiwan |
| Thailand |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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