E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
For active immunization of girls and women from 10 years of age onwards for the prevention of persistent human papillomavirus (HPV) infections and related clinical outcomes (cytological abnormalities and pre-cancerous lesions) caused by oncogenic HPV types 16 and 18. |
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MedDRA Classification |
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 demonstrate efficacy of the candidate vaccine in the prevention of (1) persistent infection (6-month definition) with HPV-16 or HPV-18 (by polymerase chain reaction [PCR]) and/or (2) histopathologically confirmed CIN1+ associated with HPV-16 or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR) (combined endpoint), overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by enzyme-linked immunosorbent assay [ELISA]). |
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E.2.2 | Secondary objectives of the trial |
To evaluate vaccine efficacy in the prevention of: - persistent infection (6-month and 12-month definition) with HPV-16 or 18. - persistent infection (6-month definition) with other oncogenic HPV types. - histopathologically confirmed CIN2+ and CIN1+ associated with HPV-16 or 18 infection within the lesional component of the cervical tissue specimen. - any cytological abnormality associated with HPV-16 or 18 cervical infection - any cytological abnormality associated with other oncogenic HPV types. To evaluate vaccine immunogenicity at Months 7, 24 and 48 (all subjects) and at Months 12, 18 and 36 in a subset of subjects. To evaluate immune correlates of protection against persistent infections (6 and 12-month definitions) with HPV 16 or 18 and CIN1+ associated with HPV-16 or 18 infection using Month 7, 24 and 48 immunogenicity evaluations. To evaluate vaccine safety throughout the study period. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All subjects must satisfy the following criteria at study entry: - A woman who the investigator believes that she can and will comply with the requirements of the protocol (e.g. completion of the diary cards, return for follow-up visits). - A women of at least 26 years of age at the time of the first vaccination. - Written informed consent obtained from the subject prior to enrolment. - Free of obvious health problems as established by medical history and clinical examination before entering into the study. - Subject must have intact cervix (e.g. no history of cauterization or surgical treatment involving damage to the transformation zone of the cervix). Note: A subset of subjects with a previous history of HPV infection/treatment are allowed to enter the study (see Section 5.2.1). For this subset of subjects, the above mentioned inclusion criterion does not apply, and is replaced by: Subject must have a cervix. - Subject must have a negative urine pregnancy test. This test is not applicable to women of non-childbearing potential (e.g. surgically sterilized or one year post-menopausal). - Subject must be of non-childbearing potential (e.g. surgically sterilized or one year post-menopausal) or, if of childbearing potential, she must be abstinent (and if so, this must be documented in the source documents at each vaccination visit) or must be using an effective method of birth control (i.e. intrauterine contraceptive device; oral contraceptives or other equivalent hormonal contraception, e.g. progestogen-only implantable cutaneous hormonal patch or injectable contraceptives; diaphragm or condom in combination with contraceptive jelly, cream or foam) for 30 days prior to the first vaccination and must agree to continue such precautions for two months after completion of the vaccination series. |
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E.4 | Principal exclusion criteria |
The following criteria should be checked at the time of study entry. If any apply, the subject must not be included in the study: - Pregnant or breastfeeding (women must be at least three months post-pregnancy and not breastfeeding to enter the study). - A women planning to become pregnant, likely to become pregnant (as determined by the investigator) or planning to discontinue contraceptive precautions during the vaccination phase of the study, i.e. up to two months after the last vaccine dose (Month 0 – 8). - Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period (up to Month 48). - Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose. (For corticosteroids, this will mean prednisone, or equivalent, at least 0.5 mg/kg/day. Inhaled and topical steroids are allowed.) - Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before and 30 days after (i.e. days 0 – 29) the first dose of study vaccine. Planned administration/administration of routine meningococcal, hepatitis A or B, inactivated influenza, diphtheria/tetanus and/or diphtheria/tetanus-containing vaccine up to 8 days before the first dose of study vaccine is allowed. Enrolment will be deferred until the subject is outside of specified window. - Previous administration of MPL® or AS04 adjuvant. - Previous vaccination against HPV or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period. - History of HPV infection/treatment or planned treatment to evaluate an abnormal cervical cytology (Pap smear) test, e.g. colposcopy. Note: A subset of subjects with a previous history of HPV infection/treatment are allowed to enter the study (see Section 5.2.1). For this subset of subjects, the above mentioned exclusion criterion is not applicable. - Any medically diagnosed or suspected immunodeficient condition based on medical history and physical examination (no lab testing required). - History of allergic disease, suspected allergy or reactions likely to be exacerbated by any component of the study vaccine, e.g. aluminium, MPL®. - Hypersensitivity to latex (found in syringe-tip cap and plunger). - Known acute or chronic, clinically significant neurologic, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests. - History of chronic condition(s) requiring treatment such as cancer, chronic hepatic or kidney disease(s), diabetes or autoimmune disease.This exclusion criterion should be understood as exclusion of subjects having significant medical conditions (such as cancer, autoimmune diseases) currently under treatment. - Administration of immunoglobulins and/or any blood product within three months preceding the first dose of study vaccine, or planned administration during the study period. Enrolment will be deferred until the subject is outside of specified window. - Acute disease at the time of enrolment. Acute disease is defined as the presence of a moderate or severe illness with or without fever. Enrolment will be deferred until condition is resolved. All vaccines can be administered to persons with a minor illness such as diarrhoea or mild upper respiratory infection with or without low-grade febrile illness, i.e. oral/axillary temperature <37.5°C (99.5°F). - Heavy bleeding (menstruation or other) or heavy vaginal discharge in which a pelvic exam cannot be performed (and no cervical sample can be taken). Enrolment will be deferred until condition is resolved according to investigators medical judgement. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Persistent infection (6-month definition) with HPV-16 or HPV 18 (by PCR) and/or histopathologically confirmed CIN1+ associated with HPV 16 or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR) (combined endpoints), overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA). Persistent cervical HPV infection (6-month definition) is defined as detection of the same HPV type(s) (by PCR) in cervical samples at two consecutive evaluations over approximately a 6-month interval. The definition of 6-month persistence will be further specified in the report analysis plan (RAP).
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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 | 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 |
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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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
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) | 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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 |
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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.8.9.1 | In the Member State concerned years | 4 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |