| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Healthy volunteers (Active immunization against measles, mumps and rubella diseases in healthy children, 12 to 15 months of age) |
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| E.1.1.1 | Medical condition in easily understood language |
| Common childhood illness, measles, mumps and rubella diseases. |
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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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10069547 |
| E.1.2 | Term | Mumps immunization |
| E.1.2 | System Organ Class | 100000004865 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039276 |
| E.1.2 | Term | Rubella with unspecified complications |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039274 |
| E.1.2 | Term | Rubella with other specified complication |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10069545 |
| E.1.2 | Term | Measles immunization |
| E.1.2 | System Organ Class | 100000004865 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10069564 |
| E.1.2 | Term | Rubella immunization |
| E.1.2 | System Organ Class | 100000004865 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028276 |
| E.1.2 | Term | Mumps with unspecified complication |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027015 |
| E.1.2 | Term | Measles like illness |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028275 |
| E.1.2 | Term | Mumps with other specified complications |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027021 |
| E.1.2 | Term | Measles without mention of complication |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027020 |
| E.1.2 | Term | Measles with unspecified complication |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027022 |
| E.1.2 | Term | Measles-like rash |
| E.1.2 | System Organ Class | 100000004858 |
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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 the safety profile (fever >39.0°C (>102.2°F)) of Inv_MMR compared to Com_MMR (pooled lots) when co-administered with VV and HAV (to all children) and PCV-13 (only to children enrolled in the US).
• To demonstrate the safety profile (fever ≥38.0°C (≥100.4°F)) of Inv_MMR compared to Com_MMR (pooled lots) when co-administered with VV and HAV (to all children) and PCV-13 (children enrolled in the US)
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| E.2.2 | Secondary objectives of the trial |
• To assess the immunogenicity of Inv_MMR and Com_MMR in terms of seroresponse and GMCs for anti-measles, anti-mumps and anti-rubella virus antibodies at Day 42.
• To assess safety and reactogenicity of Inv_MMR and Com_MMR when co-administered with Varivax and Havrix (to all children) and Prevnar 13 (only to children enrolled in the US).
• To assess any measles-like illness occurring within 5-12 days after vaccination
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female child between 12 and 15 months of age (e.g., from the 1 year birthday until the day before age 16 months) at the time of vaccination.
• Subjects’ parent(s)/Legally Acceptable Representative(s) [LAR(s)] who, in the opinion of the investigator, can and will comply, with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits, respects intervals between visits).
• Written informed consent obtained from the parent(s)/LAR(s) of the child.
• Child is in stable health as determined by investigator’s clinical examination and assessment of child’s medical history.
• For US children only: a child who received all routine vaccinations as per ACIP recommendations prior to study entry: completion of hepatitis B and rotavirus series and completion of the primary series of diphtheria, tetanus, pertussis, poliovirus, Haemophilus influenzae type b (Hib) and pneumococcal vaccines. The 3-dose infant series of Prevnar 13 should be completed at least 60 days prior to study vaccination
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| E.4 | Principal exclusion criteria |
• Child in care.
• Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) during the period starting 30 days before the day of study vaccination (i.e., 30 days prior to Day 0) or planned use during the entire study period.
• Concurrently participating in another clinical study, in which the child has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device).
• Chronic administration (defined as 14 or more consecutive days) of immunosuppressants, or other immune-modifying drugs during the period starting 180 days prior to the study vaccination at Visit 1 or any planned administration of immunosuppressive and immune-modifying drugs during the entire study.
For corticosteroids, this will mean prednisone ≥0.5 mg/kg/day or equivalent.
Inhaled and topical steroids are allowed.
• Planned administration/ administration of a vaccine not foreseen by the study protocol during the period starting 30 days prior to the day of study vaccination at Visit 1 and ending at Visit 2. Please Note:
Inactivated influenza (Flu) vaccine and monovalent Haemophilus influenzae type b conjugate vaccine (Hib) vaccines may be given at any time, including the day of study vaccination (Flu and Hib vaccines must be administered at a different location than the study vaccine/s).
Any other age appropriate vaccine may be given starting at Visit 2 and anytime thereafter.
• Administration of immunoglobulins and/or any blood products during the period starting 180 days before the study vaccination at Visit 1 or planned administration from the date of vaccination through the immunogenicity evaluation at Visit 2.
• History of measles, mumps, rubella, varicella/zoster and/or hepatitis A disease.
