| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| For active immunization of females for the prevention of cervical cancer by protecting against persistent infections, cytological abnormalities including atypical squamous cells of undetermined significance (ASC-US), cervical intraepithelial neoplasia (CIN) and pre-cancerous lesions (CIN 2/3) caused by oncogenic human papillomavirus (HPV) types 16 and 18. |
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| E.1.1.1 | Medical condition in easily understood language |
| Cervarix is a vaccine that protects women against infection caused by Human Papillomavirus (HPV) type 16 and type 18. These viruses can infect the skin or the genitals, which can lead to cancer. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| 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 |
To evaluate the immunogenicity of the HPV-16/18 L1 VLP AS04 vaccine one month after the last dose when administered at different dosages (20 or 40 µg of each HPV antigen) and on different schedules (0, 2- or 0, 6-months) compared with the standard HPV-16/18 L1 VLP AS04 vaccine administered on a 3-dose schedule (0, 1, 6-months).
To evaluate the reactogenicity of the HPV-16/18 L1 VLP AS04 vaccine when administered at different dosages (20 or 40 µg of each HPV type) and on different schedules (0, 2- or 0, 6-months) with respect to the occurrence, intensity and relationship to vaccination of solicited local and general symptoms reported within 7 days (Days 0 - 6) after each and any vaccination.
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| E.2.2 | Secondary objectives of the trial |
To evaluate the safety of the HPV-16/18 L1 VLP AS04 vaccine when administered at different dosages and on different schedules up to Month 60.To demonstrate the non-inferiority of the antibody response to the 2-dose schedule of the HPV-16/18 L1 VLP AS04 vaccine in the 9-14, then in the 15-19 and then in the 20-25 year age strata (these 3 objectives will be assessed sequentially) when administered at different dosages and on different schedules as compared to the standard 3-dose schedule in subjects 15-25 years of age, one month after the last dose of vaccine.If any of the above secondary objectives for immunogenicity are demonstrated:To examine pair-wise comparisons of the antibody response between each 2-dose schedule group and the standard 3-dose schedule, one month after the last dose of vaccine within each age stratum.To evaluate the antibody response to all dose schedules and dosages of the HPV-16/18 L1 VLP AS04 vaccine in each age stratum during the extended follow-up period.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Subjects who the investigator believes that they and/or their parents can and will comply with the requirements of the protocol should be enrolled in the study.
•A female subject between, and including, 9 and 25 years of age at the time of the first vaccination.
•Written informed consent/assent obtained from the subject prior to enrolment. For subjects above the legal age of consent, written informed consent must be obtained from the subject. For subjects below the legal age of consent, written informed consent from the subject’s parents/legally acceptable representative, and written informed assent must be obtained from the subject.
•Healthy subjects as established by medical history and history-oriented clinical examination before entering into the study.
•Subjects must be of non-childbearing potential, i.e. have a current tubal ligation, hysterectomy, ovariectomy or be pre-menarcheal; or if she is of childbearing potential, she must practice adequate contraception for 30 days prior to vaccination, have a negative pregnancy test and continue such precautions for two months after completion of the vaccination series. |
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| E.4 | Principal exclusion criteria |
•Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period.
•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,>0.5 mg/kg/day. Inhaled and topical steroids are allowed.)
•Concurrently participating in another clinical study, at any time during the study period (up to Month 24), in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device).
•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 vaccine. Planned administration/administration of routine meningococcal, hepatitis A or B, inactivated influenza, diphtheria/tetanus and/or diphtheria/tetanus-containing vaccines, 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.
•Pregnant or breastfeeding female.
•A woman planning to become pregnant or planning to discontinue contraceptive precautions during the study period, up to two months after the last vaccine dose.
•Previous vaccination against HPV or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period (up to Month 24).
•Previous administration of MPL or AS04 adjuvant.
•Cancer or autoimmune disease under treatment.
•Any medically diagnosed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).
•History of allergic disease or reactions likely to be exacerbated by any component of the vaccine, e.g. MPL, AS04.
•Hypersensitivity to latex (found in syringe-tip cap and plunger).
•Acute disease at the time of enrolment. (Acute disease is defined as the presence of a moderate or severe illness with or without fever. All vaccines can be administered to persons with a minor illness such as diarrhoea, mild upper respiratory infection with or without low-grade febrile illness, i.e. Oral temperature < 37.5°/Axillary temperature < 37.5°C).
•Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory tests.
•Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period (up to Month 24).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
•HPV-16 and HPV-18 antibody titres (by ELISA) assessed one month after the last dose of vaccine when administered at different dosages (20 or 40 µg of each HPV type) and on different schedules (0, 2- or 0, 6 or 0, 1, 6-months).
Safety
•Occurrence, intensity and causal relationship to vaccination of solicited local and general symptoms within 7 days (Days 0 - 6) after each and any vaccination.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 month after the last dose of vaccine
Safety: 7-day period following each vaccination |
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| E.5.2 | Secondary end point(s) |
•Occurrence, intensity and causal relationship to vaccination of unsolicited symptoms within 30 days (Days 0 - 29) after any vaccination.
•Occurrence of serious adverse events (SAEs) up to Month 7 and during the extended safety follow-up period (up to Month 60).
•Occurrence of medically significant conditions (MSCs) up to Month 7 and during the extended safety follow-up period (up to Month 60), regardless of causal relationship to vaccination and intensity.
•Occurrence of New Onset Chronic Diseases (NOCD)/New Onset Autoimmune Diseases (NOAD) (e.g. autoimmune disorders, asthma, type I diabetes, allergies, etc…), regardless of causal relationship to vaccination and intensity.
•Occurrence of pregnancies and pregnancy outcomes.
•Changes in haematological and biochemical parameters from blood samples taken from all subjects at Month 0 and Month 7.
•HPV-16 and HPV-18 antibody titres (by ELISA) assessed one month after the last dose of vaccine (Month 7) in all study groups and in all age strata.
•HPV-16 and HPV-18 antibody titre (by ELISA) assessed one month after the second dose of vaccine in the 2-dose schedule groups (Month 3).
•HPV-16 and HPV-18 antibody titres (by ELISA) and seroconversion status assessed during the extended follow-up period ( up to Month 60). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Unsolicited symptoms: 30-day period following each vaccination.
SAEs, MSCs, NOCD/NOAD and pregnancy: Throughout the study period.
Haematological and biochemical parameters: At Day 0 and Month 7.
ELISA: At Day 0 and Months 3, 7, 12, 18, 24, 36, 48 and 60 (in the 2-dose schedule groups), or at Day 0 and Months 7, 12, 18, 24, 36, 48 and 60 (in the 3-dose schedule group). |
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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 |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | No |
| E.8.1.5 | Parallel group | Yes |
| 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 |
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 | 21 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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 | 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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| The end of the trial is planned at Month 7 (study conclusion at Month 7). The extended safety and immunogenicity follow-up period will occur until Month 60. The results of interim analyses during the extended follow-up period will be provided in annex reports (at Month 12, Month 18, Month 24, Month 36, Month 48 and Month 60). |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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