| 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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| 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 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]).
If efficacy is demonstrated, the following objective will be assessed sequentially:
-To demonstrate efficacy of the candidate vaccine in the prevention of (1) persistent infection (6-month definition) with HPV-16 or HPV-18 (by PCR) and/or (2) histopathologically-confirmed CIN1+ associated with HPV-16 or HPV-18 cervical infection detected using the HPV TAA, overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA).
|
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| E.2.2 | Secondary objectives of the trial |
To evaluate vaccine efficacy in the prevention of:
-persistent infection (PI)(6/12-month def.) with HPV-16 or 18
-PI(6/12-month def.) with other oncogenic HPV types
-histopathologically confirmed CIN2+ & CIN1+ ass with HPV-16 or 18 infection within the lesional component of the cervical tissue specimen and using the HPV Type Assignment Algorithm
-histopathologically confirmed CIN1+ irrespective of HPV cervical infection
-any cytological abnormality ass with HPV-16 or 18 cervical infection
-any cytological abnormality ass with other oncogenic HPV types
-colposcopy referrals and local cervical therapy
To evaluate vaccine immunogenicity at Months 7,24,48,84 (all subjects) & at Months 12,18,36,60,72 in a subset of subjects
To evaluate immune correlates of protection against persistent infections (6/12-month def.) with HPV 16 or 18 & CIN1+ ass with HPV-16 or 18 infection using Months 7,24,48,84 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 84).
- 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 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 using the HPV TAA, 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.
In the second analysis, referred to as the “HPV Type Assignment Algorithm (TAA)”, the association between a lesion and an HPV type will not only be based on the detection of HPV DNA from this type in the lesion, but also on detection of the same HPV type in at least one of the two immediately preceding cytology samples in case more than one HPV type is found in the lesion. These analyses will be performed in a sequential manner, i.e., the second analysis will only be performed if statistical significance is reached for the first analysis. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to study end (Month 84) |
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| E.5.2 | Secondary end point(s) |
•Persistent infection (6-month definition) with HPV-16 or HPV-18 (by PCR), overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA).
•Persistent infection (12-month definition) with HPV-16 or HPV-18 (by PCR), overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA).
•Persistent infection (6-month definition) with oncogenic HPV types (by PCR), individually or in combinations, in subjects HPV DNA negative for the type considered, regardless of initial serostatus.
•Persistent infection (12-month definition) with oncogenic HPV types (by PCR), individually or in combinations, in subjects HPV DNA negative for the type considered, regardless of initial serostatus.
•Histopathologically-confirmed CIN2+ associated with HPV-16 or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR), and using the HPV TAA, overall and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by ELISA).
•Histopathologically-confirmed CIN1+ associated with HPV 16 or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR), and using the HPV TAA, overall and stratified according to initial (Month 0) HPV-16 or HPV 18 serostatus (by ELISA).
•Histopathologically-confirmed CIN1+ associated with HPV-16 and/or HPV-18 cervical infection detected within the lesional component of the cervical tissue specimen (by PCR), and using the HPV TAA, irrespective of baseline HPV DNA and serostatus.
•Histopathologically-confirmed CIN1+ irrespective of HPV cervical infection and irrespective of baseline HPV DNA status.
•Any cytological abnormality associated with HPV-16 or HPV-18 cervical infection (by PCR), overall and stratified according to initial (Month 0) HPV-16 or HPV 18 serostatus (by ELISA).
•Any cytological abnormality associated with oncogenic HPV types (by PCR), individually or in combinations, in subjects HPV DNA negative for the type considered, regardless of initial serostatus.
•Administration of colposcopy referrals and local cervical therapy (LEEP, CONE, KNIFE or LASER), irrespective of baseline HPV DNA status.
•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), and using the HPV TAA, irrespective of baseline HPV DNA and serostatus.
•HPV-16 and HPV-18 ELISA titres and seroconversion at Months 7, 24, 48 and 84 (all subjects) and at Months 12, 18, 36, 60 and 72 (in the immunogenicity subset). These analyses will be stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus. Viral neutralization may be assessed in a selected subset of subjects.
•HPV-16 and HPV-18 ELISA titres and seroconversion assessed in vaccine recipients with breakthrough HPV-16 and/or HPV-18 persistent infections and HPV-16 and/or HPV-18 associated CIN1+ lesions. These will be compared with selected non-cases (vaccine recipients without persistent infection or CIN1+, matched for age, race and clinic site).
•Occurrence, intensity, relationship to vaccination and resulting school or work absenteeism (as applicable) of solicited local or solicited general symptoms within 7 days (days 0 – 6) after each vaccination.
•Occurrence, intensity, relationship to vaccination and resulting school or work absenteeism (as applicable) of unsolicited symptoms within 30 days (days 0 – 29) after each vaccination.
•Occurrence and relationship to vaccination of SAEs throughout the entire study period (up to Month 48).
•Occurrence of any SAE related to vaccination, other GSK medication or study procedures, any fatal SAE and any AE/SAE leading to premature discontinuation of the study throughout the entire study period up to Month 84.
•Occurrence of new onset chronic diseases (NOCDs, e.g. autoimmune disorders, asthma, type I diabetes) throughout the entire study period (up to Month 48).
•Occurrence of new onset autoimmune diseases (NOADs)throughout the entire study period (up to Month 48).
•Occurrence of medically significant conditions (MSCs) throughout the entire study period (up to Month 48).
•Occurrence of pregnancies and their outcomes throughout the entire study period (up to Month 48). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: up to study end (Month 84).
Immunogenicity: at Months 7, 24, 48 and 84 (all subjects) and at Months 12, 18, 36, 60 and 72 (in the immunogenicity subset).
Solicited symptoms: 7-day period following each vaccination.
Unsolicited symptoms: 30-day period following each vaccination.
SAEs, NOCDs, NOADs, MSCs and pregnancies: up to Month 48.
SAE related to vaccination, other GSK medication or study procedures, fatal SAE and AE/SAE leading to premature discontinuation: up to study end (Month 84). |
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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 | 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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 3 |
| 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 | 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 |
| Australia |
| Canada |
| Mexico |
| Netherlands |
| Peru |
| Philippines |
| Portugal |
| Russian Federation |
| Singapore |
| Thailand |
| United Kingdom |
| 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.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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