| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| vaccination against HPV infection/related disease |
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| E.1.1.1 | Medical condition in easily understood language |
| vaccination against HPV infection/related disease |
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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 | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071147 |
| E.1.2 | Term | Human papilloma virus immunization |
| E.1.2 | System Organ Class | 100000004865 |
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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 |
Primary Safety Objective: To demonstrate that octavalent HPV (Types 6, 11, 16, 18, 31, 45, 52, 58) L1 VLP vaccine1, when administered to 16- to 23-year-old women, is generally well tolerated.
Primary Immunogenicity Objective: To demonstrate that octavalent HPV VLP vaccine, when administered in a 3-dose regimen, induces acceptable responses for HPV Types 6, 11, 16, 18, 31, 45, 52, and 58 at 4 weeks Postdose 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 | No |
| E.3 | Principal inclusion criteria |
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.
a. Subject is between the ages of 16 years and 0 days and 23 years and 364 days on the day of randomization.
b. Subject (or, for minor subjects, parent/legal guardian and subject) fully understands study procedures, agrees to participate in the study, and has given written informed consent.
c. Subject is judged to be in good physical health on the basis of medical history, physical examination, and laboratory results.
d. Subject has a lifetime history of 0 to 4 sexual partners (male and/or female). Male partner is defined as someone with whom the subject has 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.
e. *Subject has refrained from douching/vaginal cleansing and using vaginal medications or preparations for 2 days prior to the Day 1 visit. Subject agrees to refrain from these activities for 2 days prior to any future visit that includes collection of study specimens (cervical/genital swabs, Pap test, or
biopsy/definitive therapy tissue).
f. *Subject has refrained from sexual activity (including anal, vaginal, or genital/genital contact whether same sex or opposite sex) for 2 days prior to the Day 1 visit. Subject agrees to refrain from these sexual activities for 2 days prior to any future visit that includes collection of study specimens (cervical/genital swabs, Pap test, or biopsy/definitive therapy tissue).
g. *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.
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| 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.
a. 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).
b. Subject has never had a history of an abnormal Pap test, but has a history of a positive test for HPV.
c. Subject has a history of recent (within 1 year from the date of enrollment) or ongoing alcohol abuse or other drug abuse. Alcohol abusers are defined as those who drink despite recurrent social, interpersonal, and legal problems as a result of alcohol use.
d. 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.
e. 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 I.G.
f. 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.
g. Subject has had a splenectomy.
h. 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, Rituximab (Rituxan™), monocolonal antibody therapies, 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.
i. 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.
j. * 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.
k. Subject has thrombocytopenia or other coagulation disorder that would contraindicate intramuscular injections.
l. Subject is concurrently enrolled in clinical studies of investigational agents or studies involving collection of cervical specimens.
m. Subject has a history of participation in an HPV vaccine clinical trial and has received either active agent or placebo.
n. Subject has a history of any disease or condition which, in the investigator’s opinion, may confound the results of the study or pose an additional risk to the subject.
o. 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.
p. *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.
q. Subject is pregnant (as determined by a serum pregnancy test or urine pregnancy test that is sensitive to 20 mIU/mL β-hCG).
r. *Subject has clinical evidence of gross purulent cervicitis.
s. *Subject is having menses.
t. Subject has a history of or clinical evidence at the Day 1 pelvic examination of HPV-related external genital lesions (e.g., condyloma acuminata or vulvar intraepithelial neoplasia [VIN]), external genital cancer, external genital lesions of unknown etiology, HPV-related vaginal lesions (e.g., condyloma acuminata or vaginal intraepithelial neoplasia [VaIN]), vaginal cancer or vaginal lesions of unknown etiology.
u. Subject does not have an intact cervix uteri or has more than one cervix uteri.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety
The following measures were collected from each study subject to assess safety: 1) temperatures (oral or oral equivalent) 4 hours after vaccination and daily for the next 4 days; 2) all adverse experiences that occurred within 14 calendar days following vaccination; 3) all serious clinical adverse experiences that occurred within 14 days following vaccination; and 4) all serious clinical adverse experiences that resulted in the death of the subject or were determined to be related to the study vaccine or study procedure that occurred at any time during the study.
Immunogenicity
The primary immunogenicity endpoints for evaluating antibody response are geometric mean titers (GMTs) to HPV 6, 11, 16, and 18 at Week 4 Postdose 3 and the percentages of subjects who seroconvert for each of HPV Types 31, 45, 52, and 58 by Week 4 Postdose 3. (Seroconversion is defined as changing serostatus from seronegative at baseline to seropositive by Week 4 Postdose 3, where the anti-HPV serum cLIA cutoffs (in mMU/mL or mcg/mL units) for determining serostatus for HPV Types 6, 11, 16, 18, 31, 45, 52, and 58 will be determined. A subject with a cLIA titer at or above the serostatus cutoff for a given HPV type is considered seropositive for that type.)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety information and serum for immunogenicity will be collected at each study visit through Month 7 and analyzed at the end of the study. |
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| E.5.2 | Secondary end point(s) |
The secondary immunogenicity endpoints are the percentages of subjects who seroconvert for each of HPV Types 6, 11, 16, and 18 by Week 4 Postdose 3 and Postdose 2. In addition, GMTs of HPV 31, 45, 52, and 58 at Week 4 Postdose 3 and Postdose 2 will be summarized. Both seroconversion rates and GMTs at Week 4 Postdose 3 for HPV 31, 45, 52 and 58 will be evaluated for selecting a dose for Phase III study.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Serum for immunogenicity will be collected at each study visit through Month 7 and analyzed at the end of the study. |
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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 | 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 | 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) | 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.8.2.4 | 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 | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Colombia |
| Peru |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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