| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Cervical Cancers
Vulvar Cancer
Vaginal Cancer
Genital Lesions
PAP Test Abnormalities
HPV Infections |
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| E.1.1.1 | Medical condition in easily understood language |
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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 V503-002:
a) Safety:
- To demonstrate that administration of the 9-valent HPV L1 VLP vaccine I duces non-inferior Geometric Mean Titers (GMTs) for serum anti-HPV 6, anti- HPV 11, anti-HPV 16, anti-HPV 18, anti-HPV 31, anti-HPV 33, anti-HPV 45, anti- HPV 52, and anti-HPV 58 in preadolescent and adolescent girls 9 to 15 years of age compared to young women 16 to 26 years of age.
b) Immunogenicity
Extension study V503-002-20:
- To evaluate the anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 responses generated following administration of a 3-dose regimen of 9-valent HPV L1 VLP vaccine up to 10 years post-dose 3. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Adolescent-Adult Immunobridging Substudy
Primary Objectives:
- To demonstrate that administration of the 9-valent HPV L1 VLP vaccine I duces non-inferior Geometric Mean Titers (GMTs) for serum anti-HPV 6, anti- HPV 11, anti-HPV 16, anti-HPV 18, anti-HPV 31, anti-HPV 33, anti-HPV 45, anti- HPV 52, and anti-HPV 58 in preadolescent and adolescent girls 9 to 15 years of age compared to young women 16 to 26 years of age.
- To demonstrate that administration of the 9-valent HPV L1 VLP vaccine induces non-inferior Geometric Mean Titers (GMTs) for serum anti-HPV 6, anti- HPV 11, anti-HPV 16, anti-HPV 18, anti-HPV 31, anti-HPV 33, anti-HPV 45, anti- HPV 52, and anti-HPV 58 in preadolescent and adolescent boys 9 to 15 years of age compared to young women 16 to 26 years of age.
Manufacturing Lot Consistency Substudy
Primary Objective:
- To demonstrate that the Final Manufacturing Process (FMP) results in 9- valent HPV L1 VLP vaccine that induces consistent serum anti-HPV 6, anti-HPV 11, anti-HPV 16, anti-HPV 18, anti-HPV 31, anti-HPV 33, anti-HPV 45, anti-HPV 52, and
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| E.3 | Principal inclusion criteria |
Boys and Girls Age 9 to 15 Years:
1. Subject is male or female, between the ages of 9 years and 0 days and 15 years and 364 days on the day of enrollment.
2. Subject is judged to be in good physical health on the basis of medical history, physical examination, and laboratory 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 agrees to provide study personnel with a primary telephone number as well as an alternate telephone number for follow-up purposes.
5. Subject must not yet have had coitarche and does not plan on becoming sexually active during the Day 1 through Month 7 period.
Inclusion Criteria: Women Age 16 to 26 Years:
6. Subject is female, between the ages of 16 years and 0 days and 26 years and 364 days on the day of enrollment.
7. Subject is judged to be in good physical health on the basis of medical history, physical examination, and laboratory results.
8. 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.
9. Subject is able to read, understand, and complete the vaccination report card.
10. Subject agrees to provide study personnel with a primary telephone number as well as an alternate telephone number for follow-up purposes.
11. Subject has never had Pap testing or has only had normal Pap test results.
12. Subject has a lifetime history of 0 to 4 male and/or female sexual partners at the time of enrollment. Male partner is defined as someone with whom the subject has penile penetrative sexual intercourse. Female partner is defined as someone who has contacted, either by penetrative (with fingers or other objects) or non-penetrative means, the subject’s genitalia during sexual activity.
13. 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 (cervical/genital swabs or Pap test).
14. Subject has refrained from sexual activity (including anal, vaginal, or genital/genital contact whether same sex or opposite sex) 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 (cervical/genital swabs or Pap test).
15. 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 (an example of a failure is a male condom that ruptures during sexual intercourse). Effective contraception is defined as a marketed, approved contraceptive product that the subject has used per the manufacturer’s instructions with every act of sexual intercourse. The subject understands and agrees that during the Day 1 through Month 7 period, she should not have sexual intercourse with males without effective contraception, and the uses of the rhythm method alone, withdrawal alone, and emergency contraception, are not acceptable methods per the protocol.
Extension study V503-002-10 (Immunogenicity follow-up from 7 months to 3 years):
Boys and Girls Age 9 to 15 Years:
- As inclusion criteria 1-15 above
Extension study V503-002-20 (10 yr F-U):
- Subject was enrolled in Protocol 002 between 9 and 15 years of age and received 3 doses of 9-valent HPV L1 VLP vaccine.
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| E.4 | Principal exclusion criteria |
Exclusion Criteria: Boys and Girls Age 9 to 15 Years
1. Subject has a known allergy to any vaccine component.
2. Subject has a history of severe allergic reaction that required medical intervention.
3. Subject has thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections.
4. Subject is concurrently enrolled in clinical studies of investigational agents.
5. (Girls only) - Subject is pregnant (as determined by a serum pregnancy test or urine pregnancy test that is sensitive to 25 mIU/mL β-hCG).
