| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| 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 |
Safety
•To assess the safety, reactogenicity and occurrence of clinically relevant abnormalities in biochemistry and haematology parameters after administration of the HPV-16/18 L1 VLP AS04 vaccine according to a 2-dose schedule at 0, 6 months in 4-6 year old females, up to one month after the last dose (Month 7).
Immunogenicity
•To evaluate the immunogenicity (as determined by enzyme-linked immunosorbent assay [ELISA]) of the HPV-16/18 L1 VLP AS04 vaccine administered according to a 2-dose schedule at 0, 6 months in 4-6 year old females, one month after the last dose (Month 7). |
|
| E.2.2 | Secondary objectives of the trial |
Immunogenicity
•To assess the immune responses to the HPV-16/18 L1 VLP AS04 vaccine as determined by ELISA on Day 0 and at Months 7, 12, 18, 24 and 36.
•To assess the immunogenicity of the MMR vaccine.
•To assess the immunogenicity of the DTPa vaccine.
Safety/compliance
•To assess the safety of the HPV-16/18 L1 VLP AS04 vaccine throughout the study period.
•To evaluate compliance with completion of vaccination in both study groups. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Subjects who the investigator believes that parent(s)/Legally Acceptable Representative(s) [LAR(s)] can and will comply with the requirements of the protocol.
•A female between, and including, 4 and 6 years of age at the time of the first vaccination.
•Written informed consent obtained from the parent(s)/LAR(s) of the subject prior to enrolment in the study.
•Healthy subjects as established by medical history and clinical examination before entering into the study.
•Subjects who received four doses of DTP vaccine (i.e., three doses in the first year of life and a fourth dose in the second year of life) according to the schedule applicable in the participating countries.
•Subjects who received a first dose of MMR vaccine according to the schedule applicable in the participating countries. |
|
| E.4 | Principal exclusion criteria |
•Child in care.
•Previous vaccination against HPV or planned administration of another HPV vaccine during the study other than that foreseen in the protocol.
•Planned administration/administration of a vaccine not fore-seen by the study protocol within 30 days before the first dose of study vaccine(s). Administration of routine meningococcal, hepatitis B, hepatitis A, inactivated influenza and/or poliomyelitis vaccines up to 8 days before the first dose of study vaccine(s) is allowed. Enrolment will be deferred until the subject is outside of specified window.
•Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines within 30 days pre-ceding the first dose of study vaccine(s), or planned use during the study period.
•History of any reactions or hypersensitivity likely to be exac-erbated by any component of the study vaccines, including latex and/or obvious allergic reactions to neomycin (a history of contact dermatitis to neomycin is not a contraindication), egg protein, etc. (e.g. hives, swelling of the mouth and throat, difficulty breathing, hypotension, or shock subsequent to egg ingestion).
•Cancer or autoimmune disease under treatment.
•Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device).
•Previous administration of MPL or AS04 adjuvant.
•Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine(s) or planned administration during the study period.
•Any confirmed or suspected immunosuppressive or immu-nodeficient condition, based on medical history and physical examination (no laboratory testing required).
•Family history of congenital or hereditary immunodeficiency.
•Documented human immunodeficiency virus (HIV)-positive subject.
•Major congenital defects or serious chronic illness.
•History of seizures or serious neurological disorder, which, according to the judgment of the investigator, precludes ad-ministration of any of the study vaccines.
•Acute or chronic, clinically significant pulmonary, cardiovas-cular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests, which in the opinion of the investigator precludes administration of the study vaccine(s).
•Acute disease and/or fever at the time of enrolment.
•Fever is defined as temperature ≥ 37.5°C on oral, axillary or tympanic setting, or ≥ 38.0°C on rectal setting.
•Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may, be enrolled at the discretion of the investigator. Enrolment can be deferred until condition is resolved.
•Previous administration of the fifth dose of DTP vaccine and/or the second dose of MMR vaccine or planned administration of DTP vaccine and/or MMR vaccine outside the study (during the study period from Day 0 to Month 12).
•History of tetanus, diphtheria, pertussis, measles, mumps and/or rubella.
