| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Healthy children between 12-22 months (including the day before the 23-month birthday) of age at the time of vaccination with no history of measles, mumps, rubella and varicella diseases/vaccination. |
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| E.1.1.1 | Medical condition in easily understood language |
Measles
Mumps
Rubella
Chickenpox
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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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028257 |
| E.1.2 | Term | Mumps |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10046980 |
| E.1.2 | Term | Varicella |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039252 |
| E.1.2 | Term | Rubella |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10027011 |
| E.1.2 | Term | Measles |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 the efficacy of one dose of Varilrix in preventing confirmed varicella cases over at least two years after vaccination.
OR/AND
- To demonstrate the efficacy of two doses of Priorix™-Tetra in preventing confirmed varicella cases over at least two years after vaccination.
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| E.2.2 | Secondary objectives of the trial |
- Long-term efficacy of Varilrix or Priorix™-Tetra in preventing confirmed varicella cases. (Phase B)
- Efficacy of Varilrix or Priorix™-Tetra in preventing probable or confirmed varicella cases (Phase A & B)
- Efficacy based on varicella severity (Phase A & B)
- Assessment of complicated varicella cases (Phase A & B)
- Immune response to varicella (seroconversion/seropositivity & GMT) at 42 days, one, two, four, six, eight and ten years after the last vaccination (Phase A & B)
- Immune response to MMR (seroconversion/seropositivity & GMT) at 42 days (after each vaccination), one, two, four, six, eight and ten years after the last vaccination (subset) (Phase A & B)
- Safety of the vaccines (SAEs, herpes zoster descriptions) (Phase A & B)
- Solicited (local/general)/unsolicited symptoms at 42 days after each vaccination (subset) (Phase A)
- Factors leading to indirect cost of varicella (Phase A & B)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Subjects for whom the investigator believes that their parents/guardians can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits) for the whole duration of the study.
- Male or female subject between 12 and 22 months (including the day before the 23-month birthday) of age at the time of the first vaccination.
- Subjects free of obvious health problems, as established by medical history and physical examination before entering the study.
- Written informed consent obtained from the parents/guardians of the subject after they have been informed on the risks and benefits of the study, in a language they clearly understand and before performance of any study procedure.
- Subjects whose parents/guardians have direct access to telephone/mobile phone (either at home or at work).
- Subjects:
(1) with at least one sibling (with negative history of varicella disease/vaccination) at home, or
(2) attending day care center (subjects who are registered for attendance at day care center from 24 months of age may be considered for inclusion in the study), or
(3) attending childminders, i.e. someone taking care of several children (with at least one child without a known positive history of varicella disease/vaccination), or
(4) who are in contact for at least once a week with other children without a known positive history of varicella disease/vaccination, while playing in close physical contact for more than 5 minutes.
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| E.4 | Principal exclusion criteria |
- Previous vaccination against measles, mumps, rubella and/or varicella.
- History of previous measles, mumps, rubella and/or varicella/zoster diseases.
- Known exposure to measles, mumps, rubella and/or varicella/zoster within 30 days prior to the start of the study.
- 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.
- Administration of immunoglobulins and/or any blood products within three months prior to the first vaccine dose or planned administration during the study period.
- Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).
- Family history of congenital or hereditary immunodeficiency.
- History of allergic diseases or reactions likely to be exacerbated by any component of the vaccines, including systemic allergy to egg proteins or neomycin.
- Major congenital defects or serious chronic illness.
- Residence in the same household as newborns (0-4 weeks of age), pregnant mothers varicella-susceptible, persons with a known immunodeficiency or any other persons at high risk for varicella (At any point in time when such exclusion criterium becomes not applicable, potential study participants may come back at a later stage for study inclusion).
- History of any neurologic disorders or seizures.
- Use of any investigational or non-registered product (drug/vaccine other than the study vaccines) within 14 days prior to vaccination and planned use during the study period.
Additional exclusion criteria for subjects included in the subset:
- Administration of a licensed vaccine within 14 days prior to vaccination and planned use until approximately 42 days after the last study vaccine dose (Day 84) with the exception of oral polio vaccine (OPV).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| - Occurrence of confirmed varicella cases in all subjects 42 days post dose 2 until the end of Phase A. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| from 42 days post dose 2 until the end of Phase A. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints:
Phase A
Efficacy:
•Occurrence of probable or confirmed varicella cases in all subjects from 42 days post dose 2 until the end of Phase A.
