| 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, and persistent infection caused by Human Papillomavirus (HPV) 6, 11,
16, 18, 31, 45, 52, and 58. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10063001 |
| E.1.2 | Term | Human papilloma virus infection |
|
| 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 |
To evaluate the tolerability of the octavalent HPV L1 VLP vaccine when
administered to 16- to 26-year-old women.
To demonstrate that administration of octavalent HPV L1 VLP vaccine will
reduce the combined incidence of HPV 31-, 45-, 52-, and 58-related cervical, vulvar, and vaginal cancer, AIS, CIN 2/3, VIN 2/3, VaIN 2/3, CIN 1, VIN 1, VaIN 1, genital warts, and persistent infection, 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 confirm that the octavalent HPV L1 VLP vaccine induces noninferior
immune responses for anti-HPV 6, 11, 16, and 18 compared to GARDASIL™ |
|
| E.2.2 | Secondary objectives of the trial |
To confirm the octavalent HPV L1 VLP vaccine formulation for use in Phase
III trials with respect to HPV types 31, 45, 52, and 58.
To evaluate the persistence of anti-HPV 6, 11, 16, 18, 31, 45, 52, and 58
responses generated by octavalent HPV L1 VLP vaccine.
To evaluate whether the administration of octavalent HPV L1 VLP vaccine
results in a combined incidence of persistent HPV 6, 11, 16, and 18 infection and
HPV 6-, 11-, 16-, and 18-related cervical, vulvar, and vaginal disease that is comparable to the combined incidence observed with GARDASIL™. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be randomized and receive the first study vaccination, subjects should meet all
inclusion criteria. For items with an asterisk (*), if the subject does not meet these
inclusion criteria, the Day 1 visit may be rescheduled for a time when these criteria
can be met.
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 (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.
3. Subject is able to read, understand, and complete the vaccination report card.
4. Subject is judged to be in good physical health on the basis of medical history,
physical examination, and laboratory results.
5. 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.
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.
6. *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, Pap test, or
biopsy/definitive therapy tissue).
7. *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, Pap test, or biopsy/definitive therapy tissue).
8. *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. |
|
| E.4 | Principal exclusion criteria |
To be randomized and receive the first study vaccination, subjects should not have any exclusion criteria. For items with an asterisk (*), if the subject meets these exclusion criteria, the Day 1 visit may be rescheduled for a time when these criteria are not met.
1. Subject has a history of an abnormal Pap test (showing ASC-US or worse) or an
abnormal cervical biopsy result (showing cervical intraepithelial neoplasia [CIN] or
worse).
2. Subject has never had a history of an abnormal Pap test, but 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. Alcohol abusers are defined as those who drink despite recurrent social, interpersonal, and/or legal problems as a result of alcohol use.
4. Subject has a history of severe allergic reaction (e.g., swelling of the mouth and
throat, difficulty breathing, hypotension or shock) that required medical intervention.
5. 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]). For the purpose of this exclusion criterion, an allergy to
vaccine components is defined as an allergic reaction that met the criteria for serious
adverse experiences defined in Section 3.4.
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 the following
immunosuppressive therapies: radiation therapy, cyclophosphamide, azathioprine,
methotrexate, any chemotherapy, cyclosporin, leflunomide (Arava™), TNF-α
antagonists, monocolonal antibody therapies (including rituximab [Rituxan™]), intravenous gamma globulin (IVIG), antilymphocyte sera, or other therapy known to
interfere with the immune response. With regard to systemic corticosteroids, a
subject will be excluded if she is currently receiving steroid therapy, has recently
(defined as within 2 weeks of enrollment) received such therapy, or has received 2 or
more courses of high dose corticosteroids (orally or parenterally) lasting at least 1
week in duration in the year prior to enrollment. Subjects using inhaled, nasal, or
topical corticosteroids are considered eligible for the study.
9. Subject has received any immune globulin product (including RhoGAM™ [Ortho-
Clinical Diagnostics]) or blood-derived product within the 3 months prior to the Day
1 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 virus) 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, keep appointments, or is
planning to relocate during the study.
18. *Subject has had a fever (defined as an oral temperature of ≥100°F or ≥37.8°C)
within the 24-hour period prior to the Day 1 vaccination.
19. Subject is pregnant (as determined by a serum pregnancy test or urine pregnancy test
that is sensitive to 25 mIU/mL β-hCG).
20. *Subject has clinical evidence of gross purulent cervicitis.
See Protocol for remaining exclusion critera.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy case of persistent HPV 31, 45, 52, or 58 infection or HPV 31-, 45-,
52-, or 58-related cervical, vulvar, or vaginal cancer, AIS, CIN 2/3, VIN 2/3, VaIN 2/3,
CIN 1, VIN 1, VaIN 1, or condyloma acuminata is defined as a subject, who, after the
completion of the Month 7 visit, is found to have an incident case of persistent HPV 31, 45, 52 or 58 infection, or HPV 31/45/52/58-related clinical disease defined as any of the following: genital warts (condyloma acuminata), vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VaIN), cervical dysplasia (any grade cervical intraepithelial neoplasia [CIN]), Adenocarcinoma in Situ (AIS), and cervical, vulvar, or vaginal cancer. HPV infection or related disease is defined to have occurred when any of the following conditions are satisfied:
1. Persistent HPV 31, 45, 52 or 58 Infection. This endpoint is defined to have occurred if a subject (a) is positive for the same HPV type by the HPV 31/45/52/58 PCR assay to at least 1 common gene in 2 or more consecutive cervicovaginal/external genital or biopsy samples obtained at least 4 months apart; or (b) has a biopsy showing pathologic evidence of HPV disease as determined by the consensus diagnosis of the HPV Vaccine Program Pathology Panel AND is positive for the same HPV type to at least 1 common gene in the sample obtained immediately prior to or immediately following the biopsy showing HPV disease; or (c) demonstrates first time HPV 31/45/52/58 PCR positivity at the final visit before being lost to follow-up.
2. External genital warts, vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VaIN), vulvar cancer, or vaginal cancer related to HPV 31, 45, 52 or 58. This endpoint is defined to have occurred if on a single biopsy or excised tissue, there is the HPV Vaccine Program Pathology Panel consensus diagnosis of genital wart, VIN (any grade), VaIN (any grade), vulvar cancer, or vaginal cancer AND at least 1 of HPV types 31, 45, 52 or 58 is detected by Thinsection PCR in an adjacent section from the same tissue block.
3. Cervical intraepithelial neoplasia (CIN), Adenocarcinoma in Situ (AIS), or cervical
cancer related to HPV 31, 45, 52 or 58. This endpoint is defined to have occurred if
on a single cervical biopsy, ECC, LEEP or Conization (cold knife/laser) specimen, there is the HPV Vaccine Program Pathology Panel consensus diagnosis of CIN (any
grade), AIS, or cervical cancer AND at least 1 of HPV types 31, 45, 52 or 58 is
detected by Thinsection PCR in an adjacent section from the same tissue block.
The primary efficacy endpoint includes all of the above. The incidence of each
individual infection and disease component of the primary endpoint will also be reported.
The primary immunogenicity endpoints are geometric mean titers (GMTs) to HPV 6, 11, 16, and 18 at Week 4 Postdose 3. Other important endpoints are geometric mean titers (GMTs) to HPV 31, 45, 52 and 58 at Week 4 Postdose 3. |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| 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.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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