•Known exposure to diphtheria or household exposure to pertussis within 30 days prior to vaccination with DTPa.
•Known exposure to measles, mumps and/or rubella 30 days prior to vaccination with the MMR study vaccine.
•Confirmed or suspected tuberculosis.
•Severe allergic reactions (e.g. anaphylaxis or severe Arthus-type hypersensitivity reactions) following the administration of previous dose(s) of DTP or MMR vaccines.
•Hyperpyrexia (≥ 40.5°C) within 48 hours of administration of previous doses of DTP or MMR vaccines.
•Persistent, inconsolable crying lasting more than 3 hours, occurring within 48 hours of administration of previous doses of DTP vaccine.
•Collapse or shocking-like state (hypotonic-hyporesponsive episode) within 48 hours of administration of previous doses of DTP vaccine.
•Idiopathic thrombocytopenic purpura or bleeding disorders.
•Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose(s). (For corticosteroids, this will mean prednisone ≥ 0.5 mg/kg/day, or equivalent. Inhaled and topical steroids are allowed.) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The occurrence and intensity of solicited local adverse events (AEs).
The occurrence, intensity and relationship to vaccination of solicited general AEs.
The occurrence, intensity and relationship to vaccination of unsolicited AEs.
The occurrence, intensity and relationship to vaccination of unsolicited AEs.
The occurrence of clinically relevant abnormalities in biochemical and haematological parameters.
The occurrence of serious adverse events (SAEs).
The occurrence of AEs and SAEs leading to withdrawal.
The occurrence of potential immune mediated diseases (pIMDs) and other medically significant conditions (MSCs), regardless of causal relationship to vaccination and intensity.
Anti-HPV-16/18 seroconversion rates and antibody titres as determined by ELISA. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Solicited local and general AEs: Day 0 to Day 6 following each vaccination
Unsolicited AEs: Day 0 to Day 42 following Day 0 vaccination and Day 0 to Day 29 following Month 6 vaccination.
clinically relevant abnormalities in biochemical and haematological parameters : Day 0 to Day 42 following Day 0 vaccination and Day 0 to Day 29 following Month 6 vaccination
SAEs, pIMDs, MSCs: Up to Month 7.
seroconversion: Up to Month 7 |
|
| E.5.2 | Secondary end point(s) |
Anti-HPV-16/18 seroconversion rates and antibody titres as determined by ELISA .
Anti-measles, mumps and rubella seropositivity rates and anti-body titres.
Seroprotection rates to diphtheria (D) and tetanus (T) antigens .
The occurrence of pIMDs.
The occurrence of MSCs.
The occurrence of SAEs
The occurrence of SAEs related to the investigational products or any fatal SAE
The occurrence of AEs/SAEs leading to withdrawal
Concomitant medication administered
The percentage of subjects completing the vaccination schedule.
The occurrence, intensity and relationship to vaccination solicited fever, measles/rubella-like rash, parotid gland swelling and signs of meningism including febrile convulsion |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Seroconversion: MMR_DTPa group: Day 0, Months 7 and 12.
HPV_2D group: Day 0, Months 7, 12, 18, 24 and 36.
Anti-measles, mumps and rubella seropositivity : Days 0 and 42
Seroprotection rates to D and T antigens : at Month 7
SAEs, pIMD, MSCs: up to Month 12
SAEs related to the investigational products and AEs/SAEs leading to withdrawal : Throughout the study period (Day 0 to Month 12 for the MMR_DTPa group and Day 0 to Month 36 for the HPV_2D group)
Concomitant medication: Day 0 to Day 42 after Day 0 vaccination and Day 0 to Day 29 after Month 6 vaccination
Completion of vaccination schedule: Up to Month 6
Rash, parotid swelling and meningism: Day 0 to Day 42 following Day 0 vaccination
|
|
| 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 | 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) | 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 | Yes |
| E.8.1.4 | Double blind | No |
| 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 | 2 |
| 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 |
|
| 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.8.9.2 | In all countries concerned by the trial months | 36 |
Print