6. 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.
7. 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 rheumatoidarthritis (JRA), inflammatory bowel disease, or other autoimmune condition.
8. Subject has had a splenectomy.
9. Subject is receiving or has received in the year prior to enrollment immunosuppressive therapies prohibited by the protocol
10. 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.
11. 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.
12. Subject has received a marketed HPV vaccine, or has participated in an HPV vaccine clinical trial and has received either active agent or placebo.
13. Subject has had a fever within the 24-hour period prior to the Day 1 vaccination.
14. 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.
15. Subject is unable to give consent/assent.
16. Subject is unlikely to adhere to the study procedures, keep appointments, or is planning to relocate during the study.
17. 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 abuse or dependence.
18. Subject has a history of a positive test for HPV.
Exclusion Criteria: Women Age 16 to 26 Years
19-21. As 1, 2, 3 above
22. Subject is concurrently enrolled in clinical studies of investigational agents or studies involving collection of cervical specimens.
23.- Subject is pregnant (as determined by a serum pregnancy test or urine pregnancy test that is sensitive to 25 mIU/mL β-hCG).
24. Subject is expecting to donate eggs during Day 1 through Month 7 of the study.
25-37. As 6-18 above
38. Subject has a history of an abnormal cervical biopsy result (showing cervical intraepithelial neoplasia [CIN] or worse).
39. Subject has a history of or clinical evidence at the Day 1 pelvic examination of HPVrelated external genital lesions (e.g., condyloma acuminata or vulvar intraepithelial neoplasia [VIN]) or external genital cancer, HPV-related vaginal lesions (e.g., condyloma acuminata or vaginal intraepithelial neoplasia [VaIN]) or vaginal cancer.
40. Subject has clinical evidence of gross purulent cervicitis.
41. Subject is having menses.
42. Subject does not have an intact cervix uteri or has more than one cervix uteri
Extension study V503-002-10 (Immunogenicity follow-up from 7 months to 3 years):
Boys and Girls Age 9 to 15 Years:
- As exclusion criteria 1-18 above.
Women Age 16 to 26 Years:
- Subjects enrolled in the women age 16-26 group will not participate in the V503-002-10 Extension.
Extension study V503-002-20 (10 yr F-U):
- Subjects who are concurrently enrolled in clinical studies that would involve or interfere with the collection of genital specimens. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Geometric Mean Titers (GMTs) for Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Females [Lot 1] Versus 16- to 26-Year-Old Females [Lot 1])
2. GMTs for Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Males [Lot 1] Versus 16- to 26-Year-Old Females [Lot 1])
3. GMTs for Each of the HPV Types Contained in the Vaccine (Lot Consistency Study)
4. Percentage of Participants With Injection Site Adverse Experiences (AEs)
5. Percentage of Participants With Systemic AEs
6. Percentage of Participants With Body Temperature ≥100.0°F (≥37.8ºC)
Extension study V503-002-10 (Immunogenicity follow-up from 7 months to 3 years):
7. Additional endpoints include GMTs and seroconversion percentages at Month 12, Month 24, and Month 36 in the extension phase of the study.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. 4 weeks post-vaccination 3 (Month 7)
2. 4 weeks post-vaccination 3 (Month 7)
3. 4 weeks post-vaccination 3 (Month 7)
4. up to 5 days after any vaccination
5. up to 15 days after any vaccination
6. up to 5 days after any vaccination
Extension study V503-002-10:
7. at Month 12, Month 24, and Month 36 in the extension phase of the study.
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| E.5.2 | Secondary end point(s) |
1. Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Females [Lot 1] Versus 16- to 26-Year-Old Females [Lot 1])
2. Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Males [Lot 1] Versus 16- to 26-Year-Old Females [Lot 1])
3. Percentage of Participants Who Seroconvert to Each of the HPV Types Contained in the Vaccine (Lot Consistency Study)
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 4 weeks post-vaccination 3 (Month 7)
2. 4 weeks post-vaccination 3 (Month 7)
3. 4 weeks post-vaccination 3 (Month 7)
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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 | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 |
Immunogenicity
Manufacturing Lot Consistency |
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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) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 |
| Base Study: Manufacturing Lot double-blinded for females ages 9 to 15. |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Manufacturing Lots 1, 2 and 3 |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 |
| Chile |
| Colombia |
| Costa Rica |
| India |
| Korea, Republic of |
| Peru |
| South Africa |
| Taiwan |
| Thailand |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| The overall study ends when the last participant completes the last study-related contact, withdraws consent, or is lost to follow-up. For purposes of analysis and reporting, the overall study ends when the Sponsor receives the last laboratory result or at the time of final contact with the last participant, whichever comes last. |
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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 | 11 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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