•Occurrence of varicella cases by severity in all subjects from 42 days post dose 2 until the end of Phase A.
•Occurrence of complicated varicella cases (reported as SAEs) in all subjects.
Immunogenicity:
•Varicella antibody titres in all subjects at Day 0, Day 84, Year 1 and Year 2 time points.
•Measles, mumps and rubella antibody titres in a subset of subjects at Day 0, Day 42, Day 84, Year 1 and Year 2 time points.
Safety:
•Occurrence of SAEs in all subjects from Day 0 until the end of Phase A.
•Occurrence of herpes zoster in all subjects from Day 0 until the end of Phase A.
In a subset of subjects:
-Occurrence of fever (>=37.5 °C axillary/>=38.0 °C rectal route) from Day 0 to Day 42 after each dose.
-Occurrence of any and grade 3 solicited local symptoms within 4 days after each vaccination (Day 0-3 after each dose).
-Occurrence of any and grade 3 solicited general symptoms (rash, any sign of meningism including febrile convulsion and parotitis/ salivary gland swelling) within 43 days after each vaccination (Day 0-42 after each dose).
-Occurrence of unsolicited symptoms within 43 days after each vaccination (Day 0-42 after each dose).
Health economics:
•Number of hours/days lost from work by parents/guardians as a result of taking care of their child due to varicella during Phase A.
•Number of hours/days the child lost attendance due to varicella in day care/childminder, school, or in any extra-curricular activities (e.g. sports or recreation or any type of organized leisure activities) during Phase A.
•Number of hours/days spent by a nurse, a babysitter or any type of existing paid caregiver to look after the child due to varicella (if applicable) during Phase A.
Phase B
Efficacy:
•Occurrence of confirmed varicella cases in all subjects from Year 2 (or end of Phase A, if later) to Year 10 after vaccination.
•Occurrence of probable or confirmed varicella cases in all subjects from Year 2 (or end of Phase A, if later) to Year 10 after vaccination.
•Occurrence of varicella cases by severity in all subjects from Year 2 (or end of Phase A, if later) to Year 10 after vaccination.
•Occurrence of complicated varicella cases (reported as SAEs) in all subjects from Year 2 (or end of Phase A, if later) to Year 10 after vaccination.
Immunogenicity:
•Varicella antibody titres in all subjects at Year 4, Year 6, Year 8 and Year 10 time points.
•Measles, mumps and rubella antibody titres in a subset of subjects at Year 4, Year 6, Year 8 and Year 10 time points.
Safety:
•Occurrence of SAEs in all subjects from Year 2 (or end of Phase A, if later) to Year 10 after vaccination.
•Occurrence of herpes zoster in all subjects from Year 2 (or end of Phase A, if later) to Year 10 after vaccination.
Health economics:
•Number of hours/days lost from work by parents/guardians as a result of taking care of their child due to varicella during Phase B.
•Number of hours/days the child lost attendance due to varicella in day care/childminder, school, or in any extra curricular activities (e.g. sports or recreation or any type of organized leisure activities) during Phase B.
•Number of hours/days spent by a nurse, a babysitter or any type of existing paid caregiver to look after the child due to varicella (if applicable) during Phase B. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase A: From Day 0 onwards until at least two years after the last vaccine dose (i.e. for the efficacy analyses, at least 24 months of follow-up from 42 days post dose 2).
Phase B: from Year 2 (or at the end of Phase A, if later) to Year 10.
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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 | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Observer-blind during Phase A and B (exception of Group Varilrix in some countries) |
|
| 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 | 3 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 97 |
| 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 |
| Czech Republic |
| Italy |
| Lithuania |
| Norway |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| Slovenia |
| Sweden |
|
| 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
|
Phase-A completion: after 144 confirmed varicella cases and completed Year 2 visit (phase may be extend beyond Yr 2 until cases reached. Extension: subjects in Year-2 timepoint contacted 1x/mth for varicella exposure/occurrence. Parents contact study site immediately if subject has varicella-type rash: visit is required within 24 hours after onset/as soon as possible, if a case is suspected. Treatment with acyclovir possible.
Phase-B completion: Conclusion visit/Y10.
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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 | 11 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 11 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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