• Known exposure to measles, mumps, rubella and/or varicella/zoster during the period starting within 30 days prior to first study vaccination.
• Previous vaccination against measles, mumps, rubella, hepatitis A and/or varicella virus.
• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).
• Blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems.
• A family history of congenital or hereditary immunodeficiency.
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccines, including hypersensitivity to neomycin, latex or gelatin.
• Acute disease at the time of enrollment. (Acute disease is defined as the presence of a moderate or severe illness with or without fever). Fever is defined as temperature ≥38.0°C/100.4°F by any age appropriate route. All vaccines can be administered to persons with a minor illness such as diarrhea, mild upper respiratory infection without fever.
• Active untreated tuberculosis based on medical history.
• Any other condition which, in the opinion of the investigator, prevents the child from participating in the study.
• For US children only: a child that previously received a fourth dose of PCV-13 vaccine.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Assessment of fever.
- Occurrence of fever > 39.0°C (>102.2°F) from Day 5 through Day 12
- Occurrence of fever ≥ 38.0°C (≥100.4°F) from Day 5 through Day 12
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Immunogenicity of the MMR vaccines at Day 42.
• Seroresponse to measles, mumps and rubella viruses by ELISA. Mumps seroresponse may be assessed by Plaque Reduction Neutralization Test (PRNT) rather than ELISA for a subset of subjects when the Pharmaceutical Product Development, Inc. (PPD) ELISA will no longer be available. If performed, this testing will be used for the identification of suboptimal responders. (NB: Descriptive statistics and reverse cumulative curves will only be calculated for the PRNT assay if at least 30 subjects have valid post-vaccination titers. Otherwise only a line listing of PRNT titers will be generated.)
• Measles, mumps and rubella virus antibody concentrations by ELISA. Mumps virus antibody titers may be assessed by PRNT rather than ELISA for a subset of subjects, when mumps PPD ELISA will no longer be available. If performed, this testing will be used for the identification of suboptimal responders. (NB: Descriptive statistics and reverse cumulative curves will only be calculated for the PRNT assay if at least 30 subjects have valid post-vaccination titers. Otherwise only a line listing of PRNT titers will be generated.)
• Solicited local and general symptoms.
• Occurrence of solicited local symptoms in terms of injection site redness, pain and swelling from Day 0 to Day 3 after vaccination.
• Occurrence of solicited general symptoms in terms of drowsiness, loss of appetite and irritability from Day 0 to Day 14 after vaccination.
• Occurrence of solicited general symptoms in terms of fever (temperature ≥38.0°C / 100.4°F), rash, parotid/salivary gland swelling, any sign of meningism (including febrile convulsions) from Day 0 to Day 42 after vaccination.
• Unsolicited adverse events.
• Occurrence of unsolicited symptoms, according to the Medical Dictionary for Regulatory Activities (MedDRA) classification, from Day 0 to Day 42 after vaccination.
• Adverse events of specific interest.
• Occurrence of new onset chronic disease (NOCD) (e.g., autoimmune disorders, asthma, type I diabetes, vasculitis, celiac disease, conditions associated with sub-acute or chronic thrombocytopenia and allergies) and AEs prompting emergency room (ER) visits from Day 0 through the end of study.
• Serious adverse events.
• Occurrence of serious adverse events from Day 0 through the end of study.
• Measles-like illness
• Occurrence of any measles-like illness from Day 5 through Day 12 post vaccination
Measles-like illness is defined as the occurrence of the following signs/symptoms in the absence of another confirmed diagnosis (e.g. laboratory confirmed scarlet fever):
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
At Day 42 after vaccination for Immunogenicity
At Day 0 to 3 for Local symptoms
At Day 0 to 14 for drowsiness, loss of appetite and irritability
Day 0 to Day 42 for fever (temperature ≥38.0°C / 100.4°F), rash, parotid/salivary gland swelling, any sign of meningism (including febrile convulsions)
At Day 0-42 for unsolicited symptoms
At Day 0-180 for Serious AEs and new onset chronic illness (NOCD) (e.g., autoimmune disorders, asthma, type I diabetes, vasculitis, celiac disease, conditions associated with sub-acute or chronic thrombocytopenia and allergies) and AEs prompting emergency room (ER) visits.
At Day 5 through Day 12 for measles like illness.
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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 | No |
| 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 |
|
| 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 | 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 |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Estonia |
| Finland |
| Puerto Rico |
| Taiwan |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 21 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| 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 | 21 |
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